psycho pharmacology for the mentally ill

Clinical Manual of Psychopharmacology

in the Medically Ill

This page intentionally left blank

Washington, DCLondon, England

Clinical Manual of Psychopharmacology in

the Medically Ill

Edited by

Stephen J. Ferrando, M.D.

James L. Levenson, M.D.

James A. Owen, Ph.D.

Note: The authors have worked to ensure that all information in this book is accurateat the time of publication and consistent with general psychiatric and medical standards,and that information concerning drug dosages, schedules, and routes of administrationis accurate at the time of publication and consistent with standards set by the U.S.Food and Drug Administration and the general medical community. As medicalresearch and practice continue to advance, however, therapeutic standards may change.Moreover, specific situations may require a specific therapeutic response not includedin this book. For these reasons and because human and mechanical errors sometimesoccur, we recommend that readers follow the advice of physicians directly involved intheir care or the care of a member of their family.

Books published by American Psychiatric Publishing, Inc., represent the views andopinions of the individual authors and do not necessarily represent the policies andopinions of APPI or the American Psychiatric Association.

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Library of Congress Cataloging-in-Publication DataClinical manual of psychopharmacology in the medically ill / edited by Stephen J.Ferrando, James L. Levenson, James A. Owen. — 1st ed.

p. ; cm.Includes bibliographical references and index.ISBN 978-1-58562-367-9 (pbk. : alk. paper) 1. Psychopharmacology. 2. Psychotropic

drugs. I. Ferrando, Stephen J. II. Levenson, James L. III. Owen, James A., 1949–[DNLM: 1. Psychotropic Drugs—adverse effects. 2. Psychotropic Drugs—

pharmacokinetics. 3. Comorbidity. 4. Drug Interactions. QV 77.2 C6405 2010]RM315.C5474 2010615′.78—dc22

2010003564

British Library Cataloguing in Publication DataA CIP record is available from the British Library.

www.appi.org

Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xixAcknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . xxvIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvii

Stephen J. Ferrando, M.D.James L. Levenson, M.D.James A. Owen, Ph.D.

PART IGeneral Principles

1 Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions . . . . . . . . . . . 3


Pharmacodynamics. . . . . . . . . . . . . . . . . . . . . . . . . . . 4Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . . 20Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . . 25References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Appendix: Drugs With Clinically Significant Pharmacokinetic Interactions. . . . . . . . . . . . . . . . . . 30

2 Severe Drug Reactions. . . . . . . . . . . . . . . . . . . . . . . 39

Stanley N. Caroff, M.D.Stephan C. Mann, M.D.E. Cabrina Campbell, M.D.Rosalind M. Berkowitz, M.D.

Central Nervous System Reactions . . . . . . . . . . . . . 40Cardiovascular Reactions . . . . . . . . . . . . . . . . . . . . . 49Gastrointestinal Reactions . . . . . . . . . . . . . . . . . . . . 55

Renal Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Hematological Reactions . . . . . . . . . . . . . . . . . . . . . 64Metabolic Reactions and Body as a Whole. . . . . . . 66Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . . 71References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

3 Alternate Routes of Drug Administration . . . . . . . 79


Properties of Specific Routes of Administration. . . 80Psychotropic Medications. . . . . . . . . . . . . . . . . . . . . 87Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . . 95References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

PART IIPsychopharmacology in Organ System

Disorders and Specialty Areas

4 Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . 103

Catherine C. Crone, M.D.Michael Marcangelo, M.D.Jeanne Lackamp, M.D.Andrea F. DiMartini, M.D.James A. Owen, Ph.D.

Oropharyngeal Disorders . . . . . . . . . . . . . . . . . . . . 104Esophageal and Gastric Disorders . . . . . . . . . . . . . 106Intestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 111Liver Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115Gastrointestinal Side Effects of Psychiatric Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123Psychotropic Drug–Induced Gastrointestinal Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Psychiatric Side Effects of Gastrointestinal Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 132Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 138References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

5 Renal and Urological Disorders . . . . . . . . . . . . . . 149

James A. Owen, Ph.D.James L. Levenson, M.D.

Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 150Pharmacotherapy in Renal Disease. . . . . . . . . . . . 152Psychiatric Adverse Effects of Renal and Urological Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . 161Renal and Urological Adverse Effects of Psychotropics . . . . . . . . . . . . . . . . . . . . . . . . . . . 164Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 166Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 175References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

6 Cardiovascular Disorders . . . . . . . . . . . . . . . . . . . 181

Peter A. Shapiro, M.D.

Differential Diagnostic Considerations . . . . . . . . . 182Neuropsychiatric Side Effects of Cardiac Medications . . . . . . . . . . . . . . . . . . . . . . . . 183Alterations in Pharmacokinetics in Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Psychotropic Medication Use in Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 199Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 207References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

7 Respiratory Disorders . . . . . . . . . . . . . . . . . . . . . . 213

Wendy L. Thompson, M.D.Yvette L. Smolin, M.D.

Differential Diagnostic Considerations . . . . . . . . . 214Neuropsychiatric Side Effects of Respiratory Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 216Alteration of Pharmacokinetics . . . . . . . . . . . . . . . 219Prescribing Psychotropic Medications in Respiratory Disease. . . . . . . . . . . . . . . . . . . . . . . . . 220Effects of Psychotropic Drugs on Pulmonary Diseases . . . . . . . . . . . . . . . . . . . . . . . . 225Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 227Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 230References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

8 Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

James A. Owen, Ph.D.Stephen J. Ferrando, M.D.

Differential Diagnosis of Psychiatric Manifestations of Cancers . . . . . . . . . . . . . . . . . . . 238Psychopharmacological Treatment of Psychiatric Disorders in Cancer Patients . . . . . . . . 239Adverse Oncological Effects of Psychotropics. . . . 244Neuropsychiatric Adverse Effects of Oncology Treatments . . . . . . . . . . . . . . . . . . . . . 247Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 251Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 260References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

9 Central Nervous System Disorders. . . . . . . . . . . . 271

Saeed Salehinia, M.D.Vani Rao, M.D.

Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275Traumatic Brain Injury. . . . . . . . . . . . . . . . . . . . . . . 276Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 278Parkinson’s Disease. . . . . . . . . . . . . . . . . . . . . . . . . 280Huntington’s Disease . . . . . . . . . . . . . . . . . . . . . . . 282Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283Symptoms and Syndromes Common Across Neurological Disorders . . . . . . . . . . . . . . . . 285Adverse Neurological Effects of Psychotropic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 286Adverse Psychiatric Effects of Neurological Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 291Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 296References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

10 Endocrine and Metabolic Disorders. . . . . . . . . . . 305

Stephen J. Ferrando, M.D.Jennifer Kraker, M.D., M.S.

Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . 306Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 309Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . 311Antidiuretic Hormone . . . . . . . . . . . . . . . . . . . . . . . 311Reproductive Endocrine System Disorders. . . . . . 312Hypogonadal Disorders . . . . . . . . . . . . . . . . . . . . . 312Endocrinological Side Effects of Psychiatric Medications. . . . . . . . . . . . . . . . . . . . . . 313Psychiatric Side Effects of Endocrine Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 324Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 328References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

11 Obstetrics and Gynecology . . . . . . . . . . . . . . . . . . 339

Margaret Altemus, M.D.Mallay Occhiogrosso, M.D.

Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 340Pharmacotherapy of Premenstrual Mood Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342Pharmacotherapy of Menopause-Related Depression, Anxiety, and Insomnia . . . . . . . . . . . . 343Psychopharmacology in Pregnancy and Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . 343Adverse Obstetric and Gynecological Reactions to Psychotropic Drugs . . . . . . . . . . . . . . 354Psychiatric Adverse Effects of Obstetric and Gynecological Agents and Procedures . . . . . . . . . 355Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 358Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 361References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

12 Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . 371


Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . 372Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374Parasitic Infections: Neurocysticercosis . . . . . . . . . 393Adverse Psychiatric Effects of Antibiotics . . . . . . . 393Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 394Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 395References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

13 Dermatological Disorders . . . . . . . . . . . . . . . . . . . 405

Madhulika A. Gupta, M.D., F.R.C.P.C.James L. Levenson, M.D.

Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 406Pharmacotherapy of Specific Disorders . . . . . . . . 409Adverse Cutaneous Drug Reactions to Psychotropic Agents . . . . . . . . . . . . . . . . . . . . . . . . 415Adverse Psychiatric Effects of Dermatological Agents . . . . . . . . . . . . . . . . . . . . . . 420Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 422Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 423References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424

14 Rheumatological Disorders. . . . . . . . . . . . . . . . . . 431

James L. Levenson, M.D.Stephen J. Ferrando, M.D.

Treatment of Psychiatric Disorders . . . . . . . . . . . . 432Psychiatric Side Effects of Rheumatological Medications . . . . . . . . . . . . . . . . 433Rheumatological Side Effects of Psychotropic Medications: Psychotropic Drug–Induced Lupus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 435Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 435References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

15 Surgery and Critical Care. . . . . . . . . . . . . . . . . . . . 439


Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440Psychotropic Drugs in the Perioperative Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447Treatment of Preoperative Anxiety . . . . . . . . . . . . 449

Acute and Posttraumatic Stress in the Critical Care Setting. . . . . . . . . . . . . . . . . . . . . . . . . 451Adverse Neuropsychiatric Effects of Critical Care and Surgical Drugs . . . . . . . . . . . . . . . . . . . . . 453Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 454Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 460References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462

16 Organ Transplantation. . . . . . . . . . . . . . . . . . . . . . 469

Andrea F. DiMartini, M.D.Catherine C. Crone, M.D.Marian Fireman, M.D.

Posttransplant Pharmacological Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470Psychotropic Medications in Transplant Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475Drug-Specific Issues . . . . . . . . . . . . . . . . . . . . . . . . 484Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 491References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

17 Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . 501

Michael R. Clark, M.D., M.P.H.James A. Owen, Ph.D.

Psychiatric Comorbidity . . . . . . . . . . . . . . . . . . . . . 502Pain Description and Management . . . . . . . . . . . . 504Pharmacological Treatment . . . . . . . . . . . . . . . . . . 510Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 522Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 524References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525

18 Substance Use Disorders . . . . . . . . . . . . . . . . . . . 537

José Maldonado, M.D., F.A.P.M., F.A.C.F.E.Andrea F. DiMartini, M.D.James A. Owen, Ph.D.

Drugs for Substance Intoxication. . . . . . . . . . . . . . 538Drugs for Substance Use Disorders . . . . . . . . . . . . 539Psychiatric Adverse Effects of Drugs Used in Substance Use Disorders . . . . . . . . . . . . . . . . . . . . 547Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 547Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 549References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557

List of Tables and Figures

Figure 1–1 Relationship between pharmacokinetics and pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Figure 1–2 Concentration–response relationship . . . . . . . . . . . . . .6Table 1–1 Strategies to maximize medication compliance . . . . . . 8Figure 1–3 First-pass metabolism of orally administered drugs. .10Table 1–2 Conditions that alter plasma levels of albumin

and alpha-1 acid glycoprotein . . . . . . . . . . . . . . . . . . .13Figure 1–4 General pathways of metabolism and excretion . . . .16Table 1–3 Systemic clearance of hepatically metabolized

psychotropic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . .19Table 1–4 Psychotropic drugs that cause few

pharmacokinetic interactions. . . . . . . . . . . . . . . . . . . .26

Table 2–1 Central nervous system reactions . . . . . . . . . . . . . . . .41Table 2–2 Cardiovascular reactions . . . . . . . . . . . . . . . . . . . . . . .50Table 2–3 Gastrointestinal reactions. . . . . . . . . . . . . . . . . . . . . . .56Table 2–4 Renal reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60Table 2–5 Hematological reactions . . . . . . . . . . . . . . . . . . . . . . .65Table 2–6 Metabolic reactions and body as a whole . . . . . . . . .68

Table 3–1 Situations potentially requiring alternate routes of administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80

Table 3–2 Nonoral preparations of psychotropic medications . .82

Table 4–1 Medication absorption after Roux-en-Y gastric bypass surgery . . . . . . . . . . . . . . . . . . . . . . . 113

Table 4–2 Psychotropic drug dosing in hepatic insufficiency (HI) . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Table 4–3 Gastrointestinal adverse effects of psychiatric drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Table 4–4 Psychiatric adverse effects of gastrointestinal drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Table 4–5 Gastrointestinal drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Table 4–6 Psychotropic drug–gastrointestinal drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Table 5–1 Psychotropic drugs in renal insufficiency (RI). . . . . 154Table 5–2 Dialyzable psychotropic drugs . . . . . . . . . . . . . . . . . 158Table 5–3 Psychiatric adverse effects of renal and

urological drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Table 5–4 Renal and urological adverse effects of

psychiatric drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . 165Table 5–5 Renal and urological drug–psychotropic drug

interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168Table 5–6 Psychotropic drug–renal and urological drug

interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Table 6–1 Selected adverse neuropsychiatric effects of cardiac medications . . . . . . . . . . . . . . . . . . . . . . . . . 183

Table 6–2 Pharmacokinetic changes in heart disease. . . . . . . 185Table 6–3 Cardiac adverse effects of psychotropic drugs . . . . 187Table 6–4 Risk factors for torsade de pointes . . . . . . . . . . . . . 195Table 6–5 Clinically relevant cardiac drug–psychotropic

drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 202Table 6–6 Clinically relevant psychotropic drug–cardiac

drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Table 7–1 Psychiatric symptoms often associated with respiratory diseases . . . . . . . . . . . . . . . . . . . . . . . . . 214

Table 7–2 Neuropsychiatric side effects of drugs used to treat respiratory diseases. . . . . . . . . . . . . . . . . . . 217

Table 7–3 Respiratory side effects of psychotropic medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Table 7–4 Respiratory drug–psychotropic drug interactions . . 228

Table 8–1 Psychiatric adverse effects of oncology drugs . . . . 249Table 8–2 Oncology drug–psychotropic drug interactions . . . 252Table 8–3 Psychotropic drug–oncology drug interactions . . . 254

Table 8–4 Oncology prodrugs activated by cytochrome P450 (CYP) metabolism . . . . . . . . . . . . . . . . . . . . . 259

Table 9–1 Neurological adverse effects of psychotropic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

Table 9–1 Psychiatric adverse effects of neurological drugs . . 290Table 9–1 Neurological drug–psychotropic drug interactions . 292Table 9–1 Psychotropic drug–neurological drug interactions . 294

Table 10–1 Psychiatric symptoms of endocrine and metabolic disorders . . . . . . . . . . . . . . . . . . . . . . . . . 306

Table 10–2 Endocrinological adverse effects of psychotropic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . 313

Table 10–3 Consensus guidelines for monitoring metabolic status in patients taking antipsychotic medications . . . . . . . . . . . . . . . . . . . . 318

Table 10–4 Psychiatric adverse effects of endocrinological/hormonal treatments . . . . . . . . . . . . . . . . . . . . . . . . 321

Table 10–5 Psychotropic drug–endocrine drug interactions . . . 325Table 10–6 Endocrine drug–psychotropic drug interactions . . . 327

Table 11–1 Effects of psychiatric medications on fetus/infant 346Table 11–2 Psychiatric adverse effects of obstetrics and

gynecology drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 356Table 11–3 Obstetrics/gynecology drug–psychotropic

drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 359Table 11–4 Psychotropic drug–obstetrics/gynecology

drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 360

Table 12–1 Psychiatric adverse effects of antibiotic therapy . . . 375Table 12–2 Antibiotic drug–psychotropic drug interactions . . . 378

Table 13–1 Some dermatological drug–psychotherapeutic drug pharmacokinetic interactions . . . . . . . . . . . . . 410

Table 14–1 Psychiatric side effects of medications used in treating rheumatological disorders . . . . . . . . . . . 434

Table 14–2 Rheumatology drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

Table 15–1 Psychiatric adverse effects of drugs used in surgery and critical care . . . . . . . . . . . . . . . . . . . . 453

Table 15–2 Critical care and perisurgical drug–psychotropic drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

Table 16–1 Neuropsychiatric side effects of immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . 485

Table 16–2 Immunosuppressant metabolism and effects on metabolic systems . . . . . . . . . . . . . . . . . . . . . . . 488

Table 16–3 Immunosuppressant drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489

Table 16–4 Psychotropic drug–immunosuppressant drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490

Table 17–1 Medications for pain management . . . . . . . . . . . . . 512Table 17–2 Pain drug–psychotropic drug interactions. . . . . . . . 523

Table 18–1 Neuropsychiatric adverse effects of drugs that treat substance abuse . . . . . . . . . . . . . . . . . . . 548

Table 18–2 Psychotropic drug–drugs for substance abuse interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550

xix

Contributors

Margaret Altemus, M.D.Associate Professor of Psychiatry, Weill Cornell Medical College, New York, New York

Rosalind M. Berkowitz, M.D.Private Practice, Moorestown, New Jersey

E. Cabrina Campbell, M.D.Associate Director, Inpatient Psychiatry, Philadelphia Veterans Affairs Medi-cal Center; Associate Professor of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Stanley N. Caroff, M.D.Director, Inpatient Psychiatry, Philadelphia Veterans Affairs Medical Center; Professor of Psychiatry, University of Pennsylvania School of Medicine, Phil-adelphia, Pennsylvania

Michael R. Clark, M.D., M.P.H.Associate Professor and Director, Adolf Meyer Chronic Pain Treatment Pro-grams, Department of Psychiatry and Behavioral Sciences, The Johns Hop-kins Medical Institutions, Baltimore, Maryland

Catherine C. Crone, M.D.Associate Professor of Psychiatry, George Washington University Medical Center, Washington, D.C.; Vice Chair, Department of Psychiatry, Inova Fair-

xx Clinical Manual of Psychopharmacology in the Medically Ill

fax Hospital, Falls Church, Virginia; Clinical Professor of Psychiatry, Virginia Commonwealth University School of Medicine, Northern Virginia Branch, Fairfax, Virginia

Andrea F. DiMartini, M.D.Associate Professor of Psychiatry and of Surgery, Western Psychiatric Insti-tute; Consultation Liaison to the Liver Transplant Program, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Stephen J. Ferrando, M.D.Professor of Clinical Psychiatry and Public Health and Vice Chair for Psycho-somatic Medicine and Departmental Operations, Payne Whitney Clinic, New York-Presbyterian Hospital, Weill Cornell Medical Center, Department of Psychiatry, New York, New York

Marian Fireman, M.D.Associate Professor of Psychiatry, Oregon Health and Science University, Portland, Oregon

Madhulika A. Gupta, M.D., F.R.C.P.C.Professor, Department of Psychiatry, Schulich School of Medicine and Den-tistry, University of Western Ontario, London, Ontario, Canada

Jennifer Kraker, M.D., M.S.Resident in Psychiatry, Department of Psychiatry, Payne Whitney Clinic, New York-Presbyterian Hospital, New York, New York

Jeanne Lackamp, M.D.Assistant Professor, Department of Psychiatry, University Hospitals/Case Medical Center, Cleveland, Ohio

James L. Levenson, M.D.Professor of Psychiatry, Medicine, and Surgery, and Vice-Chair for Clinical Services, Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia

Contributors xxi

José Maldonado, M.D., F.A.P.M., F.A.C.F.E.Associate Professor of Psychiatry and Medicine; Medical Director, Forensic Psychiatry Program; Medical Director, Psychosomatic Medicine Service; Fac-ulty, Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, California

Stephan C. Mann, M.D.Medical Director, Central Montgomery Mental Health and Mental Retarda-tion Center, Norristown, Pennsylvania; Clinical Professor, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medi-cine, Louisville, Kentucky

Michael Marcangelo, M.D.Assistant Professor, Department of Psychiatry and Behavioral Neuroscience, and Director Of Medical Student Education, The University of Chicago Medical Center, Chicago, Illinois

Mallay Occhiogrosso, M.D.Assistant Professor of Psychiatry, Weill Cornell Medical College, New York, New York

James A. Owen, Ph.D.Associate Professor, Department of Psychiatry and Department of Pharma-cology and Toxicology, Queen’s University; Director of Psychopharmacology, Providence Care Mental Health Services, Kingston, Ontario, Canada

Vani Rao, M.D.Director, Neuropsychiatry Fellowship Program, and Section Head, Bayview Geriatric Psychiatry, Neuropsychiatry Program; Associate Professor, Depart-ment of Psychiatry and Behavioral Sciences, Johns Hopkins University, Bal-timore, Maryland

Saeed Salehinia, M.D.Physician Clinical Staff, Department of Health and Mental Hygiene, Devel-opmental Disabilities Administration of Maryland, Secure Evaluation and Therapeutic Treatment (SETT) Program, Sykesville, Maryland

xxii Clinical Manual of Psychopharmacology in the Medically Ill

Peter A. Shapiro, M.D.Professor of Clinical Psychiatry, Columbia University; Director, Fellowship Training Program in Psychosomatic Medicine; Director, Transplant Psychia-try Programs; Associate Director, Consultation-Liaison Psychiatry Service; New York Presbyterian Hospital–Columbia University Medical Center, New York, New York

Yvette L. Smolin, M.D.Director of Psychosomatic Medicine and Clinical Assistant Professor, Depart-ment of Psychiatry and Behavioral Science, New York Medical College at Westchester Medical Center, Valhalla, New York

Wendy L. Thompson, M.D.Director of Education and Professor of Clinical Psychiatry, Department of Psychiatry and Behavioral Science, New York Medical College at Westchester Medical Center, Valhalla, New York

Disclosure of Competing Interests

The following contributors to this book have indicated a financial interest in or other affil-iation with a commercial supporter, a manufacturer of a commercial product, a pro-vider of a commercial service, a nongovernmental organization, and/or a governmentagency, as listed below:

Margaret Altemus, M.D. Donation of study drug from Pfizer for a clinical trialotherwise funded by NIH.

E. Cabrina Campbell, M.D. Research Grant: Pfizer.Stanley N. Caroff, M.D. Research Grant: Pfizer; Consultant: Eli Lilly.Stephen J. Ferrando, M.D. Speakers Bureau: AstraZeneca, Pfizer.Jennifer Kraker, M.D., M.S. Fellowship/Award: American Psychiatric Association

(APA)/Bristol-Myers Squibb Fellowship in Public Psychiatry, 2009–2011 (travelsponsorship to APA meetings, including Institute on Psychiatric Services andcomponents meetings).

James L. Levenson, M.D. Advisory Board: Eli Lilly.James A. Owen, Ph.D. Research Support/Speakers Bureau: Lundbeck.Vani Rao, M.D. Research Grants: Forest, Pfizer.

Disclosure of Competing Interests xxiii

The following contributors to this book have no competing interests to report:Rosalind M. Berkowitz, M.D.Michael R. Clark, M.D., M.P.H.Catherine C. Crone, M.D.Andrea F. DiMartini, M.D.Marian Fireman, M.D.Madhulika A. Gupta, M.D., F.R.C.P.C.Jeanne Lackamp, M.D.José Maldonado, M.D., F.A.P.M., F.A.C.F.E.Stephan C. Mann, M.D.Michael Marcangelo, M.D.Mallay Occhiogrosso, M.D.Saeed Salehinia, M.D.Peter A. Shapiro, M.D.Yvette L. Smolin, M.D.Wendy L. Thompson, M.D.

xxv

Acknowledgments

The editors would collectively like to acknowledge multiple individuals fortheir support, encouragement, and thoughtful input during the preparationof this book. We thank our contributors, whose expertise has made this manuala rigorous and unique resource. We thank Charles Gross, M.A., for his out-standing editorial assistance and coordination efforts in the preparation andsubmission of the book manuscript. Finally, we thank Dr. Robert E. Hales,Editor in Chief of American Psychiatric Publishing, Inc. (APPI), as well asJohn McDuffie and the editorial staff of APPI for their enthusiastic receptionof the concept of this book and for their highly professional help throughoutthe course of its production.

Dr. Ferrando would like to acknowledge Drs. Jack D. Barchas and PhilipJ. Wilner for their invaluable encouragement, mentorship, and support of hisprofessional development and work on this book. Most importantly, hewould like to thank his wife, Dr. Maria Costantini-Ferrando, and children,Luke, Nicole, Marco, and David, for being his prime motivators in life andfor their patience in tolerating the many hours spent writing and editing.

Dr. Levenson would like to thank his wife and family for their support.Dr. Owen would like to thank his wife, Sue, for her encouragement and

literary support.

xxvii

Introduction




The mission of this book is to serve as a clinical manual and educational toolfor specialist and nonspecialist clinicians for the psychopharmacological treat-ment of patients with medical illness. Psychiatric comorbidity occurs in ap-proximately 30% of medical outpatients (Spitzer et al. 1999) and 40%–50%of medical inpatients (Diez-Quevedo et al. 2001; Levenson et al. 1990). Pa-tients with medical and psychiatric comorbidity have more functional impair-ment, disability days, health care services use, and medical care costs than dothose without such comorbidity. Psychopharmacological agents are a mainstayof treatment for psychiatric disorders and, in keeping with the above psychiatriccomorbidity rates, are often prescribed to patients who are medically ill. Ap-proximately 10% of medical–surgical inpatients (Haggerty et al. 1986) and5%–12% of general practice outpatients (Linden et al. 1999; Pincus et al.

xxviii Clinical Manual of Psychopharmacology in the Medically Ill

1998) are given prescribed psychotropic medication. Nearly three-fourths ofpatients seen in psychiatric consultation, young and old, receive psychotropicmedication for broad-ranging diagnoses, including depression, anxiety, delir-ium, dementia with behavioral disturbances, and substance abuse and with-drawal (Schellhorn et al. 2009).

Most psychotropic prescriptions are written by primary practitioners, fol-lowed by psychiatrists, then other medical specialists: of 45 million U.S. phy-sician visits in 1993–1994 in which a psychotropic medication was prescribed,22 million (49%) were with primary care physicians, 15 million (33%) werewith psychiatrists, and 8 million (18%) were with other medical specialists(Pincus et al. 1998). Although the principles of psychotropic prescription topatients with medical illness are therefore relevant across medical specialties,physicians outside of the field of psychosomatic medicine (who represent asmall subspecialty within psychiatry) often feel ill equipped to prescribe tosuch patients out of concerns for safety, lack of efficacy, and drug–disease anddrug–drug interactions. These concerns likely contribute to the underdiag-nosis, underprescription, and underdosing of psychotropic medications forwidespread conditions, such as major depression, in patients who are medi-cally ill (Mojtabai 2002; Seelig and Katon 2008). In fact, the vast majority ofmainstream psychopharmacology efficacy studies on which governmental reg-ulatory approval is based exclude medically ill individuals. Furthermore, stud-ies of antidepressant treatment suggest that although patients with comorbidmedical illness and depression improve with antidepressant medication, med-ical comorbidity reduces depressive symptom response and remission (Iosi-fescu et al. 2004). Fortunately, in recognition of the above issues, there is agrowing evidence base concerning the prescription, safety, and efficacy of psy-chopharmacological treatments for multiple psychiatric problems in medi-cally ill patients. Unfortunately, no current texts are specifically devoted to thistopic. This is the impetus for this manual.

How to Use This Manual

In this manual, we aim to provide clinically relevant information regardingpsychopharmacology in patients who are medically ill, including pharmaco-kinetic and pharmacodynamic principles, drug–drug interactions, and organ

Introduction xxix

system disease–specific issues. Chapters are authored by experts in the field,with editorial input to maintain consistency of format and style.

The manual has two sections. Part 1, “General Principles,” provides fun-damental background information for prescribing psychotropic drugs acrossmedical disease states and is suggested reading prior to advancing to the dis-ease-specific information in the second section. Part 1 includes discussion ofpharmacodynamics and pharmacokinetics, drug–drug interaction principles,major systemic adverse effects of psychotropic drugs, and alternate routes ofpsychotropic drug administration.

Part 2, “Psychopharmacology in Organ System Disorders and SpecialtyAreas,” includes chapters on psychopharmacological treatment in specific or-gan system diseases, such as renal and cardiovascular disease, as well as otherrelevant subspecialty areas, such as critical care, organ transplantation, pain,and substance use disorders.

With some variation, chapters are structured to include the followingelements: key differential diagnostic considerations, including adverse neuro-psychiatric side effects of disease-specific medications; disease-specific phar-macokinetic principles in drug prescribing; review of evidence forpsychotropic drug treatment of psychiatric disorders in the specific diseasestate or specialty area; disease-specific adverse psychotropic drug side effects;and interactions between psychotropic drugs and disease-specific drugs. Eachchapter has tables that summarize information on adverse neuropsychiatricside effects of disease-specific medications, adverse disease-specific side effectsof psychotropic drugs, and drug–drug interactions. Chapters are heavily ref-erenced with source information should readers wish to expand their knowl-edge in a specific area. Finally, each chapter ends with a list of key summarypoints pertaining to psychotropic prescribing in the specific medical dis-ease(s) or specialty area covered in the chapter.

With this structure, we hope that we have contributed a comprehensiveyet practical guide for psychotropic prescribing for patients who are medicallyill. We will consider this manual a success if it proves useful for a broad rangeof specialists: the psychosomatic medicine specialist caring for a delirious pa-tient with cancer, the general psychiatrist in the community mental healthclinic whose patient with schizophrenia develops liver disease in the setting ofalcohol dependence and hepatitis C infection, and the general medical prac-titioner prescribing an antidepressant to a diabetic patient who recently had

xxx Clinical Manual of Psychopharmacology in the Medically Ill

a myocardial infarction. We hope that this manual, beyond serving as aclinical guide, will also become a mainstay of curricula in general psychiatricresidency programs, in psychosomatic medicine fellowships, and in nonpsy-chiatric residency training programs that seek to provide training in psycho-pharmacology for medically ill patients.

ReferencesDiez-Quevedo C, Rangil T, Sanchez-Planell L, et al: Validation and utility of the Patient

Health Questionnaire in diagnosing mental disorders in 1003 general hospitalSpanish inpatients. Psychosom Med 63:679–686, 2001

Haggerty JJ Jr, Evans DL, McCartney CF, et al: Psychotropic prescribing patterns ofnonpsychiatric residents in a general hospital in 1973 and 1982. Hosp Commu-nity Psychiatry 37:357–361, 1986

Iosifescu DV, Bankier B, Fava M: Impact of medical comorbid disease on antidepressanttreatment of major depressive disorder. Curr Psychiatry Rep 6:193–201, 2004

Levenson JL, Hamer RM, Rossiter LF: Relation of psychopathology in general medicalinpatients to use and cost of services. Am J Psychiatry 147:1498–1503, 1990

Linden M, Lecrubier Y, Bellantuono C, et al: The prescribing of psychotropic drugsby primary care physicians: an international collaborative study. J Clin Psycho-pharmacol 19:132–140, 1999

Mojtabai R: Diagnosing depression and prescribing antidepressants by primary carephysicians: the impact of practice style variations. Ment Health Serv Res 4:109–118, 2002

Pincus HA, Tanielian TL, Marcus SC, et al: Prescribing trends in psychotropic medi-cations: primary care, psychiatry and other medical specialties. JAMA 279:526–531, 1998

Schellhorn SE, Barnhill JW, Raiteri V, et al: A comparison of psychiatric consultationbetween geriatric and non-geriatric medical inpatients. Int J Geriatr Psychiatry24:1054–1061, 2009

Seelig MD, Katon W: Gaps in depression care: Why primary care physicians shouldhone their depression screening, diagnosis, and management skills. J Occup En-viron Med 50:451–458, 2008

Spitzer RL, Kroenke K, Williams JB: Validation and utility of a self-report version ofPRIME-MD: the PHQ primary care study. Primary Care Evaluation of MentalDisorders. Patient Health Questionnaire. JAMA 282:1737–1744, 1999

PA R T I

General Principles

3

1Pharmacokinetics,

Pharmacodynamics, andPrinciples of Drug–Drug

Interactions


Psychotropic drugs are commonly employed in the management of patientswho are medically ill. At least 35% of psychiatric consultations include recom-mendations for medication (Bronheim et al. 1998). The appropriate use ofpsychopharmacology in medically ill patients requires careful consideration ofthe underlying medical illness, potential alterations to pharmacokinetics, drug–drug interactions, and contraindications. In this chapter, we review drug action,drug pharmacokinetics, and drug interactions to provide a basis for drug–drugand drug–disease interactions presented in later disease-specific chapters.

The effects of a drug—that is, the magnitude and duration of its therapeu-tic and adverse effects—are determined by the drug’s pharmacodynamic and

4 Clinical Manual of Psychopharmacology in the Medically Ill

pharmacokinetic characteristics. Pharmacodynamics describes the effects of adrug on the body. Pharmacodynamic processes determine the relationship be-tween drug concentration and response for both therapeutic and adverse ef-fects. Pharmacokinetics describes what the body does to the drug. Itcharacterizes the rate and extent of drug absorption, distribution, metabolism,and excretion. These pharmacokinetic processes determine the rate of drug de-livery to and the drug’s concentration at the sites of action. The relationship be-tween pharmacokinetics and pharmacodynamics is diagrammed in Figure 1–1.

Pharmacodynamics

For most drugs, the pharmacological effect is the result of a complex chain ofevents, beginning with the interaction of drug with receptor. Pharmacody-namic response is further modified—enhanced or diminished—by diseasestates, aging, and other drugs. For example, the presence of Parkinson’s diseaseincreases the incidence of movement disorders induced by selective serotoninreuptake inhibitors (SSRIs). Pharmacodynamic disease–drug interactions arereviewed in the relevant chapters; pharmacodynamic drug–drug interactionsare discussed later in this chapter in “Pharmacodynamic Drug Interactions.”

A drug’s spectrum of therapeutic and adverse effects is due to its interac-tion with multiple receptor sites. The effects produced depend on which re-ceptor populations are occupied by the drug; some receptor populations arereadily occupied at low drug concentrations, whereas other receptor sites re-quire high drug levels for interaction. In this way, different responses are re-cruited in a stepwise manner with increasing drug concentration. As druglevels increase, each effect will reach a maximum as all active receptors respon-sible for that effect are occupied by the drug. Further increases in drug concen-tration cannot increase this response but may elicit other effects. Figure 1–2illustrates three pharmacological effects produced by a drug in a concentration-dependent manner. In this example, Effect B is the primary therapeutic effect,Effect A is a minor adverse effect, and Effect C is a significant toxic effect. Lowdrug concentrations recruit only Effect A; the patient experiences a nuisanceside effect without any therapeutic gain. As drug concentration increases, EffectB is engaged while Effect A is maximized. Clearly, for this drug, except in therare situation where Effect B antagonizes Effect A (e.g., where the initial sedat-ing effect of a drug is counteracted by stimulating effects recruited at a higher

Prin

ciples o

f Dru

g–Drug In

teractions

5

Figure 1–1. Relationship between pharmacokinetics and pharmacodynamics.

6C

linical Manual of Psychopharm

acology in the Medically Ill

Figure 1–2. Concentration–response relationship (see text for details).

Principles of Drug–Drug Interactions 7

concentration), Effect A will always accompany a therapeutically effective dosebecause it is recruited at a lower concentration than that required for the ther-apeutic effect. Further increases in drug concentration improve the therapeuticeffect until reaching its maximum but also introduce toxic Effect C.

Optimum therapy requires that drug concentrations be confined to a ther-apeutic range to maximize the therapeutic effect and minimize any adverse and/or toxic effects. Developing a dosage regimen to maintain drug levels within thistherapeutic range requires consideration of pharmacokinetic processes.

Drug–receptor interactions produce effects on several time scales. Imme-diate effects are the result of a direct receptor interaction. Several psychoactivedrugs, including benzodiazepines, have immediate therapeutic effects andtherefore are useful on an acute or as-needed basis. However, many psychoac-tive drugs, such as antidepressant and antipsychotic agents, require chronicdosing over several weeks for a significant therapeutic response. These drugsappear to alter neuronal responsiveness by modifying slowly adapting cellularprocesses. Unfortunately, many adverse effects appear immediately—the re-sult of a direct receptor interaction. Medication adherence may be erodedwhen adverse effects are experienced before therapeutic effects are realized.Table 1–1 lists strategies to maximize medication compliance.

PharmacokineticsDrug response, including the magnitude and duration of the drug’s therapeu-tic and adverse effects, is significantly influenced by the drug’s pharmacoki-netics (absorption from administration sites, distribution throughout thebody, and metabolism and excretion). Individual differences in constitutionalfactors, compromised organ function, and disease states, or the effects ofother drugs and food, all contribute to the high variability in drug responseobserved across patients. Understanding the impact of these factors on adrug’s pharmacokinetics will aid in drug selection and dosage adjustment ina therapeutic environment complicated by polypharmacy and medical illness.

Absorption and Bioavailability

The speed of onset and to a certain extent the duration of the pharmacologi-cal effects of a drug are determined by the route of administration. The bio-availability of a drug formulation describes the rate and extent of drug


Table 1–1. Strategies to maximize medication compliance

Provide patient education

Inform the patient about potential adverse effects, their speed of onset, and whether tolerance will develop over time.

Indicate the time for onset of the therapeutic effect. Many psychotropic drugs have a considerable delay (weeks) before the appearance of significant therapeutic effects yet give rise to adverse effects immediately. Patients not aware of this temporal disconnect between adverse and therapeutic effects may consider the medication a failure and discontinue the drug if only adverse effects and no therapeutic effects are initially experienced.

Select drugs with a convenient dosing schedule

Select drugs with once-daily dosing (i.e., those with a suitably long half-life or available in an extended-release formulation) to maximize compliance.

Consider the use of depot formulations for antipsychotic agents. Some antipsychotics are available in depot formulations with a dosing interval of several weeks. Compliance can be confirmed from administration records. However, the patient must have undergone a successful trial of the equivalent oral formulation to verify therapeutic response and tolerance to adverse effects, and to establish the appropriate dose.

Minimize adverse effects

Select drugs with minimal pharmacokinetic interaction where possible (e.g., avoid cytochrome P450 inhibitors or inducers).

Gradually increase drug dosage to therapeutic levels over several days or weeks (“start low, go slow”) so that patients experience minimal adverse effects while gradually developing tolerance.

Use the minimum effective dose.

Select a drug with an adverse-effect profile the patient can best tolerate. Drugs within a class may be similar therapeutically but differ in their adverse-effect profile. Patients may vary in their tolerance to a particular effect.

Reduce peak drug levels following absorption of oral medications. Many adverse effects are concentration dependent and are exacerbated as drug levels peak following oral dosing. Consider administering the drug with food or using divided doses or extended-release formulations to reduce and delay peak drug levels and diminish adverse effects.

Schedule the dose so the side effect is less bothersome. If possible, prescribe activating drugs in the morning, and sedating drugs or those that cause gastrointestinal distress in the evening.


delivery to the systemic circulation from the formulation. Intravenous or in-tra-arterial administration delivers 100% of the drug dose to the systemic cir-culation (100% bioavailability) at a rate that can be controlled if necessary.Bioavailability is typically less than 100%, often much less, for drugs deliv-ered by other routes.

Drug absorption is influenced by the characteristics of the absorption siteand the physiochemical properties of a drug. Specific site properties affectingabsorption include surface area, ambient pH, mucosal integrity and function,and local blood flow, all of which may be altered by, for example, peptic ulcerdisease or inflammatory bowel disease, and their drug treatment.

Orally administered drugs face several pharmacokinetic barriers that limitdrug delivery to the systemic circulation. Drugs must dissolve in gastric fluidsto be absorbed, and drug dissolution in the stomach and gut may be incom-plete (e.g., after gastric bypass surgery). Drugs may be acid labile and degradein the acidic stomach environment, or may be partially metabolized by gutflora. Drugs absorbed through the gastrointestinal tract may be extensively al-tered by “first-pass” metabolism before entering the systemic circulation (seeFigure 1–3). First-pass metabolism refers to the transport and metabolism ofdrugs from the gut lumen to the systemic circulation via the portal vein andliver. Drug passage from the gut lumen to the portal circulation may be lim-ited by two processes: 1) a P-glycoprotein (P-gp) efflux transport pump,which serves to reduce the absorption of many compounds (some P-gp sub-strates are listed in the appendix to this chapter) by countertransporting themback into the intestinal lumen, and 2) metabolism within the gut wall bycytochrome P450 (CYP) 3A4 enzymes. Because P-gp is co-localized with andshares similar substrate affinity with CYP 3A4, drug substrates of CYP 3A4

Utilize therapeutic drug monitoring

Keep in mind that therapeutic drug monitoring is available for many psychotropic drugs. This is valuable for monitoring compliance and ensuring that drug levels are within the therapeutic range.

Check for patient compliance

Schedule office or telephone visits to discuss compliance and adverse effects for newly prescribed drugs.

Table 1–1. Strategies to maximize medication compliance (continued)

10C



Figure 1–3. First-pass metabolism of orally administered drugs.Many drugs undergo a “first-pass effect” as they are absorbed from the intestinal lumen before they are delivered to the systemic circu-lation. The first-pass effect limits oral bioavailability through countertransport by P-glycoprotein (P-gp) back into the intestinal lumen,and by gut wall (mainly cytochrome P450 3A4 [CYP 3A4]) and hepatic metabolism.


typically have poor bioavailability. Bioavailability may be further decreased byhepatic extraction of drugs as they pass through the liver before gaining accessto the systemic circulation. Sublingual and topical drug administration min-imizes this first-pass effect, and rectal delivery, although often resulting inerratic absorption, may reduce first-pass effect by 50%.

Bioavailability can be markedly altered by disease states and drugs that al-ter gut and hepatic function. As with the CYP and uridine 5′-diphosphateglucuronosyltransferase (UGT) enzyme systems involved in drug metabo-lism, drugs can also inhibit or induce the P-gp transporter. Common P-gp in-hibitors include paroxetine, sertraline, trifluoperazine, verapamil, and protonpump inhibitors. Because intestinal P-gps serve to block absorption in thegut, inhibition of these transporters can dramatically increase the bioavaila-bility of poorly bioavailable drugs. For example, oral fentanyl absorption inhumans is increased 2.7-fold when administered with quinidine, a known in-testinal P-gp inhibitor (Kharasch et al. 2004). P-gp inhibitors are listed in theappendix to this chapter. For drugs administered chronically, the extent ofdrug absorption is the key factor in maintaining drug levels within the thera-peutic range. In situations where bioavailability may be significantly altered,parenteral administration of drugs may be preferable.

Drug formulation, drug interactions, gastric motility, and the characteristicsof the absorptive surface all influence the rate of absorption, a key factor whenrapid onset is desired. Oral medications are absorbed primarily in the small in-testine due to its large surface area. Delayed gastric emptying or drug dissolutionwill slow absorption and therefore blunt the rise in drug levels following an oraldose. In this way, the occurrence of transient concentration-related adverse ef-fects following an oral dose may be reduced by administering a drug with food,whereas the common practice of dissolving medications in juice may producehigher peak levels and exacerbate these transient adverse reactions.

Distribution

Following absorption into the systemic circulation, the drug is distributedthroughout the body in accordance with its physiochemical properties and theextent of protein binding. The volume of distribution describes the relationshipbetween the bioavailable dose and the plasma concentration. Lipophilic drugs,including most psychotropic medications, are sequestered into lipid compart-ments of the body. Because of their low plasma concentrations relative to dose,


these drugs appear to have a large volume of distribution. In contrast, hydro-philic drugs (e.g., lithium, oxazepam, valproate), being confined mainly to thevascular volume and other aqueous compartments, have a high plasma con-centration relative to dose, suggesting a small volume of distribution. Volumeof distribution is often unpredictably altered by disease-related changes in or-gan and tissue perfusion or body composition. Edema (e.g., in congestiveheart failure, cirrhosis, nephrotic syndrome) causes expansion of the extracel-lular fluid volume and may significantly increase the volume of distributionfor hydrophilic drugs. Lipophilic drugs experience an increase in volume ofdistribution with obesity, which is sometimes iatrogenic (e.g., with corticoster-oids or antipsychotics), and age-related increases in body fat. P-gp, a majorcomponent of the blood–brain barrier, may limit entry of drugs into the cen-tral nervous system (CNS). Many antiretroviral agents have limited CNS pen-etration because they are P-gp substrates (see the appendix to this chapter).

Most drugs bind, to varying degrees, to the plasma proteins albumin oralpha-1 acid glycoprotein. Acidic drugs (e.g., valproic acid, barbiturates) bindmostly to albumin, and more basic drugs (e.g., phenothiazines, tricyclic anti-depressants, amphetamines, most benzodiazepines) bind to globulins.

Drug in plasma circulates in both bound and free (unbound to plasma pro-teins) forms. Generally, only free drug is pharmacologically active. Theamount of drug bound to plasma proteins is dependent on the presence ofother compounds that displace the drug from its protein binding sites (a pro-tein-binding drug interaction) and the plasma concentration of albumin andalpha-1 acid glycoprotein. Medical conditions may alter plasma concentrationsof albumin or alpha-1 acid glycoprotein (see Table 1–2) or increase the levelsof endogenous displacing compounds. For example, uremia, chronic liver dis-ease, and hypoalbuminemia may significantly increase the proportion of freedrug relative to total drug in circulation (Dasgupta 2007).

Changes in drug protein binding, either disease induced or the result of aprotein-binding drug interaction, were once considered a common cause ofdrug toxicity because therapeutic and toxic effects increase with increasingconcentrations of free drug. These interactions are now seen as clinically sig-nificant only in very limited cases involving rapidly acting, highly protein-bound (>80%), narrow-therapeutic-index drugs with high hepatic extraction(possible candidates include propafenone, verapamil, and intravenous lido-caine) (Benet and Hoener 2002; Rolan 1994). For drugs with low hepatic


Table 1–2. Conditions that alter plasma levels of albumin and alpha-1 acid glycoprotein

Decrease albumin

Surgery

Burns

Trauma

Pregnancy

Alcoholism

Sepsis

Bacterial pneumonia

Acute pancreatitis

Uncontrolled diabetes

Hepatic cirrhosis

Nephritis, nephrotic syndrome, renal failure

Increase albumin

Hypothyroidism

Decrease alpha-1 acid glycoprotein

Pancreatic cancer

Pregnancy

Uremia

Hepatitis, cirrhosis

Cachexia

Increase alpha-1 acid glycoprotein

Stress response to disease states

Inflammatory bowel disease

Acute myocardial infarction

Trauma

Epilepsy

Stroke

Surgery

Burns

Cancer (except pancreatic)

Acute nephritic syndrome, renal failure

Rheumatoid arthritis, systemic lupus erythematosus

Source. Compiled in part from Dasgupta 2007; Israili and Dayton 2001.


extraction, such as warfarin (Greenblatt and Von Moltke 2005) and phenytoin(Tsanaclis et al. 1984) (see Table 1–3 later in this chapter), metabolism is notlimited by hepatic blood flow, and a reduction in protein binding serves to in-crease the amount of free drug available for metabolism and excretion. Conse-quently, hypoalbuminemia or the presence of a displacing drug enhances drugelimination, which generally limits changes in circulating unbound drug levelsto only a transient, and clinically insignificant, increase. (Many warfarin druginteractions previously thought to be protein-binding interactions are now rec-ognized as pharmacodynamic and CYP 2C9 and CYP 1A2 metabolic interac-tions.) However, although free drug levels may remain unchanged, changes inprotein binding will reduce plasma levels of total drug (free + bound fractions).Although of no consequence therapeutically, therapeutic drug monitoring pro-cedures that measure total drug levels could mislead the clinician by suggestinglower, possibly subtherapeutic levels and might prompt a dosage increase withpossible toxic effects. For this reason, in patients with uremia, chronic hepaticdisease, hypoalbuminemia, or a protein-binding drug interaction, the use oftherapeutic drug monitoring for dose adjustment requires caution; clinical re-sponse to the drug (e.g., international normalized ratio [INR] for warfarin),rather than laboratory-determined drug levels, should guide dosage. Wheretherapeutic drug monitoring is employed, methods selective for unbound drugshould be used, if available, for phenytoin, valproate, tacrolimus, cyclosporine,amitriptyline, haloperidol, and possibly carbamazepine (Dasgupta 2007).

Disease-related changes to a drug’s protein binding have little effect onsteady-state plasma concentrations of free drug as long as the disease does notaffect metabolic and excretory processes (Benet and Hoener 2002). However,most diseases that affect protein binding also affect metabolism and excretion,with clinically significant consequences, especially for drugs with a low thera-peutic index.

Drug Elimination: Metabolism and Excretion

The kidney is the primary organ of drug excretion, with fecal and pulmonaryexcretion being of less importance. Hydrophilic compounds are removedfrom the body through excretion into the aqueous environment of urine andfeces. In contrast, lipophilic drugs, including most psychoactive medications,are readily reabsorbed through the intestinal mucosa (enterohepatic recircu-lation) and renal tubules, which limits their excretion. Because all drugs un-


dergo glomerular filtration, lipophilic drugs would experience significantrenal elimination were it not for renal resorption. Renal resorption, and thusthe elimination, of several drugs, including amphetamines, meperidine, andmethadone, can be significantly changed by altering urine pH (discussed un-der “Pharmacokinetic Drug Interactions” later in this chapter).

The general function of metabolism is to convert lipophilic moleculesinto more polar water-soluble compounds that can be readily excreted. Al-though biotransformation often results in less active or inactive metabolites,this is not always true. For some drugs, metabolites have pharmacological ac-tivities similar to, or even greater than, the parent compound, and thus con-tribute to the therapeutic effect. Indeed, some metabolites are separatelymarketed, including paliperidone (principal active metabolite of risperidone)and temazepam and oxazepam (both metabolites of diazepam). Some drugsare administered as prodrugs—inactive compounds requiring metabolic acti-vation—including lisdexamfetamine (metabolized to amphetamine), trama-dol, codeine, and fosphenytoin (metabolized to phenytoin). Other drugmetabolites may have pharmacological effects considerably different fromthose of the parent drug and may cause unique toxicities (e.g., the meperidinemetabolite normeperidine has proconvulsant activity).

Metabolism

Biotransformation occurs throughout the body, with the greatest activity inthe liver and gut wall. Most psychotropic drugs are eliminated by hepatic me-tabolism followed by renal excretion. Hepatic biotransformation processes areof two types, identified as Phase I and Phase II reactions. Phase I reactionstypically convert the parent drug into a more polar metabolite by introducingor unmasking a polar functional group in preparation for excretion or furthermetabolism by Phase II pathways. Phase II metabolism conjugates the drugor Phase I metabolite with an endogenous acid such as glucuronate, acetate,or sulfate. The resulting highly polar conjugates are usually inactive and arerapidly excreted in urine and feces (see Figure 1–4).

Phase I metabolism. Phase I reactions include oxidation, reduction, andhydrolysis. Most Phase I oxidation reactions are carried out by the hepaticCYP system, with a lesser contribution from the monoamine oxidases(MAOs). CYP enzymes exist in a variety of body tissues, including the gas-trointestinal tract, liver, lung, and brain. The CYP system includes 11 enzyme


Figure 1–4. General pathways of metabolism and excretion. UGTs=uridine 5′-diphosphate glucuronosyltranferases.


families, three of which are important for drug metabolism in humans: CYP1, CYP 2, and CYP 3. These families are divided into subfamilies identifiedby a capital letter (e.g., CYP 3A). Subfamilies are further subdivided intoisozymes based on the homology between subfamily proteins. Isozymes aredenoted by a number following the subfamily letter (e.g., CYP 3A4).

In humans, CYP 1A2, 2C9, 2C19, 2D6, and 3A4 are the most importantenzymes for drug metabolism. These enzymes exhibit substrate specificity.Many drugs undergo Phase I metabolism primarily through one CYPisozyme. Functional deficiencies in one CYP enzyme will impact the metab-olism of only those compounds that are substrate for that enzyme. Becausesome of these enzymes exist in a polymorphic form, a small percentage of thepopulation, varying with ethnicity, has one or more CYP enzymes with sig-nificantly altered activity. For example, polymorphisms of the 2D6 gene giverise to populations with the capacity to metabolize CYP 2D6 substrates ex-tensively (normal condition), poorly (5%–14% of Caucasians, ~1% of Ori-entals), or ultraextensively (1%–3% of the population) (Zanger et al. 2004).CYP enzyme activity can also be altered (inhibited or enhanced through in-duction) by environmental compounds or drugs, giving rise to many drug–drug interactions (discussed below in “Drug Interactions”).

Phase II metabolism. Phase II conjugation reactions mainly involve en-zymes belonging to the superfamily of UGTs. UGT enzymes are located he-patically (primarily centrizonal) (Debinski et al. 1995) and in the kidney andsmall intestine (Fisher et al. 2001). The UGT enzyme superfamily is classi-fied in a manner similar to the CYP system. There are two clinically signifi-cant UGT subfamilies: 1A and 2B. As with the CYP system, there can besubstrates, inhibitors, and inducers of UGT enzymes. For example, thosebenzodiazepines that are primarily metabolized by conjugation (oxazepam,lorazepam, and temazepam) are glucuronidated by UGT2B7. Valproic acid,tacrolimus, cyclosporine, and a number of nonsteroidal anti-inflammatorydrugs (NSAIDs), including diclofenac, flurbiprofen, and naproxen, are com-petitive inhibitors of UGT2B7. Carbamazepine, phenytoin, rifampin (ri-fampicin), phenobarbital, and oral contraceptives are general inducers ofUGTs (Kiang et al. 2005).

Drug interactions involving Phase II UGT-mediated conjugation reac-tions are increasingly becoming recognized. These interactions between crit-


ical substrates, inducers, and inhibitors follow the same rationale as for CYPinteractions (discussed in “Drug Interactions” later in this chapter).

Effect of disease on metabolism. Hepatic clearance of a drug may be lim-ited by either the rate of delivery of the drug to the hepatic metabolizing en-zymes (i.e., hepatic blood flow) or the intrinsic capacity of these enzymes tometabolize the substrate. Reduced hepatic blood flow impairs the clearance ofdrugs with high hepatic extraction (>6 mL/min/kg; flow-limited drugs) buthas little effect on drugs with low hepatic extraction (<3 mL/min/kg; capacity-limited drugs), whose clearance depends primarily on hepatic function. Table1–3 lists psychotropic drugs according to their degree of hepatic extraction.

Clinically significant decreases in hepatic blood flow, which occur in severecardiovascular disease, chronic pulmonary disease, and severe cirrhosis, impairthe clearance of flow-limited drugs. A reduction in the metabolic capacity ofhepatic enzymes, as often accompanies congestive heart failure, renal disease, orhepatic disease, mainly impairs the clearance of capacity-limited drugs. Renaldisease can significantly reduce hepatic Phase I and Phase II metabolism andincrease intestinal bioavailability by reducing metabolic enzyme and P-gp geneexpression (Pichette and Leblond 2003). Hepatic disease may preferentially af-fect anatomic regions of the liver, thereby altering specific metabolic processes.For example, oxidative metabolic reactions are more concentrated in the peri-central regions affected by acute viral hepatitis or alcoholic liver disease. Diseaseaffecting the periportal regions, such as chronic hepatitis (in the absence of cir-rhosis), may spare some hepatic oxidative function. Acute and chronic liver dis-eases generally do not impair glucuronide conjugation reactions.

Excretion

The kidney’s primary pharmacokinetic role is drug excretion. However, renaldisease may also affect drug absorption, distribution, and metabolism. Re-duced renal function, due to age or disease, results in the accumulation ofdrugs and active metabolites predominantly cleared by renal elimination. Dos-age reduction may be required for narrow-therapeutic-index drugs that un-dergo significant renal excretion.

For renally eliminated drugs, a 24-hour urine creatinine clearance deter-mination is a more useful indicator of renal function than is serum creatinine.In elderly patients, reduced creatinine production because of decreased mus-cle mass and possibly reduced exercise and dietary meat intake causes the


calculation of creatinine clearance from serum creatinine levels by the com-monly used Cockcroft-Gault formula to overestimate glomerular filtrationrate (GFR) (Sokoll et al. 1994). Creatinine clearance is sufficiently accuratefor dosage adjustment of renally eliminated drugs in this population (Barac-skay et al. 1997). In patients with severe liver disease, estimates of GFR must

Table 1–3. Systemic clearance of hepatically metabolized psychotropic drugs

High extraction ratio (clearance >6 mL/min/kg)

Amitriptyline Fluoxetine Paroxetine

Bupropion Fluvoxamine Quetiapine

Buspirone Haloperidol Rizatriptan

Chlorpromazine Hydrocodone Ropinirole

Clozapine Hydromorphone Sertraline

Codeine Imipramine Sumatriptan

Desipramine Meperidine Venlafaxine

Diphenhydramine Midazolam Zaleplon

Doxepin Morphine Zolmitriptan

Fentanyl Nortriptyline

Flumazenil Olanzapine

Intermediate extraction ratio (clearance 3–6 mL/min/kg)

Bromocriptine Flunitrazepam Risperidone

Citalopram Flurazepam Triazolam

Clonidine Protriptyline Zolpidem

Low extraction ratio (clearance <3 mL/min/kg)

Alprazolam Lamotrigine Phenytoin

Carbamazepine Levetiracetam Temazepam

Chlordiazepoxide Lorazepam Tiagabine

Clonazepam Methadone Topiramate

Clorazepate Modafinil Trazodone

Diazepam Nitrazepam Valproate

Donepezil Oxazepam

Ethosuximide Oxcarbazepine

Source. Compiled from Physicians’ Desk Reference 2008, 2009; Thummel et al. 2005.


be interpreted with caution. The reduced muscle mass and impaired metab-olism of creatine associated with severe liver disease often results in inaccurateestimates of glomerular filtration rate when based on either serum creatininelevels (Cockcroft-Gault method) or creatinine clearance (Papadakis and Ari-eff 1987).

Drug–Drug InteractionsPolypharmacy is common in medically ill patients and frequently leads toclinically significant pharmacokinetic or pharmacodynamic drug–drug inter-actions. Pharmacokinetic interactions alter drug absorption, distribution, me-tabolism, or excretion, and change the drug concentration in tissues. Theseinteractions are most likely to be clinically meaningful when the drug in-volved has a low therapeutic index. Pharmacodynamic interactions alter thepharmacological response to a drug. These interactions may be additive, syn-ergistic, or antagonistic. Pharmacodynamic interactions may occur directly byaltering drug binding to receptor site or indirectly through other mechanisms.

Pharmacokinetic Drug Interactions

The majority of drugs are substrates for metabolism by one or more CYP en-zymes. The most common pharmacokinetic drug–drug interaction involveschanges in the CYP-mediated metabolism of the substrate drug by an interact-ing drug. The interacting drug may be either an inducer or an inhibitor of thespecific CYP enzymes involved in the substrate drug’s metabolism. In the pres-ence of an inducer, CYP enzyme activity and the rate of metabolism of the sub-strate is increased. Enzyme induction is not an immediate process but occursover several weeks. Induction will decrease the amount of circulating parentdrug and may cause a decrease or loss of therapeutic efficacy. Consider a pa-tient, stabilized on risperidone (a CYP 1A2 substrate), who begins to smoke (aCYP 1A2 inducer). Smoking will increase risperidone metabolism and, unlessdrug dosage is suitably adjusted, risperidone levels will fall and psychotic symp-toms may worsen. If the interacting drug is a metabolic inhibitor, drug metab-olism mediated through the inhibited CYP isozyme will be impaired. Theresulting rise in substrate drug levels may increase drug toxicity and prolongthe pharmacological effect. Although enzyme inhibition is a rapid process, sub-strate drug levels respond more slowly, taking 5 half-lives to restabilize.


Not all combinations of substrate drug and interacting drug will result inclinically significant drug–drug interactions. For a drug eliminated by severalmechanisms, including multiple CYP enzymes or non-CYP routes (e.g.,UGTs, renal elimination), the inhibition of a single CYP isozyme only servesto divert elimination to other pathways with little change in overall elimina-tion rate. For these interactions to be clinically relevant, a critical substratedrug must have a narrow therapeutic index and one primary CYP isozymemediating its metabolism. For example, nifedipine, like all calcium channelblockers, is primarily metabolized by the CYP 3A4 isozyme. The addition ofa potent CYP 3A4 inhibitor, such as fluvoxamine, will inhibit nifedipine’s me-tabolism. Without a compensatory reduction in nifedipine dose, nifedipinelevels will rise and toxicity may result. When prescribing in a polypharmacyenvironment, the clinician should avoid medications that significantly inhibitor induce CYP enzymes and should prefer those that are eliminated by mul-tiple pathways and that have a wide safety margin. Drugs that are significantCYP isozyme inhibitors, inducers, and critical substrates are listed in the ap-pendix to this chapter.

The abundance of clinically significant pharmacokinetic interactions in-volving monoamine oxidase inhibitors (MAOIs), especially inhibitors ofMAO-A, has limited their therapeutic use. Many of these interactions involvefoods containing high levels of tyramine, a pressor amine metabolized by gutMAO-A. Several drugs, including some sympathomimetics and triptan antimi-graine medications, are also metabolized by MAO. Drugs and foods associatedwith MAO-related interactions are listed in the appendix to this chapter.

Although the role of Phase II UGT-mediated conjugation is being in-creasingly recognized in clinical pharmacology, surprisingly few clinicallysignificant drug interactions are known to involve UGTs. The clinically sig-nificant interaction between valproate and lamotrigine is considered a conse-quence of valproate inhibition of lamotrigine glucuronidation. In patientstaking lamotrigine, the addition of valproate resulted in a dose-dependent in-crease in systemic exposure (area under the curve [AUC]) to lamotrigine rang-ing from 84% at a valproate dose of 200 mg/day to 160% at 1,000 mg/day.Correspondingly, lamotrigine half-life increased from pre-valproate values by2.5-fold in the presence of 1,000 mg/day valproate (Morris et al. 2000). Inhuman subjects, the addition of the UGT-inducer rifampicin (600 mg/day)produced the opposite effect on lamotrigine levels. In comparison to the pre-


rifampicin condition, lamotrigine half-life declined by more than 40% ac-companied by a similar decrease in AUC (Ebert et al. 2000).

Only those drugs dependent on UGT biotransformation for their elimi-nation and having no other significant metabolic or excretory routes are can-didates for clinically important UGT-based drug interactions. Most drugsundergoing conjugation by UGTs are also substrates for Phase I metabolismand other metabolic and excretory processes and therefore are little affectedby the addition of UGT inhibitors or inducers. Some UGT substrates, induc-ers, and inhibitors are listed in the appendix to this chapter.

Metabolic drug interactions are most likely to occur in three situations:when an interacting drug (inhibitor or inducer) is added to an existing criticalsubstrate drug; when an interacting drug is withdrawn from a dosing regimencontaining a substrate drug; or when a substrate drug is added to an existingregimen containing an interacting drug.

The addition of an interacting drug to a medication regimen containinga substrate drug at steady-state levels will dramatically alter substrate drug lev-els, possibly resulting in toxicity (addition of an inhibitor) or loss of therapeu-tic effect (addition of an inducer).

A much overlooked interaction involves the withdrawal of an interactingdrug from a drug regimen that includes a critical substrate drug. Previously,the substrate drug dosage will have been titrated, in the presence of the inter-acting drug, to optimize therapeutic effect and minimize adverse effects.Withdrawal of an enzyme inhibitor will allow metabolism to return (increase)to normal levels. This increased metabolism of the substrate drug will lowerits levels and decrease therapeutic effect. In contrast, removal of an enzymeinducer will result in an increase in substrate drug levels and drug toxicity asits metabolism decreases to the normal rate over a period of several days toweeks.

The addition of a critical substrate drug to an established drug regimencontaining an interacting drug can result in a clinically significant interactionif the substrate is dosed according to established guidelines. Dosing guidelinesdo not account for the presence of a metabolic inhibitor or inducer and thusmay lead to substrate concentrations that are, respectively, toxic or subthera-peutic.

Metabolic drug interactions can be minimized by avoiding drugs that areknown critical substrates or potent inhibitors or inducers. Although avoiding


these drugs is not always possible, adverse effects of these metabolic interactionscan be reduced by identifying potentially problematic medications, making ap-propriate dosage adjustments, and monitoring drug levels (where possible).

An appreciation of drug interactions with the P-gp efflux transporter sys-tem is now emerging. P-gps influence the distribution and elimination ofmany clinically important hydrophobic compounds by transporting themout of the brain (P-gps are a major component of the blood–brain barrier),gonads, and other organs, and into urine, bile, and the gut. Inhibition ofP-gps can lead to drug toxicity due to dramatic increases in the oral bioavail-ability of poorly bioavailable drugs and to increased drug access to the CNS.Itraconazole, a CYP 3A4 and P-gp inhibitor, has been demonstrated to in-crease the bioavailability of paroxetine, a P-gp substrate, in human subjects.The addition of itraconazole to an existing paroxetine regimen increasedparoxetine AUC by 1.5-fold and peak blood levels by 1.3-fold in spite of onlya 10% increase in half-life (Yasui-Furukori et al. 2007). Other P-gp trans-ported psychotropic drugs include opiates, risperidone, olanzapine, nortrip-tyline, citalopram, and fluvoxamine. Some drug interactions with P-gp arelisted in the appendix to this chapter.

Drug interactions that affect renal drug elimination are clinically signifi-cant only if the parent drug or its active metabolite undergoes appreciable re-nal excretion. By reducing renal blood flow, some drugs, including manyNSAIDs, decrease GFR and impair renal elimination. This interaction is of-ten responsible for lithium toxicity.

Changes in urine pH can modify the elimination of those compoundswhose ratio of ionized to un-ionized forms is dramatically altered across thephysiological range of urine pH (4.6–8.2) (i.e., the compound has a pKawithin this pH range). Common drugs that alkalinize urine include antacidsand carbonic anhydrase inhibitor diuretics. Un-ionized forms of drugs undergogreater glomerular resorption, whereas ionized drug forms have less resorptionand greater urinary excretion. For a basic drug, such as amphetamine, alkalin-ization of urine increases the un-ionized fraction, enhancing resorption andprolonging activity. Other basic drugs, such as amitriptyline, imipramine, me-peridine, methadone (Nilsson et al. 1982), memantine (Freudenthaler et al.1998), and flecainide may be similarly affected (Cadwallader 1983).


Pharmacodynamic Drug Interactions

Pharmacodynamic interactions occur when drugs with similar or opposingeffects are combined. The nature of the interaction relates to the addition orantagonism of the pharmacological and toxic effects of each drug. Generally,pharmacodynamic interactions are most apparent in individuals who havecompromised physiological function, such as cardiovascular disease, or whoare elderly.

For example, drugs with anticholinergic activity cause a degree of cogni-tive impairment, an effect that is exacerbated when several anticholinergicagents are combined. Unfortunately, anticholinergic activity is an often un-recognized property of many common drugs, such as cimetidine, loperamide,or paroxetine (for a listing, see Owen 2010; Rudolph et al. 2008). This addi-tive interaction is most disruptive in patients with cognitive compromise,such as those who are elderly or who have Alzheimer’s disease, and forms thebasis for many cases of delirium. Often, additive pharmacodynamic interac-tions are employed therapeutically to enhance a drug response—this is the useof adjunctive medications. Antagonistic pharmacodynamic interactions aresometimes used deliberately to diminish a particular adverse effect. In thetreatment of chronic pain syndromes, psychostimulants, such as amphet-amine or methylphenidate, are frequently combined with morphine or otheropiates to reduce opiate sedation and to enhance opiate analgesia (Dalal andMelzack 1998). Unintentional antagonistic interactions may be counterther-apeutic, as with the erosion of asthma control in a patient who has success-fully employed a beta-agonist inhaler and is recently prescribed a beta-blocker, or the negation of any cognitive benefit from a cholinesterase inhib-itor when taken with an anticholinergic drug such as diphenhydramine.

Knowledge of a drug’s therapeutic and adverse effects is essential to avoidunwanted pharmacodynamic drug interactions, such as additive or synergis-tic toxicities, or countertherapeutic effects.

Drug Interactions of Psychotropic Agents

Pharmacodynamic interactions between psychoactive drugs and drugs usedto treat medical disorders are common and are discussed in the respectivemedical disorder chapters. Psychotropic drugs frequently contribute to orprecipitate pharmacodynamic interactions. Excessive sedation or delirium


frequently results from the combination of psychotropic drugs with sedatingproperties. Psychotropic polypharmacy can also precipitate severe adverse re-actions, such as serotonin syndrome or cardiac arrhythmias due to prolongedQT interval (see Chapter 2, “Severe Drug Reactions”).

Any psychotropic drug can be the recipient of a pharmacokinetic inter-action, but only a few psychotropic drugs commonly precipitate a pharma-cokinetic interaction. Fluoxetine, paroxetine, fluvoxamine, duloxetine,bupropion, modafinil, armodafinil, and atomoxetine significantly inhibit oneor more CYP isozymes. The MAOIs block metabolism of some sympathomi-metics and several triptan antimigraine medications. Carbamazepine and val-proate, mood stabilizer anticonvulsants, induce one or more CYP isozymes(see the appendix to this chapter). Preference should be given to psychotropicmedications with little ability to precipitate a pharmacokinetic interaction(see Table 1–4), especially when used in a polypharmacy situation. However,even though many psychotropic agents do not precipitate pharmacokineticinteractions, they can still be the subject of a pharmacokinetic interaction. Forexample, although ziprasidone does not affect the pharmacokinetics of otherdrugs, the AUC of ziprasidone is reduced 35% by carbamazepine.

Key Clinical Points

• Maintaining drug levels within the therapeutic range maximizesbeneficial effects and minimizes adverse effects. Drug pharma-cokinetics must be considered when developing a dosage regi-men to achieve drug levels within this therapeutic range.

• When prescribing in a polypharmacy environment, it is best toavoid medications that significantly inhibit or induce cytochromeP450 enzymes and to prefer those eliminated by multiple path-ways and with a wide safety margin.

• Over-the-counter drugs, herbal and complimentary medicines,and certain foods can all affect drug pharmacokinetics.

• For a drug administered on an acute basis, the magnitude of thetherapeutic effect is a function of peak drug levels, which aremainly determined by dose and the rate of drug absorption.


Table 1–4. Psychotropic drugs that cause few pharmacokinetic interactions

Antidepressants

SSRI/SNRI TCAs

Citalopram Amitriptyline

Desvenlafaxine Clomipramine (slight CYP 2D6 inhibition)

Escitalopram Desipramine (slight CYP 2D6 inhibition)

Sertraline (CYP 2D6 inhibition at >200 mg/day)

Doxepin

Imipramine

Venlafaxine Maprotiline

Novel action agents Nortriptyline

Amoxapine Protriptyline

Mirtazapine Trimipramine

Trazodone

Antipsychotics

All antipsychotics

Agents for drug-induced extrapyramidal symptoms

Benztropine Procyclidine

Biperiden Trihexyphenidyl

Ethopropazine

Anxiolytics/sedative-hypnotics

All benzodiazepines Zaleplon

Buspirone Zolpidem

Eszopiclone Zopiclone

Cognitive enhancers

Donepezil Memantine

Galantamine Rivastigmine

Opiate analgesics

All opiate analgesics

Psychostimulants

Amphetamine Methamphetamine

Dextroamphetamine Methylphenidate

Lisdexamfetamine

Note. CYP 2D6=cytochrome P450 3D6; SSRI/SNRI=selective serotonin reuptake inhibitor/serotonin–norepinephrine reuptake inhibitor; TCA=tricyclic antidepressant.


• For a drug administered chronically, the therapeutic effect is afunction of the extent of absorption, not the speed of absorp-tion. Rapid absorption is likely to cause transient, concentration-dependent adverse effects.

• Drug interactions involving displacement of highly protein-bound drugs are clinically significant for only a very few drugs;propafenone, verapamil, and intravenous lidocaine are possiblecandidates.

• Therapeutic drug monitoring should employ methods selectivefor free (unbound) drug.

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USP DI Editorial Board (eds): United States Pharmacopeia Dispensing InformationVolume 1: Drug Information for the Health Care Professional, 27th edition.Greenwood Village, CO, Thomson Micromedex, 2007

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Zanger UM, Raimundo S, Eichelbaum M: Cytochrome P450 2D6: overview andupdate on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs ArchPharmacol 369:23–37, 2004


Appendix: Drugs With Clinically Significant Pharmacokinetic Interactions

Cytochrome P450 isozyme

Drug 1A2 2Ca 2D6 3A4 MAO-A UGT P-gp

ACE inhibitor

Captopril X

Antianginal

Ranolazine S, X S, X

Antiarrhythmics

Amiodarone X S, X X S, X X

Disopyramide S

Flecainide S

Lidocaine S, X S X

Mexiletine X S

Propafenone X S, X S S X

Quinidine X S S, X

Anticoagulants and antiplatelet agents

R-warfarin S S S

S-warfarin S

Ticlopidine X

Anticonvulsants and mood stabilizers

Carbamazepine I I S, I S, I S

Ethosuximide S, I

Felbamate S

Lamotrigine S S

Phenytoin I S, I I I S

Tiagabine S S S

Valproate I S, X

Antidepressants

Amitriptyline S S S S S, X

Bupropion X S

Clomipramine S S S, X S

Desipramine S, X X

Desvenlafaxine S


Doxepin S

Duloxetine S S, X

Fluoxetine X X S, X S, X

Fluvoxamine S, X X X S

Gepirone S

Imipramine S S S S X

Maprotiline S X

Mirtazapine S S

Moclobemide S X X

Nefazodone S, X

Nortriptyline S S

Paroxetine S, X S, X

Phenelzine X

Sertraline X

Tranylcypromine X X

Trazodone S S I

Trimipramine S

Venlafaxine S S S

Antidiarrheal agent

Loperamide S

Antiemetic

Ondansetron S

Antihyperlipidemics

Atorvastatin S X

Fenofibrate X

Fluvastatin X S

Gemfibrozil X

Lovastatin X S S, X

Pravastatin S

Simvastatin X S X

Antihyponatremic

Conivaptan S, X X




Antimicrobials

Chloramphenicol X

Ciprofloxacin X X S

Clarithromycin X S, X X

Co-trimoxazole X

Enoxacin X S

Erythromycin X S, X S, X

Fluconazole X X

Grepafloxacin S

Griseofulvin I

Isoniazid X I X

Itraconazole S, X S, X

Ketoconazole X S, X X

Levofloxacin X

Linezolid X

Metronidazole X

Miconazole S, X S, X

Nafcillin S, I

Norfloxacin X X

Ofloxacin X X

Posaconazole X S S

Rifabutin I

Rifampin (rifampicin)

I I S, I I S, I

Roxithromycin X

Sulfaphenazole X

Sulfonamides X

Troleandomycin X S, X

Valinomycin S

Antimigraine

Eletriptan S S

Ergotamine S

Frovatriptan S




Rizatriptan S

Sumatriptan S

Zolmitriptan S S

Antineoplastic agents

Dactinomycin S, X

Dasatinib S, X

Docetaxel S S

Doxorubicin S, X

Etoposide S S

Gefitinib S

Ifosfamide S

Imatinib X S, X S

Irinotecan S S S

Lapatinib S, X S, X

Methotrexate S

Nilotinib X X S, X X S, X

Paclitaxel S S S

Procarbazine X

Sorafenib X S S, X

Sunitinib S

Tamoxifen S S S, X

Tegafur (ftorafur) S, I I

Teniposide S S

Topotecan S

Vinblastine S S, X

Vincristine S S

Vinorelbine S S

Antiparkinsonian agents

Rasagiline S

Selegiline X

Antipsychotics

Aripiprazole S S

Asenapine S S




Antipsychotics (continued)

Chlorpromazine S S X

Clozapine S S S

Haloperidol S S, X X

Iloperidone S S

Olanzapine S S S S

Perphenazine S

Pimozide S X

Quetiapine S S

Risperidone S S

Thioridazine S S S

Trifluoperazine X

Ziprasidone S

Antiretroviral agents

Amprenavir S S, I

Atazanavir X S, X X X

Darunavir S, X

Delavirdine X S, X

Efavirenz X S, X

Indinavir S, X S

Lopinavir S S

Maraviroc S S

Nelfinavir S, X S, X

Nevirapine S, I

Raltegravir S

Ritonavir I X X S, X S, X

Saquinavir S, X S, X

Tipranavir/ritonavir X S, X S, I

Zidovudine S

Anxiolytics and sedative-hypnotics

Alprazolam S

Bromazepam S

Buspirone S




Clonazepam S

Diazepam S S

Hexobarbital S

Lorazepam S

Midazolam S X

Oxazepam S

Phenobarbital I I I

Temazepam S

Triazolam S

Beta-blockers

Alprenolol S

Bisoprolol S

Bufuralol S

Labetalol S

Metoprolol S

Pindolol S

Propranolol S S S, X X

Talinolol S, X

Timolol S S

Bronchodilator

Theophylline S S

Calcium channel blockers

Amlodipine S

Diltiazem S, X S, X

Felodipine S X

Isradipine S

Nicardipine S X

Nifedipine S

Nimodipine S

Nisoldipine S

Verapamil S S S, X

Cardiac glycoside

Digoxin S




Cognitive enhancer

Tacrine S

Gastrointestinal motility modifier

Domperidone S

Gout therapy

Colchicine S, X

Probenecid X

Sulfinpyrazone X

Histamine H2 antagonists

Cimetidine X X X X S

Ranitidine X S

Immunosuppressive agents

Cyclosporine S, X S, X

Sirolimus S

Tacrolimus S S

Muscle relaxant

Cyclobenzaprine S S S

Nonsteroidal anti-inflammatory drugs and analgesic agents

Acetaminophen S

Diclofenac X X

Flurbiprofen X X

Naproxen X

Phenylbutazone S, X

Opiate analgesics

Alfentanil S

Codeine S S S

Fentanyl S X

Hydrocodone S

Meperidine S

Methadone S S X

Morphine S S

Oxycodone S

Tramadol S




Oral hypoglycemics

Chlorpropamide S

Glimepiride S

Glipizide S

Glyburide S

Pioglitazone S

Tolbutamide S, X

Proton pump inhibitors

Esomeprazole X

Lansoprazole I S S, X

Omeprazole I S, X S S, X

Pantoprazole S, X

Psychostimulants

Armodafinil I X S, I

Atomoxetine S, X

Modafinil I X S, I

Steroids

Aldosterone S

Cortisol S S

Dexamethasone I S, I

Estradiol S S

Estrogen S I

Ethinyl estradiol S, X

Hydrocortisone S, X

Prednisolone S S

Prednisone S S

Progesterone S X

Testosterone S

Triamcinolone S




Foods and herbal medicines

Caffeine S S

Cannabinoids S S, X

Cruciferous vegetablesb

I

Grapefruit juice X X

Smoking (tobacco, etc.)

I S

St. John’s wort I I

Tyramine-containing foodsc

S

Note. Pharmacokinetic drug interactions: I, inducer; S, substrate; X, inhibitor. Only significant interactions are listed.ACE=angiotensin-converting enzyme; MAO-A=monoamine oxidase type A; P-gp=P-glycoprotein efflux transporter; UGT=uridine 5′-diphosphate glucuronosyltransferase.aCombined properties on 2C8/9/10 and 2C19 cytochrome P450 isozymes.bCruciferous vegetables include cabbage, cauliflower, broccoli, brussels sprouts, kale, etc.cTyramine-containing foods include banana peel, beer (all tap, “self-brew,” and nonalcoholic), broad bean pods (not beans), fava beans, aged cheese (tyramine content increases with age), sauerkraut, sausage (fermented or dry), soy sauce and soy condiments, concentrated yeast extract (Marmite).Source. Compiled in part from Armstrong and Cozza 2002; Balayssac et al. 2005; Bezchlibnyk-Butler et al. 2007; Bristol-Myers Squibb 2009; Cozza et al. 2003; DeVane and Nemeroff 2002; Eli Lilly 2009; Gardner et al. 1996; Gillman 2005; Guedon-Moreau et al. 2003; Kiang et al. 2005; McEvoy 2008; Michalets 1998; Pal and Mitra 2006; Repchinsky 2008; USP DI Editorial Board 2007.



39

2Severe Drug Reactions

Stanley N. Caroff, M.D.

Stephan C. Mann, M.D.

E. Cabrina Campbell, M.D.

Rosalind M. Berkowitz, M.D.

This chapter diverges from others in this book by reviewing not how psy-chotropic drugs are useful in treating patients with medical illnesses, but ratherhow psychotropic drugs occasionally cause medical disorders. Although manyimportant, common side effects are associated with psychotropic drugs, thediscussion in this chapter is limited to rare, severe, acute, and potentially life-threatening drug reactions that occur at therapeutic dosages and require emer-gency medical treatment. Mirroring the book as a whole, the discussion isorganized by specific organ systems. Severe drug-induced dermatological re-actions are covered in Chapter 13, “Dermatological Disorders.”

In reading this chapter, clinicians should keep in mind that psychotropicdrugs, when indicated, are potentially beneficial for the majority of patients


and should not be withheld because of the risk of these rare reactions. Instead,the best defense against adverse reactions consists of careful monitoring of pa-tients, informed by familiarity with adverse signs and symptoms to allowprompt recognition, rapid drug discontinuation, and supportive treatment.

Central Nervous System ReactionsAlthough psychotropic drugs are selected and developed for their therapeuticeffects on specific neurotransmitter pathways in the brain, several severe andlife-threatening drug reactions have been reported stemming either from anabnormal exaggeration of the desired effect on a single neurotransmitter sys-tem (e.g., neuroleptic malignant syndrome) or from an unexpected action onsystemic or other central nervous system mechanisms that affect brain func-tion (e.g., seizures) (Table 2–1). These reactions have been associated mostlywith potent antipsychotic and antidepressant drugs.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) has been the subject of numerousclinical reports and reviews (Caroff 2003b; Strawn et al. 2007). The incidenceof NMS is about 0.02% among patients treated with antipsychotic drugs.NMS may also result from treatment with other dopamine-blocking drugs,such as the phenothiazine antiemetics (promethazine, prochlorperazine) andmetoclopramide. Risk factors include dehydration, exhaustion, agitation, cata-tonia, previous episodes, and large dosages of high-potency drugs givenparenterally at a rapid rate of titration. The effect of concurrent administrationof multiple antipsychotics and other drugs, including lithium and selective se-rotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake in-hibitors (SNRIs), in enhancing the risk of NMS has been suggested but isunproven (Stevens 2008). NMS may develop within hours but usually evolvesover days. About two-thirds of cases occur during the first 1–2 weeks after druginitiation. Classic signs are elevated temperatures (from moderate to life-threat-ening hyperthermia), generalized rigidity with tremors, altered consciousnesswith catatonia, and autonomic instability. Laboratory findings may includemuscle enzyme elevations (primarily creatine phosphokinase, median eleva-tions 800 IU/L; Meltzer et al. 1996), myoglobinuria, leukocytosis, metabolicacidosis, hypoxia, elevated serum catecholamines, and low serum iron levels.

Severe Drug R

eactions

41Table 2–1. Central nervous system reactions

Disorders Implicated drugs Risk factors Signs and symptoms Diagnostic studiesa Managementb

Neuroleptic malignant syndrome (NMS)

Dopamine antagonists (antipsychotics, antiemetics)

Dehydration, exhaustion, agitation, catatonia, prior episodes, dose and parenteral route

Hyperthermia, rigidity, mental status changes, dysautonomia

Enzyme elevations (CPK), ↑WBC, acidosis, ↓ iron, hypoxia

Specific agents? (lorazepam, dopamine agonists, dantrolene, ECT)

Parkinsonian hyperthermia syndrome

Dopamine withdrawal Parkinson’s diseaseReduced CSF HVA

Hyperthermia, rigidity, mental status changes, dysautonomia

—a Dopaminergic therapy

Neuroleptic sensitivity syndrome

Antipsychotics Lewy body dementia

Confusion, immobility, rigidity, postural instability, falls, fixed-flexion posture, poor oral uptake

—a —b

Lithium–neuroleptic encephalopathy

Antipsychotics plus lithium

Same as for NMS plus lithium toxicity

Same as for NMS plus lithium toxicity (ataxia, dysarthria, myoclonus, and seizures)

Lithium level —b

42C



Serotonin syndrome

Antidepressants (MAOIs, SNRIs, SSRIs, TCAs)

LinezolidTriptans

Overdose, polypharmacy

Behavioral (delirium, agitation, restlessness)

Neuromotor (tremor, myoclonus, hyperreflexia, ataxia, rigidity, shivering)

—a Serotonin antagonists? (cyproheptadine)

Some opiates (dextromethorphan, fentanyl, meperidine, tramadol)

Dysautonomia (tachycardia, tachypnea, hyperthermia, mydriasis, blood pressure lability)

Gastrointestinal (diarrhea, nausea, vomiting, incontinence)

Mortality in dementia-related psychosis

Antipsychotics Elderly Cerebrovascular eventsCardiovascular (heart

failure, sudden death)Infections (pneumonia)

—a —b

Table 2–1. Central nervous system reactions (continued)


Severe Drug R

eaction

s43

Seizures Antipsychotics (chlorpromazine, clozapine)

Antidepressants (bupropion, clomipramine)

Epilepsy, substance abuse, brain injury, overdose, drug interactions, dose and rate of titration

— Brain imaging, EEG

—b

Lithium toxicityWithdrawal of

anticonvulsants or benzodiazepines

Flumazenil

Note. CPK=creatine phosphokinase; CSF HVA=cerebrospinal fluid homovanillic acid; ECT=electroconvulsive therapy; EEG=electroencephalogram;MAOIs=monoamine oxidase inhibitors; SNRIs=serotonin–norepinephrine reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors;TCAs=tricyclic antidepressants; WBC=white blood cell count.aStandard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associatedwith or specific for each reaction are listed.bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medicalcare. Only specific therapies that have been reported are listed. ?= lack of evidence of safety and efficacy.

Table 2–1. Central nervous system reactions (continued)



The differential diagnosis of NMS is complex, including other disorderswith elevated temperatures and encephalopathy, such as malignant catatoniadue to psychosis, infections, benign extrapyramidal side effects, agitated de-lirium of diverse causes, heatstroke, serotonin syndrome, and withdrawalfrom dopamine agonists, sedatives, or alcohol. Although no single laboratorytest is diagnostic for NMS, a thorough laboratory assessment and neuroimag-ing are essential to exclude other serious medical conditions. Several lines ofevidence strongly implicate drug-induced dopamine blockade as the primarytriggering mechanism in the pathogenesis of NMS.

Once dopamine-blocking drugs are withheld, two-thirds of NMS casesresolve within 1–2 weeks, with an average duration of 7–10 days (Caroff2003b). Patients may experience prolonged symptoms if injectable long-act-ing drugs are implicated. Occasional patients develop a residual catatonic andparkinsonian state that can last for weeks unless electroconvulsive therapy(ECT) is administered (Caroff et al. 2000). NMS is still potentially fatal insome cases due to renal failure, cardiorespiratory arrest, disseminated intra-vascular coagulation, pulmonary emboli, or aspiration pneumonia.

Treatment consists of early diagnosis, discontinuing dopamine antago-nists, and supportive medical care. Benzodiazepines, dopamine agonists, dan-trolene, and ECT have been advocated in clinical reports, but randomized,controlled trials comparing these agents with supportive care have not beendone and may not be feasible because NMS is rare, often self-limited afterdrug discontinuation, and heterogeneous in presentation, course, and out-come. We have proposed that these agents may be considered empirically inindividual cases, based on symptoms, severity, and duration of the episode(see Strawn et al. 2007 for details).

For additional information about the diagnosis and management ofNMS, the Neuroleptic Malignant Syndrome Information Service offers ac-cess to volunteer consultants at a toll-free hotline (888-667-8367) and pro-vides educational material and E-mail access through their Web site (http://www.nmsis.org).

Neuroleptic Sensitivity Syndromes in Parkinson’s Disease and Lewy Body Dementia

In view of the underlying nigrostriatal dopamine deficiency in Parkinson’sdisease and Lewy body dementia, patients with these disorders are at risk for

http://www.nmsis.org

http://www.nmsis.org

Severe Drug Reactions 45

severe exacerbations of extrapyramidal motor symptoms as well as NMS. InParkinson’s disease, there are few reports of NMS attributable to antipsychot-ics alone without concomitant withdrawal of dopamine agonist therapy oraddition of cholinesterase inhibitors. However, following withdrawal ofdopaminergic drugs alone or during “off” episodes, patients with Parkinson’sdisease may develop a parkinsonian-hyperthermia syndrome that is indistin-guishable from NMS (Harada et al. 2003). Reports suggest an incidence of2%–3%, including several deaths. Ueda et al. (2001) showed that Parkinson’sdisease patients with reductions in cerebrospinal fluid homovanillic acid con-centrations are more likely to develop the syndrome after drug withdrawal.

The neuroleptic sensitivity syndrome is considered a supporting criterionin the diagnosis of Lewy body dementia (McKeith et al. 1992). McKeith et al.(1992) reported that 4 (29%) of 14 patients receiving antipsychotics showedmild extrapyramidal symptoms, but 8 (57%) showed severe symptoms withhalf the survival of untreated patients. Neuroleptic sensitivity is defined as se-dation followed by rigidity, postural instability, and falls. Rapid deteriorationwith increased confusion, immobility, rigidity, fixed-flexion posture, and de-creased food and fluid intake was not reversed by anticholinergic medications.Death resulted usually from complications of immobility and/or reduced foodand fluid intake. If antipsychotics must be used for patients with Parkinson’sdisease or Lewy body dementia, clozapine or quetiapine should be selecteddue to reduced risk, and patients should be carefully monitored for worseningmotor symptoms and mental status changes (Weintraub and Hurtig 2007)(see also Chapter 9, “Central Nervous System Disorders”).

Lithium–Neuroleptic Encephalopathy

In 1974, a severe encephalopathic syndrome was reported in four patientstreated with lithium and haloperidol, suggesting synergistic toxic effects (Co-hen and Cohen 1974). Subsequently, Miller and Menninger (1987) reportedneurotoxicity consisting of delirium, extrapyramidal symptoms, and ataxia in8 (19.5%) of 41 patients receiving concurrent treatment with lithium andantipsychotics. Similar cases, most often associated with haloperidol, havecontinued to be reported (Caroff 2003a).

The manifestations of neurotoxicity in these cases include stupor, delir-ium, catatonia, rigidity, ataxia, dysarthria, myoclonus, seizures, and fever.Spring and Frankel (1981) proposed two types of combined lithium–antipsy-


chotic drug toxicity: an NMS-like reaction associated with haloperidol andother high-potency antipsychotics, and a separate reaction associated withphenothiazines, especially thioridazine, resulting in lithium toxicity. Gold-man (1996) reviewed 237 cases of neurotoxicity ascribed to lithium with orwithout antipsychotics and found support for Spring and Frankel’s bipartiteconcept. However, the heterogeneity of cases led Goldman to suggest that ad-verse reactions to combination therapy form a continuum ranging from pre-dominantly antipsychotic-induced to largely lithium-induced reactions. Themechanism for possible toxic synergy remains unknown.

Lithium–neuroleptic encephalopathy is extremely rare, and concernabout this effect should not outweigh the potential benefit and tolerance ofthis drug combination in the vast majority of patients presenting with maniaand psychosis. Rather, the clinician is obligated to carefully monitor the re-sponse to treatment, including lithium levels, and to promptly recognize thisreaction in order to rapidly discontinue medications and institute supportivemedical care.

Serotonin Syndrome

The serotonin syndrome generally results when two or more serotonergicdrugs are taken concurrently but also occurs following overdose and duringsingle drug exposure. Nearly all serotonergic drugs have been implicated.Agents associated with severe or fatal cases include combinations of monoam-ine oxidase inhibitors (MAOIs) and other antidepressants or certain opioidsthat potentiate serotonergic activity (meperidine, tramadol, dextromethor-phan, fentanyl), as well as abuse of “ecstasy” (Boyer and Shannon 2005).Morphine has not been implicated in this interaction and is a reasonablechoice for pain control in the context of concurrent serotonergic treatment,provided an allowance is made for possible potentiation of its depressive nar-cotic effect (Browne and Linter 1987). Some nonpsychiatric drugs that in-crease serotonergic activity, including triptans and linezolid, also have beenimplicated in serotonin syndrome. The incidence among patients on selectiveserotonin reuptake inhibitor (SSRI) monotherapy has been estimated in therange of 0.5–0.9 cases per 1,000 patient-months of treatment (Mackay et al.1999), but increases to 14%–16% in persons who overdose on SSRIs (Boyerand Shannon 2005). The onset of symptoms is usually abrupt, and clinicalmanifestations range from mild to fatal.


Sternbach (1991) developed diagnostic criteria based on a triad of cogni-tive-behavioral, neuromuscular, and autonomic abnormalities. Serotoninsyndrome presents with alterations in consciousness and mood, restlessness,and agitation. Gastrointestinal symptoms include diarrhea, incontinence,nausea, and vomiting. Autonomic disturbances include tachycardia, labileblood pressure, diaphoresis, shivering, tachypnea, mydriasis, sialorrhea, andhyperthermia. Neurological signs include tremor, myoclonus, ankle clonus,hyperreflexia, ataxia, incoordination, and muscular rigidity. The differentialincludes NMS, anticholinergic toxicity, heat stroke, the carcinoid syndrome,infection, drug or alcohol withdrawal, lithium toxicity, and SSRI withdrawal.

Management entails cessation of serotonergic medications and supportivecare. Based on anecdotal clinical reports, moderate cases appear to benefitfrom administration of 5-HT2A antagonists such as cyproheptadine (Grau-dins et al. 1998).

Cerebrovascular Events and Mortality Associated With Antipsychotics in Elderly Patients With Dementia-Related Psychosis

In 2003, the U.S. Food and Drug Administration (FDA) issued an advisorythat the incidence of cerebrovascular adverse events, including fatalities, wassignificantly higher in elderly patients with dementia-related psychosistreated with atypical antipsychotics. Collectively, 11 risperidone and olanza-pine trials indicated that 2.2% of drug-treated subjects experienced cere-brovascular adverse events compared with 0.8% taking placebo (Jeste et al.2008). In 2005, the FDA analyzed 17 placebo-controlled trials and followedwith a black-box warning of increased mortality (relative risk of 1.6–1.7 vs.placebo), due primarily to cardiovascular (heart failure, sudden death) orinfectious (pneumonia) causes, associated with atypical antipsychotics inelderly patients with dementia-related psychosis (U.S. Food and Drug Ad-ministration 2005).

Although these data implicated newer drugs, higher or equivalent mortal-ity with typical as compared with atypical antipsychotics among older adultswas reported in retrospective analyses of large health system databases (Kaleset al. 2007; Schneeweiss et al. 2007; Wang et al. 2005). In a community sam-ple, Rochon et al. (2008) reported that compared with controls, older adultswho received atypical antipsychotics were 3 times more likely and those who


received typical antipsychotics were almost 4 times more likely to experiencea serious adverse advent within 30 days of starting therapy.

The use of antipsychotic drugs to treat psychosis, aggression, and agitationin elderly patients with dementia is a standard off-label practice. Data fromrandomized, controlled trials are inconclusive on the risk–benefit ratio ofthese drugs in elderly patients (Schneider et al. 2006; Sink et al. 2005; Sultzeret al. 2008). However, given the lack of evidence to support the efficacy andsafety of other agents or psychosocial treatments, the use of antipsychotics af-ter informed discussion with patients and caregivers, and with careful clinicalmonitoring, is reasonable (Jeste et al. 2008).

Several mechanisms may be suggested for antipsychotic-associated cere-brovascular adverse events and death, including cardiac conduction disturbances,sedation leading to venous stasis or aspiration pneumonia, metabolic distur-bances, orthostatic hypotension, tachycardia, and increased platelet aggregation.

Seizures

The risk of drug-induced seizures is difficult to estimate due to predisposingfactors, such as epilepsy, drug interactions, or substance abuse, which are in-frequently cited in clinical trials (Alper et al. 2007; Montgomery 2005; Stim-mel and Dopheide 1996). Thus, if a seizure occurs in a given patient, athorough history and neurological investigation are necessary to identify un-derlying risk factors. Patients with epilepsy are at risk of drug-induced seizures;however, psychotropic drugs are not contraindicated but require more carefulmonitoring of anticonvulsant therapy, and have been shown to improve sei-zure control once psychiatric symptoms are controlled (Alper et al. 2007;Stimmel and Dopheide 1996). As a rule, seizures correlate with drug dosageand rate of titration, and are more likely to be observed after overdosage.

Clozapine is associated with the highest rate of seizures among antipsy-chotics, followed by chlorpromazine (Stimmel and Dopheide 1996; Wongand Delva 2007). Olanzapine and quetiapine may have proconvulsant effectscompared with other atypical drugs (Alper et al. 2007). Because clozapine ismost often indicated and most effective for patients with treatment-refractoryschizophrenia, lowering the dosage or adding valproic acid may be worth-while prior to switching to a different antipsychotic if a seizure occurs.

Among antidepressants, tricyclic drugs at therapeutic dosages were asso-ciated with an incidence of seizures of about 0.4%–2% and are particularly


hazardous in overdose (Montgomery 2005). Clomipramine is consideredmost likely to be associated with seizures. MAOIs are considered to have lowrisk for seizures. Bupropion has a 10-fold increase in seizure risk in dosagesover 600 mg/day and is relatively contraindicated in patients with epilepsy orsevere eating disorders, or at least requires careful documentation and moni-toring in these patients (Alper et al. 2007). Venlafaxine is not associated withseizures at therapeutic dosages. The SSRIs have a low risk of seizures, even inoverdose, and have been associated with reduction in seizure frequency com-pared with placebo (Alper et al. 2007). However, some SSRIs can increaseplasma levels of other drugs, with potential for increasing seizure activity.

Among mood stabilizers, lithium is associated with seizures only duringintoxication. Carbamazepine has been associated with seizures after overdoseand can increase the risk of seizures during withdrawal; as a rule, the risk ofwithdrawal seizures can be minimized by not abruptly stopping carbamaz-epine, valproic acid, or any anticonvulsant, and by slowly tapering the drugover a 2-week period (Stimmel and Dopheide 1996). Short- and intermedi-ate-acting benzodiazepines, especially alprazolam, have been associated withwithdrawal seizures. Finally, seizure induction is a serious complication of thebenzodiazepine receptor antagonist flumazenil, with fatal cases of status epi-lepticus having been reported.

Cardiovascular ReactionsSevere adverse cardiovascular reactions in association with sudden death are of-ten the most unexpected and catastrophic reactions to psychotropic drugs(Table 2–2). Cardiac reactions are observed primarily with antipsychoticdrugs, especially clozapine, and with tricyclic antidepressants, whereas hyper-tensive crises are associated with nonselective and irreversible monoamine oxi-dase inhibitors.

Ventricular Arrhythmias and Sudden Cardiac Death

Reports of sudden death in patients receiving antipsychotic drugs emerged soonafter the drugs’ introduction. Several studies have confirmed a twofold to fivefoldincreased risk of sudden cardiac death in patients receiving antipsychotics (Hen-nessy et al. 2002; Liperoti et al. 2005; Mehtonen et al. 1991; Modai et al. 2000;Ray et al. 2001; Reilly et al. 2002; Straus et al. 2004). The risk is dosage related

50C



Table 2–2. Cardiovascular reactions


Ventricular arrhythmias and sudden death

QTc prolongation and torsade de pointes

Antipsychotics (chlorpromazine, clozapine, droperidol, haloperidol, mesoridazine, pimozide, sulpiride, thioridazine, ziprasidone)

Long QT syndrome; cardiac, renal, or hepatic disease; family history; syncope; drug history; electrolytes; drug interactions; abnormal ECG; QTc>500 msec

Palpitations, syncope, chest pain

ECGs in at-risk patients

—b

Brugada syndrome AntipsychoticsAntidepressants

Genetic predisposition, overdose, drug combinations

ECG (RBBB, ST elevations)

ECGs in at-risk patients

—b

Heart block Antidepressants (TCAs)

Intraventricular conduction defects

Heart block ECGs in at-risk patients

—b

Severe Drug R

eactions

51

Hypertensive crisis MAOIs Tyramine-containing food

Sympathomimetic drugs

Hypertension, stiff neck, nausea, palpitations, diaphoresis, confusion, seizures, arrhythmias, headache, stroke

Blood pressure monitoring

Phentolamine iv, nifedipine for headache

Myocarditis, cardiomyopathy, and pericarditis

Antipsychotics (clozapine)

Cardiovascular and pulmonary disease

Fever, dyspnea, flulike symptoms, chest pain, fatigue

Echocardiography (reduced ejection fraction, ventricular dysfunction), ECG (T wave changes), leukocytosis, eosinophilia, cardiac enzyme elevations

—b

Note. ECG=electrocardiogram; iv= intravenous; MAOIs=monoamine oxidase inhibitors; RBBB=right bundle branch block; TCAs=tricyclic antide-pressants.aStandard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associatedwith or specific for each reaction are listed.bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medicalcare. Only specific therapies that have been reported are listed.

Table 2–2. Cardiovascular reactions (continued)



and heightened by preexisting cardiovascular disease and use of some first-generation drugs. Implicated drugs include thioridazine, mesoridazine, pimo-zide, sertindole, sulpiride, clozapine, and low-potency phenothiazines, whereasother atypical drugs appear to have reduced risk. Butyrophenones, includinghaloperidol and droperidol used parenterally, have also been implicated.

The reasons for increased risk of arrhythmias and sudden death have beenattributed to specific drug effects on cardiac conduction (Glassman and Big-ger 2001; Sicouri and Antzelevitch 2008). QTc prolongation predicts risk oftorsade de pointes, ventricular fibrillation, syncope, and death. AlthoughQTc is the best available predictor, it is imperfect; the threshold for increasedrisk is usually set at 500 msec, but other risk factors (see below) may deter-mine occurrence of torsade (De Ponti et al. 2001; Glassman and Bigger2001). Among psychotropic drugs, the antipsychotic drugs, particularly thio-ridazine, have the highest potential for QTc prolongation and resultingarrhythmias. Although ziprasidone has not been associated with torsade, thisdrug does prolong the QTc interval and is considered contraindicated inpatients with a history of QTc prolongation, recent myocardial infarction, oruncompensated heart failure.

A second mechanism for sudden death may be the Brugada syndrome,which is characterized by right bundle branch block and ST elevation in rightprecordial leads, but relatively normal QTc intervals. This syndrome has beenassociated with genetic predisposition, as well as with the use of antipsychoticand antidepressant drugs, mostly in the context of overdose or use of drugcombinations.

Early concerns over cardiac effects of tricyclic antidepressants derived pri-marily from the occurrence of heart block and arrhythmias observed afterdrug overdoses. However, subsequent studies suggested that risk of conduc-tion disturbances also existed when therapeutic dosages were used (Roose etal. 1989). QTc prolongation and torsade have been reported with tricyclics,but far less often than with antipsychotics (Sala et al. 2006). QTc prolonga-tion with tricyclics is due primarily to prolonged QRS conduction, whichalong with increased PR intervals reflects delays in the intraventricular His-Purkinje conduction system involved in depolarization. Tricyclics proved tobe effective Type 1A quinidine-like antiarrhythmics, capable of suppressingventricular ectopy. Although in patients with healthy hearts, tricyclic-inducedsuppression of conduction at therapeutic dosages is of no consequence, there


is a 10-fold risk of significant atrioventricular block in patients with preexist-ing intraventricular conduction defects (Roose et al. 1989). Newer antide-pressants have less risk of arrhythmias and sudden death (Feinstein et al.2002; Sala et al. 2006); however, there have been isolated reports of torsadefollowing SSRI overdose (Lherm et al. 2000; Tarabar et al. 2008).

Patients who are considered for antipsychotic and antidepressant treat-ment should be screened for heart disease, congenital long QT or Brugada syn-drome, family history of sudden death, syncope, prior drug history of adversecardiac effects, electrolyte imbalance (especially hypokalemia, hypocalcemia,or hypomagnesemia), and renal or hepatic disease. The list of drugs implicatedin QTc prolongation and torsade when used concurrently can be divided intothe following: drugs that prolong QTc, including antiarrhythmics (quinidine,procainamide, sotalol, amiodarone), antihistamines (diphenhydramine), anti-biotics/antivirals (erythromycin, clarithromycin, amantadine), and others(cisapride, methadone); drugs that interfere with metabolism of agents associ-ated with torsade, including antifungals (ketoconazole), antivirals (indinavir,ritonavir), calcium antagonists (diltiazem, verapamil), antibiotics (erythromy-cin, clarithromycin), and grapefruit juice; and drugs that may affect electro-lytes or other risk factors (diuretics) (Kao and Furbee 2005). An electrocardio-gram (ECG) should be obtained at baseline and after drug administration inpatients with any of these risk factors. Conservative dosages of psychotropicdrugs should be prescribed and polypharmacy should be minimized, withclose clinical monitoring and warnings for patients to report promptly anynew symptoms, such as palpitations or near-syncope, as well as the prescrip-tion of new medications. Cessation and change of medication should be con-sidered if the ECG shows significant prolongation of the QTc, a QTcintervalgreater than 500 msec, new T wave abnormalities, marked bradycar-dia, or a Brugada phenotype.

Hypertensive Crisis Due to Monoamine Oxidase Inhibitors

Irreversible MAOIs may produce a potentially fatal hypertensive crisis. Symp-toms include throbbing headaches with marked blood pressure elevations,nausea, neck stiffness, palpitations, diaphoresis, and confusion, sometimescomplicated by seizures, cardiac arrhythmias, intracerebral hemorrhage, anddeath. Episodes follow ingestion of sympathomimetic drugs or foods contain-ing high concentrations of tyramine (Rapaport 2007). Prior to recognition of


the need for dietary restrictions, rates of hypertensive reactions were estimatedto range from 2.4% to 25% (Krishnan 2007). Previous MAOI diets wereprobably overly conservative, but more recent dietary restrictions are lessdaunting (Gardner et al. 1996).

Monoamine oxidase (MAO) is the principal enzyme responsible for theoxidative deamination of monoamines. There are two subtypes of MAO isoen-zymes: MAO-A and MAO-B. MAO-A occurs primarily in the brain, where itsprimary substrates are epinephrine, norepinephrine, dopamine, and serotonin,and in the intestine and liver, where it plays a critical role in the catabolism ofdietary tyramine. Inhibition of MAO-A by MAOIs permits uptake of tyramineinto the systemic circulation, triggering a significant release of norepinephrinefrom sympathetic nerve terminals with resultant hypertensive crisis.

All sympathomimetic drugs may cause a hypertensive crisis in MAOI-treated patients. Intravenous phentolamine is the preferred treatment to re-verse the acute rise in blood pressure in hypertensive crisis. Patients are oftenprovided with nifedipine to take in case they have a hypertensive headache.

Several selective and reversible inhibitors of MAO-A that do not requiredietary restrictions have been developed but are not currently marketed in theUnited States. Selegiline, a selective but irreversible inhibitor of MAO-B atdosages used to increase dopaminergic activity in Parkinson’s disease, becomesan inhibitor of both MAO-A and MAO-B at dosages needed to treat depres-sion. A transdermal delivery system has become available that allows selegilineto be directly absorbed into the systemic circulation, bypassing the gas-trointestinal tract and avoiding the need for dietary restrictions (see Chapter3, “Alternate Routes of Drug Administration”). However, dietary restrictionsare still required at higher dosages. Rasagiline is similar and still contains thetyramine warning.

Myocarditis, Cardiomyopathy, and Pericarditis

Disorders of the myocardium and pericardium are associated primarily withclozapine (Haas et al. 2007; Merrill et al. 2005). The risk of myocarditis fromclozapine ranges from 0.015% to 1.2%, with a mortality rate of 10%–51%.The median age of affected patients has been 30–36 years. Myocarditis occursat therapeutic dosages, and the median time of onset is less than 3 weeks afterinitiation of treatment. Symptoms can be diverse and nonspecific, such as fe-ver, dyspnea, flulike illness, chest discomfort, and fatigue. Laboratory studies


may reveal ventricular dysfunction and reduced ejection fraction on echocar-diography; ECG abnormalities, particularly T wave changes; leukocytosisand eosinophilia; and elevations in cardiac enzymes. Symptoms may improvefollowing discontinuation of clozapine, but several recurrences on rechallengehave been reported. The exact pathophysiology has yet to be determined butis thought to reflect an acute hypersensitivity reaction to the drug.

Dilated or congestive cardiomyopathy, characterized by ventricular dilata-tion, contractile dysfunction, and congestive heart failure, has also been asso-ciated with clozapine (Merrill et al. 2005). As with myocarditis, the medianage of patients with clozapine-related cardiomyopathy is in the 30s, and dos-ages are within the therapeutic range. However, the duration of treatment withclozapine before cardiomyopathy onset ranges from weeks to years, with a me-dian duration of 9 months. Improvement after clozapine discontinuation hasbeen described. Cardiomyopathy could represent a direct cardiotoxic effect ofclozapine, but more likely evolves from clozapine-induced myocarditis.

Pericarditis and polyserositis (involving the pleura as well) have also beendescribed in association with clozapine (Merrill et al. 2005; Wehmeier et al.2005). These inflammations occur within the first few weeks after drug initi-ation and appear to resolve after drug discontinuation.

Clozapine should be used cautiously in patients with cardiovascular andpulmonary disease. Patients and families should be informed of symptomsand questioned for any signs of cardiac dysfunction. A baseline ECG shouldbe obtained prior to starting clozapine and repeated 2–4 weeks afterward.The value of repeat ECGs, echocardiography, magnetic resonance imaging,serum cardiac enzymes, and eosinophilia has not been substantiated butshould be considered together with cardiology consultation if new symptomsof cardiovascular disease develop. If myocarditis, pericarditis, or cardiomyop-athy is suspected, clozapine should be discontinued immediately and shouldnot be reinstituted if the diagnosis is confirmed.

Gastrointestinal Reactions

While mild gastrointestinal upset is not uncommon as a side effect associatedwith several psychotropic drug classes (e.g., SSRIs, lithium), severe hepaticand pancreatic toxicity is rarely reported but is most often described followingadministration of anticonvulsant drugs, particularly valproic acid (Table 2–3).

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Table 2–3. Gastrointestinal reactions


Hepatotoxicity Anticonvulsants (carbamazepine, lamotrigine, topiramate, valproic acid)

Antipsychotics (phenothiazines)

Children, multiple anticonvulsants

Lethargy, jaundice, nausea, vomiting, anorexia, hemorrhages, seizures, fever, facial edema

Transaminitis, hyperbilirubinemia

L-Carnitine for valproate toxicity?

Hyperammonemic encephalopathy

Valproic acid — Decreased consciousness, focal deficits, impaired cognition, lethargy, vomiting, seizures

Serum ammonia, EEG L-Carnitine for valproate toxicity?

Acute pancreatitis Valproic acid Children, multiple anticonvulsants

Abdominal pain, nausea, vomiting, anorexia, fever

Serum amylase, lipase —b

Note. EEG=electroencephalogram.aStandard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associatedwith or specific for each reaction are listed.bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medicalcare. Only specific therapies that have been reported are listed. ?= lack of evidence of safety and efficacy.


Hepatotoxicity

Transient elevations in transaminases are common with drugs metabolized bythe liver. Severe hepatotoxicity is much less common but has been reportedwith older phenothiazines, nefazodone, and anticonvulsant drugs, includingcarbamazepine, lamotrigine, topiramate, and valproic acid (Dreifuss et al.1987; Fayad et al. 2000; Konig et al. 1999; Lheureux et al. 2005; Morales-Diaz et al. 1999). Drug-induced liver failure associated with anticonvulsantsis more common in children and in patients taking multiple agents.

Valproic acid, the drug that has been most often implicated in drug-induced hepatotoxicity, occurs in two forms. Reversible elevations in transami-nases without clinical symptoms occur in up to 44% of patients (Dreifuss et al.1987). Less commonly, irreversible, idiosyncratic, and potentially fatal hepaticfailure occurs. The onset is usually within 6 months of treatment initiation. Theincidence has been estimated to be 1 per 5,000 to 1 per 50,000 patients, butmay increase in high-risk groups, including children under age 2 years, thosewith concomitant neurological or metabolic illness, and those taking multipleanticonvulsant drugs (Dreifuss et al. 1987; Lheureux et al. 2005). Among re-ported cases in adults, patients’ ages ranged from 17 to 62 years, duration oftreatment ranged from 7 weeks to 6 years, and most patients had concomitantillnesses and received more than one anticonvulsant (Konig et al. 1999).

Symptoms of hepatotoxicity include lethargy, jaundice, nausea, vomiting,hemorrhages, worsening seizures, anorexia, fever, and facial edema. Liverfunction test results are variable; transaminases and bilirubin vary from mildto extreme elevations and are not reliable predictors of progression to fatalhepatotoxicity. Regular clinical monitoring for prodromal symptoms is essen-tial, followed by withholding of the suspected drug if symptoms emerge orenzyme elevations are found. The mechanisms of hepatotoxicity are incom-pletely understood, but it may result either from direct drug toxicity or froma hypersensitivity reaction. Evidence suggests that valproic acid–induced lipidperoxidation, glutathione depletion, and accumulation of toxic metabolitescontribute to hepatic damage. Valproic acid also decreases levels and stores ofcarnitine, an amino acid derivative involved in mitochondrial metabolism,resulting in accumulation of toxic metabolites of the drug and ammonia(Lheureux et al. 2005). Recent evidence suggests that supplementation withL-carnitine may improve survival.


Hyperammonemic Encephalopathy

Although hyperammonemia occurs in nearly 50% of patients receiving val-proic acid, it remains asymptomatic in most cases (Lheureux et al. 2005).Rare patients develop hyperammonemic encephalopathy, characterized bydecreased consciousness, focal neurological deficits, cognitive slowing, vom-iting, lethargy, and increased seizure frequency (Segura-Bruna et al. 2006).These symptoms should prompt screening for blood ammonia levels, whichcan be elevated despite normal liver functions. Signs of severe encephalopa-thy, which are evident on an electroencephalogram, can be reversed once val-proic acid is discontinued. Carnitine supplementation has shown promise inreducing ammonia levels and associated symptoms.

Acute Pancreatitis

Acute pancreatitis has been reported as an idiosyncratic reaction to therapeu-tic dosages of valproic acid in 1 per 40,000 treated patients (Gerstner et al.2007). Pancreatitis is most common in children, especially when treated withmultiple anticonvulsants. Onset is variable, ranging from drug initiation toseveral years of treatment. Diagnosis is based clinically on abdominal pain,nausea, vomiting, anorexia, and fever, and is associated with elevations inamylase and lipase. Mortality may reach 15%–20%. Treatment is supportiveafter discontinuation of valproic acid. The mechanisms are unknown.

Renal Reactions

Severe renal toxicity, including renal insufficiency and nephrogenic diabetesinsipidus, has been associated primarily with lithium administration (Table2–4). However, the syndrome of inappropriate antidiuretic hormone secre-tion (SIADH) leading to hyponatremia has been associated with several drugclasses. These disorders necessitate careful clinical and laboratory monitoringto prevent irreversible kidney damage.

Chronic Renal Insufficiency

Lithium has been implicated in several disorders of kidney function, includ-ing renal tubular acidosis, interstitial nephritis, proteinuria with nephroticsyndrome, acute renal failure after intoxication, nephrogenic diabetes insipi-


dus, and chronic renal insufficiency progressing to end-stage renal disease(Boton et al. 1987; Raedler and Wiedemann 2007). Histopathological stud-ies reveal that about 10%–20% of patients receiving long-term lithium ther-apy demonstrate changes including tubular atrophy, interstitial fibrosis, cysts,and glomerular sclerosis.

Recent studies have confirmed an association between long-term lithiumtreatment and progressive renal insufficiency (Raedler and Wiedemann 2007).Studies have shown that about 15%–20% of patients show evidence of re-duced renal function after 10 years of taking lithium. Abnormalities may de-velop as early as 1 year after beginning treatment. Kidney dysfunction is relatedto duration of lithium treatment and is progressive, even after lithium is dis-continued in some cases. The rate of progression is variable; although manypatients show a decreased filtration rate, few develop renal insufficiency, andfrank renal failure is rare. In a study among dialysis patients, 0.22% had lith-ium-induced nephropathy (Presne et al. 2003). No reliable risk factors predictrenal failure, but decreased renal function has been associated with duration oftreatment, age, concomitant medications (e.g., nonsteroidal anti-inflamma-tory drugs, especially indomethacin), and episodes of lithium toxicity.

Management focuses on prevention by screening patients for underlyingkidney disease, discussing risks and benefits of treatment, using lowest effec-tive dosages, avoiding lithium intoxication, careful monitoring of lithium lev-els, measurement of serum creatinine and creatinine clearance every 6 monthsor as indicated by the patient’s condition, and reassessing risks of lithium ifrenal function declines.

Nephrogenic Diabetes Insipidus

In early studies, impairment in urine concentration with resulting polyuria,which was observed in 20%–30% of patients receiving lithium, was consid-ered benign (Khanna 2006). However, lithium is the most common cause ofnephrogenic diabetes insipidus (NDI). NDI is defined as the inability of thekidneys to concentrate urine, resulting in excessive volumes of dilute urine dueto the insensitivity of the distal nephron to the antidiuretic hormone vaso-pressin. Although mild cases can be compensated by increased fluid intake, se-vere cases can result in dehydration, neurological symptoms, encephalopathy,and lithium intoxication. NDI can be congenital or acquired from drugs in-cluding pimozide and alcohol apart from lithium. The diagnosis of NDI can

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Table 2–4. Renal reactions


Chronic renal insufficiency

Lithium Elderly, duration of treatment, concomitant drugs (NSAIDs), lithium toxicity

— Creatinine, creatinine clearance (at least every 6 months)

—b

Nephrogenic diabetes insipidus

AlcoholLithiumPimozide

— Volume depletion Water deprivationSerum vasopressinResponse to

exogenous vasopressin

Monitor urinary output

Specific agents? (amiloride, NSAIDs, thiazides)

Hyponatremia (SIADH)

Acute Antidepressants (SSRIs or SNRIs, TCAs)

AntipsychoticsOpiates

— Nausea, vomiting, anorexia, dysgeusia, disorientation, confusion, fatigue, headaches, weakness, irritability, lethargy, muscle cramps, → delirium, hallucinations, diminished consciousness, seizures, coma, respiratory arrest

Hyponatremia, elevated urine/reduced plasma osmolality

Hyponatremic encephalopathy, hypertonic fluidsc

Specific agents? (conivaptan, demeclocycline)

Severe Drug R

eactions

61

Chronic Antidepressants (SSRIs or SNRIs, TCAs)

AntipsychoticsOpiates

— Impaired cognition, falls, mood change

—a Fluid restrictionc

Specific agents? (clozapine, conivaptan, demeclocycline, tolvaptan)

Note. NSAID=nonsteroidal anti-inflammatory drug; SIADH=syndrome of inappropriate antidiuretic hormone secretion; SNRIs=serotonin–norepi-nephrine reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants.aStandard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associatedwith or specific for each reaction are listed.bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medicalcare. Only specific therapies that have been reported are listed. ?= lack of evidence of safety and efficacy.cRisk of central or extrapontine myelinolysis (mood changes, lethargy, mutism, dysarthria, pseudobulbar palsy, and quadriplegia) if serum sodium cor-rected at >12 mMol/L over 24-hour period.

Table 2–4. Renal reactions (continued)



be confirmed and distinguished from primary psychogenic polydipsia bycomparing urine and plasma osmolality during a water deprivation or dehy-dration test (Garofeanu et al. 2005; Khanna 2006); in primary polydipsia, pa-tients will show concentration of urine (osmolality >500 mOsmol/kg, withplasma osmolality >295 mOsmol/kg) after water deprivation, whereas pa-tients with NDI will continue to show a dilute urine (<300 mOsmol/kg). Todistinguish NDI from central diabetes insipidus (CDI), plasma vasopressin ismeasured after dehydration. In NDI, plasma vasopressin exceeds 5 ng/L,whereas in CDI, vasopressin will be reduced or negligible. After exogenous va-sopressin, patients with CDI will have increased urine osmolality, whereas pa-tients with NDI will experience little or no change (Khanna 2006).

The mechanism of lithium-induced NDI has been attributed to the ef-fects of lithium on aquaporin-2, probably through interference in the adeny-late cyclase system (Khanna 2006). Aquaporin-2 is the primary target forvasopressin regulation of collecting duct water permeability. Downregulationof aquaporin-2 expression is only partially reversed after lithium discontinu-ation, which is consistent with findings suggesting that NDI can become ir-reversible even after lithium discontinuation depending on the duration oftreatment. Although impaired concentration is usually reversible within 1–2years of treatment, concentrating capacity may not improve at all after 10–20years of lithium treatment (Garofeanu et al. 2005).

Management of NDI consists of regular monitoring of urinary symptomsand output, with testing as necessary, followed by discontinuation of lithium.NDI has also been treated with thiazide diuretics, amiloride, and nonsteroidalanti-inflammatory drugs, although close monitoring of lithium levels, whichcan be raised by these agents, is required.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

The converse of diabetes insipidus is the retention of water resulting in hypo-natremia. Hyponatremia may occur in 5%–15% of chronic psychiatric pa-tients (Siegel 2008). Severity of symptoms is related to the rate of onset as wellas the absolute serum sodium. In acute-onset hyponatremia, patients mayfirst develop nausea, vomiting, anorexia, dysgeusia, disorientation, headache,fatigue, weakness, irritability, lethargy, confusion, and muscle cramps, withprogression to hypotonic encephalopathy characterized by impaired respon-


siveness, delirium, and hallucinations. If not corrected, the resulting cerebraledema may result in seizures, coma, and death from cerebral herniation, brainstem compression, and respiratory arrest (Ellison and Berl 2007; Siegel2008). Patients with slow-onset or chronic hyponatremia may be asymptom-atic or present with impaired cognition, frequent falls, anxiety, and depres-sion, after an adaptive response to hypotonicity restores brain volume.

The syndrome of inappropriate antidiuretic hormone (vasopressin) secre-tion (SIADH) is the most frequent cause of hyponatremia (Ellison and Berl2007). SIADH is diagnosed in patients with normal renal, thyroid, and adre-nal function who develop hyponatremia with reduced osmolality, renal excre-tion of sodium, absence of volume depletion or overload, and elevated urineosmolality, despite plasma hypotonicity. Phenothiazines, tricyclics, anticon-vulsants (carbamazepine), atypical antipsychotics (except perhaps clozapine,which has shown positive results correcting idiopathic hyponatremia inschizophrenia patients; Canuso and Goldman 1999), opiates, and SSRIs andSNRIs have been implicated in causing SIADH due to stimulating release ofor enhancing renal sensitivity to vasopressin. The incidence of hyponatremiawith SSRIs has been reported in 0.5%–32% of patients, with elderly patientsat highest risk (Siegel 2008). SIADH associated with psychotropic drugs usu-ally has a slow onset and reverses within 24–48 hours after the drugs are dis-continued. However, if asymptomatic and undetected, sodium levels candecrease to dangerous levels, resulting in acute encephalopathy.

Treatment depends on the severity of hyponatremia, neuropsychiatricsymptoms, and duration. Definitive treatment consists of discontinuing thecausative drug. Acute, life-threatening hyponatremic encephalopathy is amedical emergency, dictating the need for treatment with hypertonic solu-tions to reverse cerebral edema. Management of patients with chronic hypo-natremia, uncertain onset, or absence of symptoms is less clear. With a lowerrisk of neurological sequelae of hyponatremia, patients with longer durationsof hyponatremia are paradoxically at higher risk for osmotic demyelination ifthe serum sodium is corrected by more than 12 mMol/L over a 24-hour pe-riod (Ellison and Berl 2007). Osmotic demyelination, resulting in centralpontine or extrapontine myelinolysis, begins with affective changes and leth-argy, progressing to mutism, dysarthria, spastic quadriplegia, and pseudobul-bar palsy. For chronic patients, fluid restriction is the critical intervention.Several drugs have been tried (e.g., demeclocycline, which inhibits vaso-


pressin), but recently developed vasopressin-receptor antagonists (e.g., coni-vaptan, tolvaptan) offer a promising treatment for hyponatremia resultingfrom drug-induced SIADH (Josiassen et al. 2008).

Hematological Reactions

Essentially all classes of psychotropic drugs have been associated with blooddyscrasias (Table 2–5) (Flanagan and Dunk 2008; Stübner et al. 2004). Seri-ous hematological toxicity is rare, however, with an annual incidence of only1–2 per 100,000 population (Flanagan and Dunk 2008; Stübner et al. 2004).The white blood cells are affected most commonly, resulting in neutropenia(neutrophils <1,500/mm3) or agranulocytosis (neutrophils <500/mm3).Blood dyscrasias may result from a direct toxic effect on the bone marrow, pe-ripheral destruction, or formation of antibodies that target the hematopoieticcells or their precursors. Antipsychotics are most likely to cause neutropeniaor agranulocytosis (Flanagan and Dunk 2008; Stübner et al. 2004). Amongpatients beginning therapy with clozapine, 3% may develop neutropenia,whereas 0.8% may develop agranulocytosis, usually in the first year of treat-ment (Alvir et al. 1993). The risk of neutropenia in patients taking phenothi-azines may be 1 per 10,000, and the risk of agranulocytosis for patients takingchlorpromazine is 0.13% (Flanagan and Dunk 2008). Tohen et al. (1995) re-ported that 2.1% of 977 patients given carbamazepine developed mild(3,000–4,000/mm3) or moderate (<3,000/mm3) neutropenia, about 6–7times higher in rate than valproic acid or antidepressants.

Clinically, drug-induced neutropenia will become evident after 1–2 weeksof therapy; the degree of the neutropenia is related to the dosage and durationof exposure. Recovery can be expected within 3–4 weeks after stopping thecausative drug. Agranulocytosis can take longer to appear, up to 3–4 weeks af-ter starting treatment. With clozapine, the risk of agranulocytosis is greatestduring the first 6–18 weeks of treatment and in females, and its occurrence ismore frequent and more severe in elderly patients (Alvir et al. 1993).

For patients taking drugs known to cause neutropenia or agranulocytosis,proper management involves obtaining a complete blood count (CBC) withdifferential initially and periodically. A strict protocol of monitoring in patientstaking clozapine, along with treatment including broad-spectrum antibiotics,supportive care, and agents to stimulate the production of granulocytes, has re-

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eaction

s65

Table 2–5. Hematological reactionsDisorders Implicated drugs Risk factors Signs and symptoms Diagnostic studiesa Managementb

Neutropenia and agranulocytosis

Antipsychotics (chlorpromazine, clozapine)

Anticonvulsants (carbamazepine)

— Fever, infection CBC with differential —b

Thrombocytopenia AntipsychoticsAntidepressants

(SSRI effects on platelet function)

Benzodiazepines

Existing coagulopathies

Hemorrhages Platelet count —b

Anemia Antipsychotics (chlorpromazine, clozapine, risperidone)

— Weakness, fatigue CBC —b

Antidepressants (MAOIs, SSRIs)

Anticonvulsants (oxcarbazepine, valproic acid)

Benzodiazepines

Note. CBC=complete blood count; MAOIs=monoamine oxidase inhibitors; SSRIs=selective serotonin reuptake inhibitors.aStandard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associatedwith or specific for each reaction are listed.bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medicalcare.


sulted in a decrease in the mortality from clozapine-induced agranulocytosisfrom 3%–4% to 0.01% (Meltzer et al. 2002). Fever or infection may be theonly symptom of neutropenia or agranulocytosis, and is an indication for with-holding the drugs until a CBC with differential can be performed.

Although they occur less frequently than problems with white blood cells,platelet abnormalities have been associated with psychotropic drugs. SSRIsdecrease platelet serotonin, which may cause a decrease in platelet functionand prolongation of bleeding time. Patients with known coagulation dis-orders or von Willebrand disease and those taking nonsteroidal anti-inflam-matory drugs and coumarins should be monitored if SSRIs are prescribed(Halperin and Reber 2007). Most of the typical and atypical antipsychoticshave been reported to cause thrombocytopenia. Clozapine has also been re-ported to cause thrombocytosis, and there are case reports of quetiapine-induced thrombotic thrombocytopenic purpura. Valproate monotherapy hasbeen associated with thrombocytopenia and rare bleeding complications,with potential risk factors being increasing serum level, female gender, andlower baseline platelet count (Nasreddine and Beydoun 2008). Thrombocy-topenia has also been reported with tricyclic antidepressants, MAOIs, andbenzodiazepines.

Chlorpromazine, clozapine, risperidone, and sertraline have also been as-sociated with anemia. There are case reports of valproic acid causing pure redcell aplasia, which resolves when the drug is discontinued (Bartakke et al.2008). Oxcarbazepine was reported to cause hemolytic anemia in an elderlyman, but the anemia resolved after discontinuation of the drug (Chaudhry etal. 2008). Lithium has been well known to cause leukocytosis and thrombo-cytosis. Pancytopenia has been reported with fluphenazine and lamotrigine.

Discontinuation of the offending drug is usually followed by hematolog-ical recovery. If the patient cannot be treated with a different class of drug,hematology consultation should be obtained regarding appropriate monitor-ing of hematological parameters.

Metabolic Reactions and Body as a Whole

Although other body systems may be affected idiosyncratically by psychotro-pic drugs in susceptible individuals, we chose to highlight three additionallife-threatening disorders that are often invoked in discussions of severe drug


reactions, are of clinical significance in everyday clinical settings, and shouldbe familiar to practicing physicians (Table 2–6). These are antipsychotic-induced heatstroke, diabetic ketoacidosis, and rhabdomyolysis.

Antipsychotic-Induced Heatstroke

Patients with serious chronic mental illness have an increased risk of heat-stroke (Bark 1998), related to behavioral and environmental factors. In addi-tion, antipsychotic drugs can promote heatstroke by impairing heat loss(Mann and Boger 1978). Substantial evidence supports a key role for dopa-mine in preoptic anterior hypothalamic thermoregulatory heat-loss mecha-nisms (Lee et al. 1985). All typical antipsychotics promote hyperthermia byblocking dopamine receptors. The role of atypical antipsychotics in suppress-ing heat loss appears less clear. While atypicals block dopamine receptors,they also block 5-HT2C and postsynaptic 5-HT1A receptors, which partici-pate in heat-loss mechanisms, suggesting that atypicals could further promotehyperthermia in a hot environment (Mann 2003).

In most cases, anticholinergic-induced inhibition of sweating appears tocontribute significantly to the development of antipsychotic-induced heat-stroke. Low-potency typical antipsychotic drugs having marked anticholin-ergic activity are frequent offenders, whereas heatstroke associated with high-potency typical antipsychotics often involves concurrent treatment with anti-cholinergic drugs (Clark and Lipton 1984). In addition, some atypical anti-psychotics (clozapine, quetiapine, and olanzapine) possess anticholinergicactivity.

Clark and Lipton (1984) reviewed 45 cases of antipsychotic-induced heat-stroke and concluded that the majority of cases mimicked classic heatstroke.Classic heatstroke is characterized by body temperature above 40.6°C, anhi-drosis, and profound central nervous system (CNS) dysfunction, typically oc-curring during summer heat waves in elderly and medically compromisedpatients. Other cases associated with antipsychotics, however, resembled exer-tional heatstroke, which occurs primarily in young, healthy people with nor-mal thermoregulatory capacity in whom muscular work in a hot environmentexceeds the body’s capacity for heat loss. Both forms of heatstroke may resultin multiorgan failure, with rhabdomyolysis and renal failure occurring morecommonly in exertional heatstroke. CNS manifestations include delirium,stupor, coma, seizures, pupillary dysfunction, and cerebellar symptoms.

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Table 2–6. Metabolic reactions and body as a whole


Drug-induced heatstroke

Classic AnticholinergicsAntipsychotics

Heat waves, systemic illness, elderly

Hyperthermia, anhidrosis, confusion; → multiorgan failure, delirium, coma, seizures

—a Rapid cooling measures

Exertional AnticholinergicsAntipsychotics

Exertion, heat waves

Hyperthermia, rhabdomyolysis, metabolic acidosis, →multiorgan failure, delirium, coma, seizures

—a Rapid cooling measures

Diabetic ketoacidosis

Antipsychotics (clozapine, olanzapine)

African Americans, younger age

Anorexia, nausea, vomiting, polydipsia, polyuria, →altered mental status, coma

Urine ketones —b

Rhabdomyolysis Antipsychotics Agitation, trauma, substance abuse, injections, restraints, dystonia

Weakness, myalgias, edema, dark urine, → compartment syndromes, DIC, renal failure, hyperkalemia, arrhythmias

Serum CPK, urine myoglobin

Fluids, mannitol, alkalinization, hemodialysis

Note. CPK=creatine phosphokinase; DIC=disseminated intravascular coagulation.aStandard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associatedwith or specific for each reaction are listed.bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medicalcare. Only specific therapies that have been reported are listed.


Antipsychotic-induced heatstroke is a preventable condition. Duringsummer heat waves, psychiatric patients must be warned to avoid excessiveheat, sunlight, and exertion, and urged to drink fluids. Heatstroke is a medi-cal emergency that may be fatal in up to 50% of cases. All forms of treatmentaim at rapid cooling, fluid and electrolyte support, and management of sei-zures.

Diabetic Ketoacidosis

A serious life-threatening complication of diabetes mellitus is diabetic keto-acidosis. Having schizophrenia doubles the rate of diabetes, and the addedrisk with typical and atypical antipsychotics prompted development of guide-lines for monitoring glucose given the gravity of this chronic illness and thepotential lethality of diabetic ketoacidosis (American Diabetes Association etal. 2004).

Diabetic ketoacidosis occurs in patients requiring exogenous insulin andcan be the first indication that diabetes has developed. It occurs when insulinis no longer present and glucose cannot be transported into the cells. Hence,fatty acids are broken down for energy, creating an acidotic state. The clinicalmanifestations are anorexia, nausea, vomiting, polydipsia, and polyuria. Oneof the first-line laboratory assessments to determine diabetic ketoacidosis is totest urine for ketones. If diabetic ketoacidosis is untreated, an altered mentalstatus ensues and eventually coma. The mortality rate is approximately 10%.

In a study comparing typical and atypical antipsychotics in patients withschizophrenia in the Veterans Affairs health care system (Leslie and Rosen-heck 2004), 0.2% of all patients on antipsychotic medications required hos-pitalization for diabetic ketoacidosis. Hazard ratios for diabetic ketoacidosiswere significant only for clozapine and olanzapine.

Apart from treatment with clozapine or olanzapine, risk factors for dia-betic ketoacidosis in patients receiving antipsychotics include African Ameri-can descent, younger age, and schizophrenia (Ramaswamy et al. 2007). Therisk is not dosage dependent and continues with extended treatment. In pa-tients taking atypical antipsychotics, it is imperative to monitor weight, fastinglipids, and glucose. If hyperglycemia develops, changing to a metabolicallyneutral agent may reverse glucose elevation. Glucose should be carefully mon-itored and hypoglycemic agents adjusted accordingly when changing antipsy-chotic agents in patients with diabetes.


Rhabdomyolysis

Rhabdomyolysis results from injury to skeletal muscle cells, with leakage ofmyoglobin, aldolase, potassium, lactate dehydrogenase, aspartate transami-nase, creatine phosphokinase (CPK), and phosphate into the extracellularspace and general circulation. Clinical symptoms include weakness, myalgias,and edema, in association with cola-colored urine if myoglobinuria occurs.Serious complications include compartment syndromes, arrhythmias fromhyperkalemia, and disseminated intravascular coagulation; the most seriouscomplication is acute tubular necrosis with renal failure, which occurs in upto 16.5% of patients with myoglobinuria (David 2000).

The diagnosis of rhabdomyolysis can be confirmed by the CPK level,which is the most sensitive indicator of muscle damage and correlates with de-gree of muscle necrosis. Most authorities agree that a fivefold increase in CPKis consistent with the diagnosis (Walter and Catenacci 2008). Myoglobin isreleased and cleared earlier than CPK, and is therefore less reliable in diagnos-ing muscle breakdown and is not predicted by a specific CPK level.

Elevations of CPK are often observed in psychiatric patients, who are atrisk for several reasons (e.g., agitation, physical trauma, restraints, abuse of co-caine or alcohol, intramuscular injections, prolonged immobility, dystonia)(Melkersson 2006; Meltzer et al. 1996). Also, psychotropic drugs, most oftenantipsychotics, have been implicated independently in causing increases inCPK, occasionally resulting in clinical signs of rhabdomyolysis. For example,Meltzer et al. (1996) found significant increases in CPK levels in 11 of 121patients (10%) who received antipsychotic drugs. Peak levels ranged from1,591 to 177,363 IU/L (median 11,004 IU/L), with only one patient devel-oping myoglobinuria. Onset ranged from 5 days to 2 years after beginningdrug treatment, and elevations lasted from 4 to 28 days. Most patients wereasymptomatic without complications. CPK elevations were more commonwith atypical antipsychotics. Similarly, Melkersson (2006) studied 49 patientsreceiving clozapine (median 66 IU/L, range 30–299 IU/L), olanzapine (me-dian 81 IU/L, range 30–713 IU/L), or typical drugs (median 48 IU/L, range17–102 IU/L) and found that CPK levels were higher and more often elevatedin patients receiving the atypical drugs, although reported increases were min-imal in comparison with those reported by Meltzer et al. (1996).


Management of frank rhabdomyolysis rests on monitoring to detect clin-ical signs, including checking CPK levels and myoglobinuria. Discontin-uation of suspected drugs, correction of any predisposing risk factors, andprevention of complications are essential. General supportive measures in-clude aggressive volume and fluid repletion, correction of electrolyte abnor-malities, and use of mannitol or alkalinization of the urine to prevent renalfailure; hemodialysis may become necessary in some cases. In contrast, theclinical significance of mild or asymptomatic CPK elevations during pharma-cotherapy is unclear. A careful differential diagnosis of CPK elevations shouldbe considered. Although patients with pronounced elevations should be fol-lowed for progression to rhabdomyolysis and renal failure, and risk factorsshould be identified and corrected (by holding or switching suspected drugs,such as antipsychotics), only limited data suggest that mild asymptomaticCPK elevations correlate with risk of developing NMS or other acute orchronic complications of antipsychotic therapy (Hermesh et al. 2002a,2002b).

Key Clinical Points• Severe psychotropic drug reactions are best managed by careful

monitoring, familiarity with adverse symptoms, prompt recogni-tion, rapid drug discontinuation, and supportive treatment.

• Adverse central nervous system syndromes are diverse andmostly associated with antipsychotic and antidepressant drugs.

• Antipsychotic drugs have been associated with arrhythmias andsudden death.

• Severe hepatic toxicity is mostly associated with anticonvulsants.• Severe renal syndromes are primarily associated with lithium,

but SIADH has been associated with several drug classes.• Several psychotropic drug classes have been associated with he-

matological toxicity.• Lives can be saved by being aware of these potentially lethal

syndromes and maintaining careful follow-up with a high indexof suspicion for iatrogenic drug reactions.


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http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/UCM053171

79

3Alternate Routes of Drug

Administration


Psychotropic medications are usually delivered orally, but this administra-tion route may not be the best or may not even be possible for many patients.Oral administration of medications may be difficult in patients who are med-ically compromised, including patients with severe nausea or vomiting, dys-phagia, or severe malabsorption; unconscious or uncooperative patients; andpatients who are unable or unwilling to take medications by mouth (see Table3–1). In such situations, a nonoral route is preferred or necessary.

Medication administration is especially problematic with patients whoare cognitively impaired and acutely psychotic. With an alternate deliveryroute, compliance may be more easily verified and may improve if the routeis perceived as more convenient. Nonoral routes of administration include in-travenous, intramuscular, subcutaneous, sublingual or buccal, rectal, topicalor transdermal, and intranasal.

In this chapter, I review the availability of nonoral formulations of anxi-olytics and sedative-hypnotics, antidepressants, antipsychotics, mood stabiliz-


ers, psychostimulants, and cognitive enhancers. Many formulations discussedare commercially available, although not necessarily in the United States orCanada (see Table 3–2). The Lundbeck Institute provides an internationaldatabase of approved psychotropic formulations that may help to locate for-mulation sources (Lundbeck Institute 2003). This chapter also reports cus-tomized formulations for a few agents. Caution is indicated when using aformulation for unapproved purposes and for which adequate studies ofsafety and efficacy are lacking.

Properties of Specific Routes of Administration

Intravenous

Intravenous administration delivers drug directly to the patient’s circulationand avoids first-pass metabolism. It provides rapid drug distribution with

Table 3–1. Situations potentially requiring alternate routes of administration

Severe nausea and vomiting

Cancer chemotherapy

Severe gastroparesis

Gastric outlet obstruction

Intestinal obstruction

Esophageal disorders

Severe gastroesophageal reflux disease

Carcinoma

Severe dysphagia (e.g., poststroke)

Severe malabsorption

Short gut syndrome

Inflammatory bowel disease

Pancreatic insufficiency

Delirium, stupor, or coma

Patient’s refusal of oral medication

NPO (nothing per oral) orders in effect

Perioperative period

Intra-abdominal abscesses or fistulae

Alternate Routes of Drug Administration 81

100% bioavailability and ensures compliance. The rate of drug delivery canbe controlled from very rapid to slow infusion. Potential complications in-clude difficulty with venous access, infiltration, and infection. Intravenousforms of several benzodiazepines (in the United States and Canada) and val-proate (in the United States) are available. Intravenous administration ofshort-acting intramuscular forms of some typical antipsychotics is a commonclinical practice.

Intramuscular

Fast absorption, avoidance of first-pass metabolism, and ensured complianceare advantages of intramuscular administration, but bioavailability is oftenless than 100% because of drug retention or metabolism by local tissues. In-tramuscular injections should be avoided in cachectic patients and those withpoor muscle perfusion, such as cardiac insufficiency. Repeated injections ofsome drugs may cause muscle irritation, necrosis, or abscesses.

Sublingual or Buccal

The rapid sublingual absorption and good bioavailability of small lipid–solu-ble drugs suggest that many psychotropic medications could be administeredsublingually. Drugs absorbed sublingually avoid first-pass metabolism andmay have fewer gastrointestinal adverse effects. Sublingual delivery can beused in patients who are fasting, have difficulty swallowing, or are unable toabsorb medication from the gastrointestinal tract. Sublingual administrationmay not be practical in patients with severe nausea or who cannot tolerate thetaste of some medications.

A few psychotropics are available in a sublingual or buccal form, includ-ing the anxiolytic lorazepam (in Canada), the hypnotic zolpidem, the mono-amine oxidase B (MAO-B) inhibitor selegiline, and the newly introducedatypical antipsychotic asenapine. However, substantial sublingual or buccalabsorption of many drugs can occur for tablets, especially rapidly disintegrat-ing oral tablets, or oral solutions when held under the tongue or in the mouth.

Rectal

Rectal administration of medications can be used in patients with severe nau-sea, in those who cannot tolerate any gastric stimulation (including sublin-

82C



Table 3–2. Nonoral preparations of psychotropic medications

Medication Route of administration

IV IM Sublingual Rectal Transdermal Intranasal

Anxiolytics

Alprazolam n

Clonazepam n n

Diazepam US,C US,Ca n US,C

Flunitrazepam O n

Lorazepam US,C US,C C n n

Lormetazepam n

Midazolam US,C US,C n n n

Prazepam n

Temazepam O

Triazolam n n

Hypnotics

Zolpidem US

Antidepressants

Amitriptyline O n

Citalopram O

Clomipramine O n

Doxepin O n

Alternate R

outes o

f Dru

g Ad

min

istration

83

Fluoxetine n

Imipramine O n

Maprotiline O

Mirtazapine n

Selegiline USb US

Trazodone O n

Viloxazine O

Antipsychotics, atypical

Aripiprazole US

Asenapine US

Olanzapine US,CDepot: US

Paliperidone Depot: US

Risperidone Depot: US,C

Ziprasidone US

Antipsychotics, typical

Chlorpromazine US,C

Droperidol US,C US,C

Table 3–2. Nonoral preparations of psychotropic medications (continued)



84C



Antipsychotics, typical (continued)

Flupenthixol Depot: C

Fluphenazine US,CSubQ: CDepot: US,C

Haloperidol US,CDepot: US,C

Loxapine C

Methotrimeprazine C

Pipotiazine Depot: C

Prochlorperazine US,C US,C

Promazine C

Thiothixene US

Zuclopenthixol CDepot: C

Mood stabilizers

Carbamazepine n

Lamotrigine n

Topiramate n

Valproate US n




Alternate R

outes o

f Dru

g Ad

min

istration

85

Psychostimulants

Dextroamphetamine n

Methamphetamine n

Methylphenidate US

Cognitive enhancers

Galantamine n

Rivastigmine US,C

Note. Depot=long-acting depot formulation; IM=intramuscular; IV=intravenous; n=noncommercial formulation; SubQ=subcutaneous.Approved formulations: C=Canada; O=country other than United States or Canada; US=United States.aBut not advised due to erratic absorption.bBuccal administration.(See text for details.)





gual administration), and for drugs for which a parenteral form is unavailableor not tolerated. Drug absorption from the rectal mucosa is often incompleteand erratic because it lacks the extensive microvilli and surface area of thesmall intestine. Because a substantial portion of rectal venous drainage by-passes the portal circulation, first-pass metabolism is about 50% of oral ad-ministration. Bioavailability increases with the enema volume because themucosa surface in contact with drug expands; however, increasing the enemavolume may cause discomfort, and suppositories may be preferred to enemas.

Diazepam and prochlorperazine are the only psychotropic drugs availablein rectal forms. However, rectal administration of many drugs, includinglorazepam, dextroamphetamine, anticonvulsants, and antidepressants, hasbeen reported. Parenteral formulations and oral solutions have been adminis-tered as enemas, and rectal insertion of oral capsules has delivered acceptablebioavailability. Suppositories may be compounded from tablets or capsules.Where possible, therapeutic serum level monitoring is recommended.

Topical or Transdermal

Continuous drug delivery from a transdermal patch reduces the peak-to-trough fluctuation of drug levels produced by oral dosing and provides near-constant plasma drug levels, even for drugs with a short half-life, over longerdosing intervals. Transdermal drug delivery bypasses the gut, avoids first-passmetabolism, reduces gastrointestinal adverse effects, and is unaffected by foodintake. Local irritation can be avoided by varying the administration site.Transdermal preparations of psychotropics are now approved for depression(selegiline), attention-deficit disorders (methylphenidate), and Alzheimer’sdisease (rivastigmine).

Intranasal

Intranasal administration has been suggested as the best alternative toparenteral injection for rapid systemic drug delivery. However, there are noapproved intranasal formulations of psychotropic medications. Custom for-mulations are reported for anxiolytics (midazolam and lorazepam), psycho-stimulants (methamphetamine), antipsychotics (haloperidol), and cognitiveenhancers (galantamine), and Phase II trials of intranasal midazolam are on-going. Several devices to atomize drug solutions for intranasal delivery areavailable (Wolfe and Bernstone 2004).


Psychotropic MedicationsAnxiolytics and Sedative-Hypnotics

Internationally, many benzodiazepines are available in intravenous, intramus-cular, rectal, sublingual, and intranasal preparations. Injectable forms of diaz-epam, lorazepam, and midazolam are marketed in the United States andCanada; diazepam rectal gel is also available in both countries. Sublinguallorazepam is available in Canada. Buspirone and the nonbenzodiazepine hyp-notics eszopiclone, zopiclone, zaleplon, melatonin, and ramelteon are avail-able only in oral forms. A sublingual preparation of zolpidem was recentlyapproved in the United States.

Intravenous benzodiazepines are commonly used to treat status epilepti-cus and severe alcohol or sedative withdrawal, and to calm severely agitatedpatients. Intravenous lorazepam is preferred because of its more favorable andpredictable pharmacokinetics. In patients with status epilepticus, intravenouslorazepam controlled seizures within 3 minutes and for more than 12 hoursin adults (Griffith and Karp 1980), and within 6 minutes and for at least 3hours in children and adolescents (Lacey et al. 1986). Because intravenouslorazepam redistributes more slowly from the central nervous system to pe-ripheral tissues than does diazepam or midazolam, it has a longer duration ofeffect after a single dose. Midazolam is a rapid-acting short-duration benzo-diazepine frequently used in preoperative sedation, induction and mainte-nance of anesthesia, and treatment of status epilepticus. The effects ofintravenous midazolam begin within minutes but last for less than 2 hours(Rey et al. 1999). Intravenous flunitrazepam, available in Europe and Japan,has been used for severe insomnia (Matsuo and Morita 2007) and for thetreatment and prevention of alcohol withdrawal (Pycha et al. 1993). Becausesevere respiratory depression may accompany intravenous benzodiazepineadministration, facilities for respiratory resuscitation should always be avail-able when using this route.

Injectable forms of lorazepam, midazolam, and diazepam are available forintramuscular delivery. For behavioral emergencies, lorazepam is preferredbecause it is readily absorbed and has no active metabolites. Midazolam is alsorapidly absorbed after intramuscular administration, with an onset of actionbetween 5 and 15 minutes. Intermittent or sustained continuous subcutane-ous infusion of injectable midazolam is reported for management of delirium,


especially in a palliative care setting (Bottomley and Hanks 1990). Intramus-cular diazepam is not recommended because of its erratic absorption (Rey etal. 1999).

Rectal administration of benzodiazepines is useful for the acute manage-ment of seizures in children. Diazepam is available as a rectal gel for use whenother delivery routes are not readily available. A pharmacokinetic study of aparenteral solution of lorazepam administered rectally to healthy adults foundaverage bioavailability of 80% but with considerable variation in the rate andextent of absorption. Peak concentrations were considerably lower and laterthan the equivalent intravenous dose. The authors suggested that to achieverapid therapeutic effect, rectal doses may need to be 2–4 times the intrave-nous dose and that these higher doses may cause prolonged toxicity (Graveset al. 1987). Other benzodiazepines, such as clonazepam, triazolam, andmidazolam (Aydintug et al. 2004), have also been administered rectally. Al-though rectal benzodiazepine absorption is rapid, it is not always reliablebecause rectal bioavailability is highly variable and the onset of action is de-layed (Rey et al. 1999).

Sublingual benzodiazepines are often used to control anxiety in patientsundergoing dental procedures. Only lorazepam in Canada and temazepam inEurope (Russell et al. 1988) are marketed in a sublingual form, although sev-eral benzodiazepines, including alprazolam, clonazepam, diazepam, fluni-trazepam, lormetazepam, midazolam, prazepam, and triazolam, have beenadministered sublingually using commercial nonsublingual formulations orcustom preparations. Pharmacokinetic studies comparing sublingual admin-istration of oral tablets against intramuscular administration suggest slightlyslower sublingual drug absorption but similar bioavailability.

The pharmacokinetics of a sublingual form of lorazepam has been com-pared with that of an intramuscular injection or a sublingual dosage of an oraltablet in 10 fasting subjects. Lorazepam blood levels peaked more rapidlywith intramuscular injection (1.15 hours postdose) than with sublingual oraltablets (2.35 hours) or the sublingual lozenge (2.25 hours), but these differ-ences were not significant. Bioavailability for all preparations was indistin-guishable from 100% (Greenblatt et al. 1982).

The pharmacokinetics of alprazolam oral tablets administered either sub-lingually or orally has been studied in 13 fasting volunteers. Although not sig-nificantly different, plasma drug levels peaked faster and higher following


sublingual administration. Sublingual administration of oral tablets may bean alternative for patients with panic disorder who are unable to swallow tab-lets (Scavone et al. 1987).

Although no benzodiazepines are available in intranasal formulations, in-tranasal formulations of midazolam and lorazepam sprays have been reportedto be effective (Kain et al. 1997). Intranasal midazolam produces peak plasmalevels within 14 minutes and much higher bioavailability (83%) than the oralform (approximately 20%) (Bjorkman et al. 1997). Intranasal lorazepam hassimilar bioavailability (78%) to intramuscular (100%) or oral (93%) admin-istration but with more rapid absorption (0.5 hours) than the intramuscularroute (3 hours) (Wermeling et al. 2001).

Intrathecal administration of a buffered, preservative-free midazolam so-lution is a safe and effective adjunctive treatment for postoperative pain man-agement in a variety of settings (Duncan et al. 2007).

A sublingual formulation of zolpidem, a nonbenzodiazepine hypnotic,has recently been approved in the United States. In a clinical study, the sub-lingual form produced a significantly earlier sleep initiation than the oralpreparation (Staner et al. 2008).

Antidepressants

The monoamine oxidase inhibitor (MAOI) selegiline, available in a transder-mal patch, is the only nonoral antidepressant formulation approved in theUnited States. The antidepressant dosage of oral selegiline requires dietarytyramine restriction because of clinically significant inhibition of intestinalMAO-A. By avoiding intestinal exposure to selegiline, transdermal admin-istration reduces intestinal MAO-A inhibition and the need for dietary tyra-mine restrictions at dosages of 6 mg/day or less, as well as circumventing first-pass metabolism to provide higher plasma levels and reduced metabolite for-mation. Short-term (8-week; Feiger et al. 2006) and long-term (52-week;Amsterdam and Bodkin 2006) placebo-controlled double-blind clinical trialshave demonstrated antidepressant efficacy with similar adverse effects to pla-cebo, except for application site reactions and insomnia. An oral disintegrat-ing tablet of selegiline, designed for buccal absorption, is approved in theUnited States for Parkinson’s disease (Valeant 2009). There are no reports ofits use for the treatment of depression.


Injectable preparations of amitriptyline, citalopram, clomipramine, dox-epin, imipramine, maprotiline, trazodone, and viloxazine are available in Eu-rope and are sometimes used for the initial treatment of hospitalized, severelydepressed patients. However, the safety and efficacy of intravenous antide-pressants in medically ill patients is uncertain because studies to date havebeen performed only in medically healthy patients.

No injectable antidepressants are currently available in the United Statesor Canada. It has been suggested that antidepressants with extensive first-passmetabolism act more rapidly if given intravenously than orally, but superiorefficacy has not been demonstrated (Moukaddam and Hirschfeld 2004).

Intravenous mirtazapine (15 mg/day) was well tolerated and effective intwo small uncontrolled trials (Konstantinidis et al. 2002; Muhlbacher et al.2006). Citalopram is the only selective serotonin reuptake inhibitor availablein an intravenous formulation. To date, open and double-blind controlledclinical studies have shown citalopram infusion followed by oral citalopram(Kasper and Müller-Spahn 2002) or escitalopram (Schmitt et al. 2006) to beeffective and well tolerated for severe depression.

Transdermal amitriptyline was reported to be well absorbed and effectivein a case report (Scott et al. 1999), but to have no significant systemic absorp-tion in a small open trial (Lynch et al. 2005). The variability may be due todifferent transdermal formulations.

Several antidepressants, including amitriptyline, clomipramine, imip-ramine, and trazodone, have been compounded as rectal suppositories, withanecdotal reports of success in depression (Koelle and Dimsdale 1998; Miras-sou 1998). Therapeutic serum levels of doxepin were produced in three offour cancer patients following rectal insertion of oral capsules (Storey andTrumble 1992). The rectal bioavailability of fluoxetine oral capsules, admin-istered rectally, was only 15% that of oral administration, but rectal adminis-tration of oral capsules was reasonably well tolerated in seven healthy subjects(Teter et al. 2005). With an appropriate dosage adjustment, rectal adminis-tration of antidepressants may be feasible in patients who cannot take oralmedications. Serum drug levels (if available) and clinical response shouldguide dosage.

Sublingual administration of fluoxetine oral solution has been studied intwo medically compromised patients with depression. After 4 weeks of20-mg/day dosing, plasma levels of fluoxetine plus norfluoxetine were in the


low therapeutic range, and depressive symptoms had improved in both pa-tients (Pakyurek and Pasol 1999).

Mirtazapine is available in an oral disintegrating tablet for gut absorption,but the extent of sublingual or buccal absorption from this formulation isunknown.

Antipsychotics

The atypical antipsychotics aripiprazole, olanzapine, and ziprasidone, as wellas many typical agents, are available as short-acting intramuscular prepara-tions. Long-acting intramuscular depot formulations of risperidone, paliperi-done, olanzapine, fluphenazine, and haloperidol are available in the UnitedStates. In Canada, long-acting intramuscular depot formulations of risperi-done, fluphenazine, haloperidol, flupenthixol, pipotiazine, and zuclopen-thixol are approved. Olanzapine is the only atypical antipsychotic available inoral, short-acting intramuscular, and depot intramuscular formulations.

Antipsychotic agents are not approved by the U.S. Food and Drug Ad-ministration (FDA) or Health Canada for intravenous use in psychiatric con-ditions. However, typical antipsychotics, primarily haloperidol, are oftenadministered intravenously in medical inpatient settings, especially for delir-ium.

Intravenous droperidol has been used for rapid tranquilization eventhough it is approved only as an anesthetic adjunct. Droperidol causes dos-age-dependent prolongation of the QTc interval and has been associated withtorsade de pointes, although this association is controversial (Nuttall et al.2007). As a result, droperidol has been withdrawn from the United Kingdomand is subject to a black-box warning in North America.

Intramuscular forms of atypical antipsychotics are less likely than halo-peridol to cause acute dystonia and akathisia (Currier and Medori 2006; Zim-broff 2008), but there has been much less experience using them in medicallyill patients, and the medications are considerably more expensive. Haloperi-dol, but not any of the atypical antipsychotics, can be mixed with a benzodi-azepine in the same syringe. Ziprasidone and aripiprazole can be administeredin conjunction with an intramuscular benzodiazepine, but concurrent intra-muscular olanzapine with a parenteral benzodiazepine is not recommendedbecause of excessive sedation and cardiorespiratory depression (Eli Lilly2009).


Subcutaneous administration of haloperidol, methotrimeprazine (avail-able in Canada and Europe), and fluphenazine (Health Canada approved forsubcutaneous administration) can be used to manage terminal restlessnessand nausea or vomiting in palliative care patients (Fonzo-Christe et al. 2005).Most other phenothiazines are too irritating for subcutaneous injection.

Intranasal delivery of antipsychotics is the subject of patent applications,and reports of intranasal quetiapine abuse suggest the feasibility of anti-psychotic delivery by this route (Morin 2007). In a recent small trial, an intra-nasal haloperidol preparation was more rapidly absorbed and had greaterbioavailability than the intramuscular form (Miller et al. 2008).

A transdermal haloperidol patch has been developed and tested in ani-mals but no human trials have been reported (Samanta et al. 2003). Prochlor-perazine is the only phenothiazine currently available in the United States andCanada as a rectal suppository; chlorpromazine suppositories were discontin-ued in 2002.

Asenapine, recently FDA approved, is the first and only antipsychoticavailable in a sublingual preparation; it is not available in other delivery formsat this time. Oral disintegrating tablets (ODTs), designed to deliver drug forintestinal absorption, are available for most atypical agents. Sublingual ab-sorption of olanzapine ODTs has been studied in healthy volunteers (Marko-witz et al. 2006). Sublingual administration resulted in a similar extent andrate of drug absorption compared with regular administration of the ODTand faster absorption than the standard oral tablet. Sublingual or buccal ab-sorption of ODTs for other antipsychotics has not been reported.

Mood Stabilizers

Lithium is marketed in the United States and Canada in an oral form only,but intravenous, intraperitoneal, and sublingual forms of lithium administra-tion have been reported. Nonoral administration of lithium is not approvedby the FDA, and insufficient clinical experience or data are available torecommend nonoral routes. Because lithium is not metabolized, parenteraladministration has fewer pharmacokinetic advantages than for other psycho-tropic drugs. Successful intraperitoneal administration of lithium to a bipolarpatient with end-stage renal disease undergoing continuous ambulatory peri-toneal dialysis is described in one case report. A sterile lithium chloride solu-


tion was prepared and added to the dialysate bag. Lithium levels in serum andthe dialysate were well correlated (Flynn et al. 1987).

Intravenous valproic acid has been available in Europe for over 18 yearsand in the United States since 1997. (It was discontinued in Canada in 2004.)Valproate is the only mood stabilizer, apart from several atypical antipsychot-ics, with an approved parenteral formulation for which case reports exist de-scribing its use in psychiatric conditions (Grunze et al. 1999; Norton andQuarles 2000; Regenold and Prasad 2001). The infusion does not require car-diac monitoring and causes no significant orthostatic hypotension (Norton2001). There are no randomized, controlled trials documenting its safety andefficacy for psychiatric disorders.

Rapid systemic loading of valproate with the intravenous formulation hasbeen proposed to accelerate its antimanic effect, but two small case seriesfound no such advantage over orally administered valproate (Jagadheesan etal. 2003; Phrolov et al. 2004). Rectal valproate delivery using diluted oralsyrup may be an alternative with comparable bioavailability when the oraland parenteral routes are unavailable (Cloyd and Kriel 1981).

Findings from several studies indicate that rectal administration of car-bamazepine, lamotrigine, and topiramate provides acceptable bioavailabilityand tolerability. Carbamazepine has been rectally administered as a solution(Neuvonen and Tokola 1987) and as a crushed tablet in a gelatin capsule (Sto-rey and Trumble 1992), attaining therapeutic blood levels in some but not allpatients. Rectal preparations of lamotrigine and topiramate have been pre-pared from oral formulations. Compared with oral dosing, rectal lamotriginehad reduced bioavailability (approximately 50%), leading to lower drug levelsand slower absorption (Birnbaum et al. 2001), whereas blood levels wereidentical after rectally and orally administered topiramate (Conway et al.2003). Provided relative bioavailability is considered, rectal administration ofan aqueous suspension of these tablets may be acceptable.

Rectal absorption of other anticonvulsants, including felbamate, gaba-pentin, oxcarbazepine, and phenytoin, is not reliable (Clemens et al. 2007).Oxcarbazepine is available as an oral suspension, but its rectal administrationachieved only 10% of the oral bioavailability for the parent drug or active me-tabolite (Clemens et al. 2007). Thus, rectal delivery is not an appropriateroute for oxcarbazepine.


Psychostimulants

Transdermal methylphenidate was approved for children in 2006 in theUnited States. The patch is worn for 9 hours but provides therapeutic effectthrough 12 hours. Several patch doses are available, and the duration of effectcan be modified by early removal of the patch (Manos et al. 2007). In childrenwith attention-deficit/hyperactivity disorder, the adverse-effect profile is sim-ilar to that of a placebo patch (McGough et al. 2006). No clinical trial com-paring oral and transdermal methylphenidate has been published, let alone atrial in adults with serious medical illness.

Although no other nonoral forms of psychostimulants are available, custompreparations are described. Dextroamphetamine has been administered intrave-nously to human subjects in research, but not clinically (Ernst and Goldberg2002). There is one published case report of 5-mg dextroamphetamine suppos-itories compounded by a pharmacy that significantly improved depressed moodin a woman with gastrointestinal obstruction (Holmes et al. 1994).

Cognitive Enhancers

The only cognitive enhancer available in a nonoral formulation is rivastigmineas a transdermal patch. The rivastigmine patch is dosed daily and provides lessfluctuating plasma levels than the twice-daily oral capsules or solution. Thepatch provides greater bioavailability but with slower absorption, which re-duces peak drug levels by 20%. This more consistent drug exposure might im-prove efficacy, but this possibility remains to be investigated. The incidence ofnausea and vomiting declined from 33% with the oral form to 20% with thepatch (Lefevre et al. 2008).

Conclusion

Nonoral formulations are now approved in the United States for at least oneagent in each psychotropic drug class, and several others are routinely pre-pared by compounding pharmacies. There is no single best administrationroute for all patients. In addition to the availability of dosing forms, admin-istrative and pharmacokinetic concerns govern formulation choice. In thisregard, nonoral routes of drug delivery have several advantages over oral ad-ministration. Medication compliance may improve if the delivery route is


perceived as more convenient, and compliance is more easily verified withcertain routes. Preparations can be selected to provide rapid drug delivery foracute treatment or more continuous drug absorption for chronic therapy. Bydecreasing the variation in plasma drug levels, continuous drug delivery re-duces adverse effects, improves tolerability and patient compliance, and en-hances therapeutic effect. Drugs delivered by a nonoral route at least partlybypass the gastrointestinal tract and avoid first-pass metabolism. Bioavailabil-ity is often improved, and metabolite formation, a potential source of adverseeffects, is reduced. Also, by avoiding the high gut concentration of drug fol-lowing oral administration, gastrointestinal adverse effects are lessened.

The recent trend in the development of intranasal and transdermal psy-chotropic drug delivery systems realizes many of these advantages of nonoralpreparations. However, there remains a need for drug forms that are easier,less expensive, and less invasive to administer, especially in situations wheremedical resources are limited.

Key Clinical Points

• Drug delivery by nonoral routes may improve medication ad-ministration in patients with severe nausea or vomiting, dys-phagia, or severe malabsorption: unconscious or uncooperativepatients; and patients unable or unwilling to take medicationsby mouth.

• In comparison with oral drug delivery, drugs delivered by a non-oral route may have fewer gastrointestinal adverse effects.

• Bioavailability of medications can vary considerably between dif-ferent routes of administration. Literature recommendations,therapeutic drug monitoring, and clinical response should beused to guide dosing.

• Oral tablets of many benzodiazepines achieve faster absorptionwhen administered sublingually.

• Transdermal drug delivery reduces the peak-to-trough fluctua-tion of drug levels produced by oral dosing and provides near-constant plasma drug levels, even for short-half-life drugs, overlonger dosing intervals.


• Transdermal formulations are available for antidepressant, cog-nitive enhancer, and psychostimulant medications.

• Sublingual or buccal formulations are available for antipsychotic,anxiolytic (lorazepam: Canada only), and hypnotic medications.The MAO-B inhibitor selegiline is available in a sublingual prep-aration for use in Parkinson’s disease.

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PA R T I I

Psychopharmacologyin Organ System Disorders

and Specialty Areas

103

4Gastrointestinal Disorders

Catherine C. Crone, M.D.

Michael Marcangelo, M.D.

Jeanne Lackamp, M.D.

Andrea F. DiMartini, M.D.


Diseases of the gastrointestinal (GI) system are prevalent and are frequentlyassociated with distress and psychiatric disorders, which may cause, exacerbate,or be a reaction to these disorders (Jones et al. 2007; Sandler et al. 2002). Inthis chapter, we review the use of psychotropic medications in the treatmentof GI disorder symptoms and comorbid psychopathology, potential interac-tions between GI medications and psychotropic agents, risks of prescribingpsychiatric medications in the presence of particular GI disorders, and alter-ations in the pharmacokinetics of psychotropic drugs induced by GI disorders


(e.g., hepatic failure, short bowel syndrome). The chapter is organized first byorgan system and then by specific GI disorder.

Oropharyngeal Disorders

Burning Mouth Syndrome

Burning mouth syndrome (BMS) is a clinical syndrome characterized by “un-remitting oral burning or similar pain in the absence of detectable oral mu-cosal changes” (Scala et al. 2003, p. 175). Often accompanied by dysgeusiaand xerostomia, BMS primarily impacts perimenopausal and postmeno-pausal women. A variety of causative factors (e.g., allergies, infection, endo-crine disorders, gastroesophageal reflux disease [GERD], medications) havebeen implicated for BMS, buts its etiology remains unknown (Klasser et al.2008). Angiotensin-converting enzyme inhibitors, angiotensin II receptorblockers, antiretrovirals, and selective serotonin reuptake inhibitors (SSRIs)have been linked to onset of BMS (Levenson 2003; Salort-Llorca et al. 2008),although more often antidepressants have been found to be helpful. Psychiat-ric comorbidity is high among BMS patients, with 38%–72% demonstratinganxiety disorders, depression, or hypochondriasis (Bogetto et al. 1998).

Treatment of BMS is challenging due to lack of a definitive approach(Zakrzewska et al. 2005). Topical clonazepam has been the most effectiveagent. In an open trial of oral clonazepam, 43% of subjects reported improve-ment at a mean dosage of 1 mg/day (Grushka et al. 1998). In a randomizedcontrolled trial requiring patients to suck three times daily on a 1-mg clonaz-epam tablet for 3 minutes and then spit, 66% responded after 14 days (Gre-meau-Richard et al. 2004). Sertraline 50 mg/day, amisulpride 50 mg/day, andparoxetine 20 mg/day were effective in an 8-week single-blind study (Mainaet al. 2002). Some benefit has also been derived from use of topical capsaicinor alpha-lipoic acid (Scala et al. 2003).

Xerostomia

Xerostomia is a subjective complaint of dry mouth that may be accompaniedby decreased saliva production. It may be due to a number of conditions, in-cluding connective tissue disorders, radiation therapy, anxiety, and depression(Guggenheimer and Moore 2003). Psychotropic agents are a contributing

Gastrointestinal Disorders 105

cause of xerostomia in 10%–50% of patients. All antidepressants, benzodiaz-epines, typical and atypical antipsychotics, lithium, and carbamazepine cancause xerostomia (Clark 2003; Friedlander and Mahler 2001; Friedlander etal. 2004; Masters 2005). This symptom may be particularly problematic forpatients also on other medications that produce xerostomia (e.g., antihyper-tensives, diuretics, opioids, anticholinergics). Management includes medica-tion changes, avoidance of caffeine and alcohol, sips of water, sugarless gumor candies, saliva substitutes, topical fluoride, and cholinergic agents, such aspilocarpine (1% solution diluted from eye drops) or bethanechol (5–10 mgsublingually) (Masters 2005).

Dysphagia

Dysphagia affects 16%–22% of adults over age 50, with the greatest preva-lence among hospital and nursing home patients (Spieker 2000). Nutritionaldeficiencies, esophageal rupture, aspiration, and aspiration pneumonia are se-rious complications of dysphagia. Neurological disorders, such as cerebrovas-cular accidents, multiple sclerosis, myasthenia gravis, and Parkinson’s disease,often produce incoordination of swallowing efforts (Logemann 1988). Casereports frequently cite psychotropic medications as a cause of dysphagia. Thisis especially true with typical or atypical antipsychotics (e.g., clozapine, mo-lindone, haloperidol, trifluoperazine, risperidone, olanzapine), secondary todystonia, parkinsonism, or tardive dyskinesia, often in the absence of othermovement disorder symptoms (Dziewas et al. 2007; Nieves et al. 2007; Sagaret al. 2005; Varghese et al. 2006). Xerostomia, sedation, or pharyngeal weak-ness secondary to antidepressants, benzodiazepines, and other psychotropicmedications can also produce dysphagia (Dantas and Souza 1997; Spieker2000). Lastly, dysphagia can manifest as part of the clinical presentation forneuroleptic malignant syndrome and in rare cases serotonin syndrome (Pass-more et al. 2004; Shamash et al. 1994).

Acute dystonia responds to intravenous diphenhydramine or benztropine.Dysphagia due to drug-induced parkinsonism is not responsive to anticholin-ergic agents and responds to reduced dosing of antipsychotic medications,switching agents, or discontinuation of therapy (Dziewas et al. 2007; O’Neiland Remington 2003). Tardive dyskinesia–associated dysphagia responds tosimilar measures, with additional benefits from clonazepam, although caution


is recommended with sedative medications (Nieves et al. 2007; O’Neil andRemington 2003). For patients whose dysphagia prevents the swallowing ofmedications, see Chapter 3, “Alternate Routes of Drug Administration.”

Globus Hystericus

The globus sensation refers to the feeling of having something lodged in one’sthroat. The term globus hystericus reflects the classic view that its etiology waspsychogenic (conversion, anxiety, depression) (Finkenbine and Miele 2004),but somatic contributing factors have been identified, including GERD, cer-vical osteophytes, and lingual tonsil hypertrophy (Caylakli et al. 2006; K.H.Park et al. 2006).

A few case reports indicate success with using tricyclic antidepressants(TCAs) and monamine oxidase inhibitors for globus, but reassurance and edu-cation are of primary importance (Brown et al. 1986; Finkenbine and Miele2004). The role of anxiolytics is uncertain, except in those cases where globussymptoms are secondary to panic disorder (Finkenbine and Miele 2004).

Esophageal and Gastric Disorders

Gastroesophageal Reflux Disease

GERD is the most common cause of noncardiac chest pain and of upper air-way cough, affecting up to 20%–30% of people in Western countries (Eslickand Fass 2003; Ho et al. 1998). GERD is thought to be secondary to laxity ofthe lower esophageal sphincter, which allows acidic stomach contents to washup into the esophagus. Traditional explanations for the connection betweenstress and heartburn involve stress-induced changes, such as increased gastricacid production, inhibition of gastric emptying, and breathing changes lead-ing to impaired lower esophageal sphincter–diaphragm interaction (Naliboffet al. 2004).

Conventional treatments of GERD include antacids, proton pump in-hibitors, and histamine (H2) blockers (Eslick and Fass 2003). Psychotropics,including antidepressants and benzodiazepines, can produce overall improve-ment in well-being, sleep, and gastric transit (Clouse and Lustman 2005;Drossman 2006; Prakash and Clouse 1999; Wulsin et al. 1999). Additionally,TCAs and serotonin-norepinephrine reuptake inhibitors may reduce visceral


hypersensitivity by conferring local and central analgesia (Drossman 2006).Diazepam (ranging from 5 mg twice daily to 10 mg three times daily) has alsobeen shown to markedly improve GERD in several cases (Sontag 2002). Psy-chiatric treatment can improve subjective distress even if the underlying phys-iological abnormalities do not change. Most psychiatric medications do notworsen GERD symptoms, with the exception of anticholinergic drugs (vanSoest et al. 2008). Thus, use of tertiary amine TCAs and low-potency anti-psychotics should be avoided in patients with GERD.

Esophageal Motility Disorders and Other Noncardiac Chest Pain

Other non-GERD-related noncardiac pain of presumed esophageal originmay involve visceral hypersensitivity, esophageal dysmotility, abnormal cen-tral nervous system processing of afferent signals, and psychological factors(Fass and Navarro-Rodriguez 2008; Galmiche et al. 2006). Anxiety, depres-sive, and somatoform disorders have been reported in at least 60% of patientswith noncardiac chest pain (Clouse 1997). Panic disorder may be present inup to 50% of such patients (Olden 2006).

Psychopharmacological agents thought to modulate pain sensitivity orperception constitute the primary drug treatment approach for non-GERD-related noncardiac chest pain. Low-dose trazodone and TCAs have beeneffective in controlled clinical trials, as have sertraline, paroxetine, and citalo-pram used at standard therapeutic doses (Broekaert et al. 2006; Clouse et al.1987; Doraiswamy et al. 2006; Varia et al. 2000). Notably, reductions inchest pain have been independent of improvements in psychological scores oresophageal motility. Alprazolam and clonazepam have been effective in trialsof patients with noncardiac chest pain and panic disorder (Beitman et al.1989; Wulsin et al. 1999).

Functional Dyspepsia (Nonulcer Dyspepsia)

Functional dyspepsia is defined as epigastric pain or discomfort not attributableto anatomic pathology (Drossman 2006; Jones et al. 2007; Levy et al. 2006).Bloating, early satiety, and nausea and/or vomiting may also be present, andsymptoms may be worsened by food. Patients with functional dyspepsia havehigh rates of comorbid psychopathology, including neuroticism, anxiety, de-pression, hostility, tension, posttraumatic stress disorder, and somatization


(Levy et al. 2006; North et al. 2007). A history of physical, sexual, and emo-tional abuse appears to be more prevalent in patients with functional GI dis-orders (Levy et al. 2006). Treatment often includes H2 blockers and protonpump inhibitors, although studies have found variable efficacy for these med-ications (Talley 2003). Other options include prokinetic agents (e.g., metoclo-pramide, erythromycin) and fundus-relaxing agents (e.g., sumatriptan) (Tackand Lee 2005).

As in GERD, psychotropic medications are used in functional dyspepsia.Antidepressants may offer symptomatic relief and analgesia, with more datasupporting TCAs than SSRIs, and judicious use of benzodiazepines maybenefit patients with predominant anxiety symptoms (Clouse and Lustman2005). In a small randomized controlled trial, buspirone compared with pa-roxetine and venlafaxine improved aggregate symptom and nausea scores(Chial et al. 2003). Medications should be selected based on individual symp-toms and potential side effects; for example, SSRIs should be avoided for pa-tients with marked nausea.

Peptic Ulcer Disease

Found in both the stomach and duodenum, peptic ulcers have been etiologi-cally linked to infection with Helicobacter pylori and chronic use of anti-inflammatory medications. In addition, psychological stress is an independentrisk factor for the development and recurrence of duodenal ulcer (Rosenstocket al. 2003). Patients report a gnawing sensation in the abdomen, and this sen-sation often improves with food, as opposed to functional dyspepsia, whichmay worsen with food. Anxiety and depression are common comorbidities.

Patients with peptic ulcer are often started on multiple medications, in-cluding antibiotics plus antacids, proton pump inhibitors, and/or H2 block-ers (Peterson et al. 2000). Several small randomized controlled trials in the1980s demonstrated benefits of TCAs (doxepin, trimipramine) in the treat-ment and prevention of duodenal ulcers, perhaps via antihistaminic and an-ticholinergic effects (e.g., MacKay et al. 1984; Shrivastava et al. 1985).

Gastroparesis

Gastroparesis is characterized by abnormal gastric motility and delayed gastricemptying without identifiable obstruction. Symptoms include abdominalpain, nausea and/or vomiting, bloating, and early satiety (Patrick and Epstein


2008). The most common etiologies of gastroparesis are diabetes mellitus,postsurgical complications, iatrogenic causes (medication side effects), andidiopathic causes. Overlap in symptoms between gastroparesis and other GIdisorders may complicate diagnosis. Anxiety, depression, and somatization arecommon, although it is difficult to tell if they are precursors or sequelae ofgastroparesis.

Nonpharmacological treatments include advising patients to eat multiplelow-fat small meals and encouraging more liquids than solids; in patients withdiabetes, ensuring tight glucose control is important (M.I. Park and Camilleri2006; Patrick and Epstein 2008). Pharmacological treatments include proki-netic medications, such as metoclopramide, erythromycin, bethanechol, andpossibly pyridostigmine. Metoclopramide, a dopamine D2 receptor–blockingantiemetic agent, can produce extrapyramidal symptoms. Because thesesymptoms include tardive dyskinesia, chronic use should be avoided (Kenneyet al. 2008). SSRIs demonstrate prokinetic effects and are another treatmentoption (Drossman et al. 1999). Psychotropic drugs (e.g., phenothiazines, anti-depressants, benzodiazepines) may also be used for their antiemetic properties(M.I. Park and Camilleri 2006). Mirtazapine acts by virtue of its effects onserotonin and norepinephrine, along with its ability to block 5-HT3 receptors(e.g., ondansetron) (Kim et al. 2006). Anticholinergic psychiatric drugs canworsen gastroparesis and should be avoided (Patrick and Epstein 2008).

Nausea and Vomiting

Vomiting of unknown origin was traditionally attributed to psychologicalstress (so-called psychogenic vomiting), particularly anxiety and panic (Oldenand Crowell 2005). Physical and/or sexual abuse history is common in pa-tients with idiopathic nausea and vomiting. Specific syndromes of nausea andvomiting include cyclic vomiting syndrome, hyperemesis gravidarum, andcancer-related nausea and vomiting. In patients without evident cause ofvomiting, anorexia nervosa and bulimia should be considered.

Cyclic vomiting syndrome is more commonly reported in children, butoccurs in adults as well (Drossman 2006; Olden and Crowell 2005). Thissyndrome is characterized by episodes of vomiting, separated by prolongedperiods without vomiting. These vomiting episodes may have triggers (e.g.,migraine headaches, seizures, menstrual cycles, stress) or may be unrelated toany triggers or environmental cues (Chepyala et al. 2007; Prakash et al.


2001). There is no consensus on effective treatment for cyclic vomiting syn-drome, although treatment modalities have included prokinetics, antiemet-ics, erythromycin, sumatriptan, TCAs, benzodiazepines, and anticonvulsantssuch as valproate and topiramate (Chepyala et al. 2007; Prakash et al. 2001).Novel treatments include the newer anticonvulsants zonisamide and leveti-racetam (Clouse et al. 2007).

Upward of 80% of women experience transient nausea and vomiting dur-ing the early stages of pregnancy. Hyperemesis gravidarum—that is, persis-tent and severe nausea and vomiting leading to nutritional problems, fluidand electrolyte imbalance, and possible hospitalization—affects only 0.3%–2% of pregnant women (Einarson et al. 2007; Wright 2007). The belief thathyperemesis gravidarum was a psychogenic disorder has largely been discred-ited, but one recent study suggested that for some hyperemesis gravidarumpatients, vomiting might be a physical symptom of pregnancy-related psycho-logical distress (Seng et al. 2007). Such patients may be difficult to distinguishclinically.

Many medications have been used for hyperemesis gravidarum, includingGI medications (e.g., metoclopramide, ondansetron, prochlorperazine, pro-methazine), corticosteroids, and nontraditional treatments (e.g., acupunc-ture, pyridoxine [vitamin B6], ginger root powder) (Einarson et al. 2007;Wright 2007). Acting on central brain chemoreceptors, first-generation anti-psychotics (particularly chlorpromazine) also have been used in hyperemesisgravidarum, postoperative nausea and/or vomiting, and cancer-related nauseaand/or vomiting (Lohr 2008; Wright 2007). Mirtazapine has also been foundhelpful in hyperemesis gravidarum, although clinicians should be aware ofpotential withdrawal symptoms in the neonate (Schwarzer et al. 2008). De-spite the relative safety of these medications in pregnancy, clinicians shouldremain vigilant in assessing adverse effects, particularly extrapyramidal symp-toms (acute dystonia, akathisia), when using dopamine antagonists (Wright2007). See also Chapter 11, “Obstetrics and Gynecology,” for discussion ofpsychotropic drug use in pregnancy.

Cancer patients experience nausea and vomiting for many reasons, in-cluding the cancer and its complications (tumor location/metastases, medica-tion effects, metabolic problems, pain, anxiety, impaired gastric emptying), aswell as its treatment with chemotherapy and radiation (Warr 2008). Theprevalence of chemotherapy-induced nausea and vomiting has improved with


the use of corticosteroids plus 5-HT3 receptor blockers, and further progresswas made by adding aprepitant (neurokinin 1 [NK1] receptor antagonist)(Lohr 2008). Classes of medications used to treat cancer-related nausea andvomiting include typical antipsychotics, 5-HT3 receptor antagonists, neuro-kinin receptor antagonists, anticholinergics, antihistamines, cannabinoids,and benzodiazepines (Lohr 2008; Warr 2008). Mirtazapine has been foundhelpful for both depression and nausea in cancer patients (Kim et al. 2008).Other medications that have somewhat less empirical support for their usebut may prove helpful include olanzapine (Srivastava et al. 2003).

Intestinal Disorders

Gastric Bypass

Gastric bypass surgery restricts the amount of food comfortably entering thesmall intestine and is often combined with malabsorptive procedures that fur-ther limit caloric uptake (Miller and Smith 2006). Following procedures thatinduce malabsorption, such as the Roux-en-Y or biliopancreatic diversion,patients have less area in their small bowel to absorb nutrients and vitamins.After gastric bypass surgery, bowel transit times decrease, further compound-ing malabsorption, because nutrients spend less time in contact with the re-maining area of bowel. Drugs in aqueous solution are absorbed faster thanthose in suspension or solid form (Miller and Smith 2006). In patients whohave had gastric bypass surgery or who have rapid transit times for other rea-sons, putting medications into solution can increase absorption and effective-ness. Roux-en-Y procedures remove a major portion of the absorptive area ofthe small intestine, and reduced absorption of medications may occur (Millerand Smith 2006; Seaman et al. 2005). Extended-release preparations are alsosignificantly affected by changes produced by bariatric surgery. The decreasedtransit time causes these drugs to be moved into the large intestine beforetheir protective coating has dissolved. Because many psychotropic agents areavailable in both extended- and immediate-release formulations (e.g., ven-lafaxine, bupropion, paroxetine), switching a patient to the latter after surgeryis relatively straightforward. A number of psychotropic medications are avail-able as orally disintegrating tablets (i.e., risperidone, olanzapine, aripiprazole,mirtazapine, clozapine, clonazepam). Use of this alternative formulation mayproduce more reliable drug levels in patients following gastric bypass surgery.


The effects of psychotropic medications after bariatric surgery can be hardto predict because of the widely variable absorption patterns. A comparisonbetween dissolution test models representing Roux-en-Y patients and preop-erative control subjects found that more medication was absorbed in controlsfor most psychotropic medications tested (Seaman et al. 2005). The excep-tions were bupropion and lithium (see also Table 4–1). In situations whereabsorption is uncertain, blood levels (if available) should be checked and pa-tients should be closely monitored for changes in clinical status suggestive ofmedication ineffectiveness. If orally disintegrating tablets or liquid solutiondo not provide adequate absorption in patients after bariatric surgery or withdiseases causing faster intestinal transit, other routes of administration shouldbe considered (see Chapter 3, “Alternate Routes of Drug Administration”).

Celiac Disease

Celiac disease is an autoimmune process that impairs intestinal absorption ofnutrients. Patients often present with diarrhea, steatorrhea, flatulence, andweight loss (Martucci et al. 2002). Gluten, found in wheat, rye, barley, and oats,worsens the disease; withdrawal of these grains improves symptoms for patientswith celiac disease. Transit through the GI tract is speeded in patients not ongluten-free diets, leading to reduced absorption of medications (Tursi 2004).

Inflammatory Bowel Disease

Inflammatory bowel diseases (IBDs) include Crohn’s disease and ulcerativecolitis. Crohn’s disease affects all portions of the GI tract and is marked bytransmural inflammation, a tendency to form fistulae, and strictures. Ulcer-ative colitis typically begins in the rectum and extends caudally, only affectingthe mucosal layer of the bowel. Patients with IBD have rates of depression upto three times that of the general population (Fuller-Thomson and Sulman2006). Depression has also been shown to be a risk factor for failure ofCrohn’s to respond to infliximab, an antibody against tumor necrosis factor-alpha (Persoons et al. 2005). Relapse of IBD may also be caused by stress-induced elevations in inflammatory cytokines and hypothalamic-pituitary-adrenal axis hyperactivity.

Antidepressants have been used in IBD both to improve psychiatricsymptoms and to decrease IBD symptoms (Mikocka-Walus et al. 2006). Par-oxetine has been reported to improve quality of life, and there are case reports


of disease remission with bupropion and phenelzine (Kast 1998; Kast andAltschuler 2001). Possible mechanisms include bupropion decreasing levelsof tumor necrosis factor-alpha (Kast and Altschuler 2001), and phenelzine re-ducing gut permeability, thereby limiting the passage of antigens that activateinflammation (Kast 1998).

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is the most common of the functional GI dis-orders, with prevalence estimates ranging from 4% to 22% (Drossman et al.2002). Symptoms include abdominal pain or discomfort that is relieved bydefecation and associated with altered stool frequency or form. IBS is consid-ered to be complex and multifactorial, and to involve altered gut reactivity,altered pain perception, and brain-gut dysregulation. Axis I psychiatric diag-noses have been found in 40%–94% of IBS patients seen in specialty clinics(Palsson and Drossman 2005). Depression, anxiety, and somatoform spec-trum disorders are commonly reported as being more prevalent in patientswith IBS, but attention-deficit disorder, adjustment disorders, and substanceabuse are also found more frequently in patients with IBS than in the generalpopulation (Whitehead et al. 2007). Higher rates of sexual abuse have beenreported, and a history of abuse has been shown to predict poorer response totreatment (Drossman et al. 1996).

Table 4–1. Medication absorption after Roux-en-Y gastric bypass surgery

Greater after surgery Unchanged after surgery Reduced after surgery

Bupropion Buspirone Amitriptyline

Lithium Citalopram Clonazepam

Diazepam Clozapine

Haloperidol Fluoxetine

Lorazepam Olanzapine

Methylphenidate Paroxetine

Oxcarbazepine Quetiapine

Trazodone Risperidone

Venlafaxine Sertraline

Zolpidem Ziprasidone

Source. Seaman et al. 2005.


In a Cochrane review, Quartero et al. (2005) concluded that antidepres-sants were ineffective in IBS but might be useful in selected subpopulations,such as patients with comorbid mood disorders. Regardless of equivocal re-sults, antidepressants continue to be widely used for IBS. A meta-analysis ofstudies that used older antidepressants (TCAs and mianserin) found thatantidepressants were superior to placebo, with a number needed to treat of3.2 (Jackson et al. 2000). Because of their anticholinergic effects, TCAs haveoften been chosen for IBS patients with diarrhea and abdominal spasms. De-sipramine and amitriptyline have been effective in providing symptom reliefand improving quality of life (Greenbaum et al. 1987; Rajagopalan et al.1998). In a head-to-head analysis of imipramine and citalopram, imipramineproduced greater improvement in both GI symptoms and mood than citalo-pram, but neither agent had any positive effect on the global impact of IBS(Talley et al. 2008). TCAs should not be given to patients with constipation-predominant IBS.

In recent years, SSRIs have been examined in treating IBS. Fluoxetine hasbeen found to be effective for pain and constipation-predominant IBS in adouble-blind randomized trial (Vahedi et al. 2005). A controlled crossoverstudy found that citalopram improved pain and overall well-being indepen-dent of its effects on depression or anxiety (Tack et al. 2006). Paroxetine andpsychotherapy have both been shown to improve patients’ quality of life(Creed et al. 2003). The presence of anxiety does not appear to predict betterresponse to paroxetine among patients with IBS (Masand et al. 2002). Thereare also case reports of improvement with fluvoxamine and mirtazapine (Em-manuel et al. 1997; Thomas 2000). Practically speaking, patients with con-stipation-predominant IBS may benefit from SSRIs, whereas patients withdiarrhea-predominant IBS should be prescribed TCAs.

Incontinence

Fecal incontinence occurs in 0.3%–2.2% of community-dwelling adults andis much more common in nursing homes, where rates may approach 50%(Whitehead et al. 2001). Incontinence adversely affects quality of life, as wellas occupational and social functioning. Medications that slow transit time,such as the opioid loperamide, bulk-forming agents, or anticholinergic med-ications (e.g., amitriptyline), can all improve incontinence, particularly whenaccompanied by diarrhea (Scarlett 2004). Amitriptyline at low dosages


(20 mg/day) decreased incontinence in 89% of patients and decreased thestrength and frequency of rectal motor discharges (Santoro et al. 2000).

Diarrhea

Functional diarrhea can be part of IBS or a stand-alone, painless syndrome.Patients often have reduced bowel transit time, and those with diarrhea-predominant IBS may have increased sensitivity to rectal pressure (Farthing2005). In addition to loperamide and centrally acting opioids, desipraminehas been recommended as the tricyclic of choice in functional diarrhea, withdosages of 25–200 mg/day (Dellon and Ringel 2006).

Constipation

Constipation can result from diet, metabolic diseases such as diabetes orhypothyroidism, neurological disease, and medications, including many psy-chotropics (Wald 2007) (see discussion of constipation in “GastrointestinalSide Effects of Psychiatric Drugs” later in this chapter). Behavioral interven-tions include increased fiber and fluid intake, physical activity, and use ofbulking agents. Stool softeners and osmotic laxatives (e.g., polyethylene gly-col, nonabsorbable sugars) may also be considered.

Liver Disorders

General Pharmacokinetics in Liver Disease

Impaired hepatic function will impact many critical aspects of pharmacoki-netics. These range from absorption, through first-pass metabolism and he-patic biotransformation, to the production of drug-binding proteins, as wellas overall fluid status, which will determine the volume of drug distribution(see Chapter 1, “Pharmacokinetics, Pharmacodynamics, and Principles ofDrug–Drug Interactions,” for a discussion of pharmacokinetics).

Oral absorption may be slowed due to vascular congestion, which mayexist in cirrhotic patients with portal hypertension and/or portal hypertensivegastropathy. In patients with liver insufficiency, both first-pass metabolismand hepatic biotransformation may be slowed, increasing oral bioavailabilityand prolonging drug effect. Bioavailability may also be increased in cirrhoticpatients because of portosystemic shunting. Although liver disease reduces


plasma proteins and alters protein binding, compensatory changes in metab-olism and excretion result in only transient and generally clinically insignifi-cant changes in free drug levels (Adedoyin and Branch 1996; Blaschke 1977).However, disease-related changes in metabolism, excretion, and volume ofdistribution do alter plasma drug levels, often in complex ways. Ascites andperipheral edema increase the volume of distribution of water-soluble drugsand reduce their plasma concentration. In contrast, hepatic disease may im-pair cytochrome P450–mediated drug metabolism, reducing drug clearanceand increasing drug levels.

Drug-Specific Issues and Dosing in Liver Disease

The clinician prescribing psychotropic medications for a patient with liverdisease should consider the severity of the liver disease, the medication beingconsidered, the margin between therapeutic and toxic plasma levels, and thepresence or high risk of hepatic encephalopathy. Clinical response and signsof toxicity should guide dosage. Therapeutic drug monitoring may be ofvalue, but results must be interpreted with caution, because changes in pro-tein binding may lead to falsely low estimates of active drug levels. Only ther-apeutic drug monitoring methods selective for unbound drug should be used(see Chapter 1, “Pharmacokinetics, Pharmacodynamics, and Principles ofDrug–Drug Interactions”). In general, drugs with a narrow therapeutic win-dow (e.g., lithium) should be used with caution or avoided.

Patients with hepatic encephalopathy may have additional differentialdiagnostic considerations. An initial assessment is necessary to establishwhether affective symptoms represent an underlying mood disorder or affec-tive dysregulation associated with encephalopathy. In some cases, treatmentof encephalopathy will address mood symptoms. If additional psychotropicmedication is needed, avoidance of drugs that can worsen encephalopathy(i.e., sedative-hypnotics, anticholinergic medications) is recommended.

Unlike the creatinine clearance rate used for dosage adjustment of drugsprimarily excreted by the kidneys, no biochemical measure exists to estimatehepatic clearance and guide drug dosage adjustment. The Child-Pugh score(CPS) has often been used to estimate the degree of cirrhosis, thereby provid-ing some guidance regarding hepatic clearance. The CPS reflects the severityof cirrhosis (rated as mild, moderate, or severe), not hepatic clearance or drugkinetics (Albers et al. 1989). Nevertheless, the degree of cirrhosis as measured


by the CPS does reflect relevant consequences of liver disease (i.e., albumin,ascites, and encephalopathy), and can provide general dosing guidance.

The safest treatment strategy is to begin with lower initial dosages and per-haps longer dosing intervals and then titrate gradually so that drug levels reachsteady state more slowly (see Table 4–2). From our clinical experience, we havefound that patients rated with CPS-A (mild) liver failure are early in the dis-ease process and can usually tolerate 75%–100% of a standard initial dosage.Those with CPS-B (moderate) disease should be dosed more cautiously. A50%–75% reduction in the normal starting dosage is prudent. Because pro-longation of the elimination half-life will delay drug levels from reachingsteady state, smaller incremental dosing increases are recommended. Patientswith CPS-C (severe) cirrhosis will commonly have some degree of hepatic en-cephalopathy, and medications must be cautiously monitored to avoid toxicityor worsening of the encephalopathy.

In some cases, cirrhotic patients will require dosage reductions as their liverfunction deteriorates over time. Certain drugs require more consideration thanothers. Dosage adjustment for drugs that require multistep biotransformationor are metabolized into active metabolites (e.g., amitriptyline, imipramine,venlafaxine, bupropion) may be more complicated than for drugs that onlyundergo one-step biotransformation or are converted to inactive drug with thefirst biotransformation step (e.g., most SSRIs). Drugs with long half-lives,such as fluoxetine, usually should be avoided. Extended- or slow-release drugformulations usually should be avoided as the pharmacokinetics are less pre-dictable in liver insufficiency. Benzodiazepines should be avoided in patientsat risk for hepatic encephalopathy, but when they are needed (e.g., for deliriumtremens), a benzodiazepine requiring only glucuronidation and not oxidativemetabolism should be prescribed (lorazepam, temazepam, or oxazepam). Glu-curonidation is generally preserved in cirrhosis (Pacifici et al. 1990).

Caution is warranted even for drugs not requiring hepatic metabolism.Drugs distributed in total body water (e.g., lithium) or drugs that require re-nal clearance of the parent drug or active metabolites (e.g., gabapentin) canbe difficult to manage in cirrhotic patients with fluid overload. In addition,even patients with mild cirrhosis can have impaired renal function (due tohepatorenal syndrome or secondary hyperaldosteronism), including a re-duced glomerular filtration rate. Possible abnormal renal hemodynamics, anincrease in volume of distribution, and dramatic changes in fluid status may


Table 4–2. Psychotropic drug dosing in hepatic insufficiency (HI)Medication Dosing information

Antidepressants

MAOIs Potentially hepatotoxic. No dosing guidelines.

SSRIs Extensively metabolized; decreased clearance and prolonged half-life. Initial dose should be reduced by 50%, with potentially longer dosing intervals between subsequent doses. Target doses are typically substantially lower than usual.

TCAs Extensively metabolized. Potentially serious hepatic effects. No dosing guidelines.

Bupropion Extensively metabolized; decreased clearance. In even mild cirrhosis, use at reduced dose and/or frequency. In severe cirrhosis, do not exceed 75 mg/day for conventional tablets, or 100 mg/day for sustained-release formulations.

Desvenlafaxine Primarily metabolized by conjugation. No adjustment in starting dose needed in HI. Do not exceed 100 mg/day in severe HI.

Duloxetine Extensively metabolized; reduced metabolism and elimination. Do not use in patients with any HI.

Mirtazapine Extensively metabolized; decreased clearance. No dosing guidelines.

Nefazodone May cause hepatic failure. Avoid use in patients with active liver disease.

Selegiline Extensively metabolized; caution in HI. No dosing guidelines.

Trazodone Extensively metabolized. No dosing guidelines.

Venlafaxine Decreased clearance of venlafaxine and its active metabolite O-desmethylvenlafaxine. Reduce dosage by 50% in mild to moderate HI, per manufacturer.

Atypical antipsychotics

Aripiprazole Extensively metabolized. No dosage adjustment needed in mild to severe HI, per manufacturer.

Clozapine Extensively metabolized. Discontinue in patients with marked transaminase elevations or jaundice. No dosing guidelines.

Iloperidone Extensively metabolized. Unknown pharmacokinetics in mild or moderate HI. Not recommended in patients with HI, per manufacturer.


Olanzapine Extensively metabolized. Periodic assessment of transaminases recommended. No dosage adjustment needed, per manufacturer.

Paliperidone Primarily renally excreted. No dosage adjustment needed in mild to moderate HI. No dosing guidelines in severe HI.

Quetiapine Extensively metabolized; clearance decreased 30%. Start at 25 mg/day; increase by 25–50 mg/day.

Risperidone Extensively metabolized; free fraction increased 35%. Starting dosage and dose increments not to exceed 0.5 mg twice daily. Increases over 1.5 mg twice daily should be made at intervals of ≥1 week.

Ziprasidone Extensively metabolized; increased half-life and serum level in mild to moderate HI. In spite of this, manufacturer recommends no dosage adjustment.

Conventional antipsychotics

Haloperidol, etc. All metabolized in the liver. No specific dosing recommendations. Avoid phenothiazines (e.g., thioridazine and trifluoperazine). If nonphenothiazines are used, reduce dosage and titrate more slowly than usual.

Anxiolytic and sedative-hypnotic drugs

Alprazolam Decreased metabolism and increased half-life. Reduce dosage by 50%. Avoid use in patients with cirrhosis.

Buspirone Extensively metabolized; half-life may be prolonged. Reduce dosage and frequency in mild to moderate cirrhosis. Do not use in patients with severe impairment.

Chlordiazepoxide, clonazepam, diazepam, flurazepam, triazolam

Extensively metabolized; reduced clearance and prolonged half-life. Avoid use if possible.

Lorazepam, oxazepam, temazepam

Metabolized by conjugation; clearance not affected. No dosage adjustment needed. Lorazepam preferred choice.

Ramelteon Extensively metabolized. Exposure to ramelteon increased fourfold in mild HI and 10-fold in moderate HI. Use with caution in patients with moderate HI. Not recommended in severe HI.

Table 4–2. Psychotropic drug dosing in hepatic insufficiency (HI) (continued)Medication Dosing information


Anxiolytic and sedative-hypnotic drugs (continued)

Zaleplon, zolpidem Metabolized in liver. Reduced clearance. Usual ceiling dose 5 mg.Not recommended in severe HI.

Eszopiclone, zopiclone

Metabolized in liver. No dosage adjustment needed for mild to moderate HI. Reduce dose by 50% in severe HI.

Mood stabilizers

Carbamazepine Extensively metabolized. Perform baseline liver function tests and periodic evaluations during therapy. Discontinue for active liver disease or aggravation of liver dysfunction. No dosing guidelines.

Oxcarbazepine No dosage adjustment needed in mild to moderate HI, per manufacturer.

Gabapentin Renally excreted; not appreciably metabolized. No dosage adjustment needed.

Lamotrigine Initial, escalation, and maintenance dosages should be reduced by 50% in moderate HI (Child-Pugh B) and by 75% in severe HI (Child-Pugh C).

Lithium Renally excreted; not metabolized. Adjust dosage based on fluid status.

Topiramate Reduced clearance. No dosing guidelines.

Valproate Extensively metabolized; reduced clearance and increased half-life. Reduce dosage; monitor liver function tests frequently, especially in first 6 months of therapy. Avoid in patients with substantial hepatic dysfunction. Caution in patients with prior history of hepatic disease.

Cholinesterase inhibitors and memantine

Donepezil Mildly reduced clearance in cirrhosis. No specific recommendations for dosage adjustment.

Galantamine Use with caution in mild to moderate HI. Dose should not exceed 16 mg/day in moderate HI (Child-Pugh 7–9). Use not recommended in severe HI (Child-Pugh 10–15).

Rivastigmine Clearance reduced 60%–65% in mild to moderate HI, but dose adjustment may not be necessary.

Memantine Primarily renally eliminated. No dosage adjustment expected, per manufacturer.



make maintaining stable therapeutic drug levels difficult, if not impossible.Rapid changes in fluid status may occur in the routine medical managementof cirrhotic patients (e.g., paracentesis, adjustment of diuretics or aggressivediuresis, or fluid loss from diarrhea caused by medications used for the treat-ment of hepatic encephalopathy). In these situations, as the volume of totalbody fluid contracts, a previously therapeutic drug level could rise dramati-cally. Such changes may be delayed due to the slow equilibration of the drugbetween intracellular and extracellular fluid compartments.

Hepatitis C and the Management of Neuropsychiatric Effects of Interferon-Alpha

Infection with the hepatitis C virus (HCV) is one of the leading causes of pro-gressive liver disease in the United States and is the most common indicationfor liver transplantation. The most common route of infection in the UnitedStates is intravenous drug use (65%–80% of intravenous drug users are HCVpositive), and high rates of other psychiatric illnesses are common in popula-tions of HCV patients (El-Serag et al. 2002). Treatment for HCV includesinterferon-alpha (IFN-α) in combination with ribavirin, which causes signif-icant neuropsychiatric side effects.

Neuropsychiatric side effects attributed to IFN-α include cognitive im-pairment (amotivation, apathy, impaired executive function, and memory

Psychostimulants

Atomoxetine Extensively metabolized. Reduce initial and target dose by 50% in moderate HI and 75% in severe HI, per manufacturer.

Methylphenidate Unclear association with hepatotoxicity, particularly when coadministered with other adrenergic drugs. No dosing guidelines.

Armodafinil, modafinil

Decreased clearance. Reduce dose by 50% in severe HI.

Note. MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibitor;TCA=tricyclic antidepressant.Source. Compiled from Crone et al. 2006; Jacobson 2002; Monti and Pandi-Perumal 2007; and manufacturers’ product information.



loss), affective disturbances (depression and less often mania), agitation/anger(including impulsivity and physical aggression), neurovegetative symptoms(fatigue, lethargy, malaise, and bodily pains), and suicidal ideation. Frank de-lirium or psychosis secondary to IFN-α is rare. During treatment with IFN-α, 10%–50% of patients experience depression, which is the most commonreason for discontinuation of IFN-α therapy. Depressive symptoms at baselinemay predispose an individual to developing depression when taking IFN-α,making prescreening and treatment of depression important prior to initiatingIFN-α. In addition, there should be a low threshold for initiating antidepres-sants during IFN-α therapy if depressive symptoms appear, not only to allowthe patient to more comfortably complete the full therapeutic course, but alsobecause of increased risk for suicidal ideation and suicide while on IFN-α ther-apy. IFN-α treatment typically continues for at least 6–12 months, makingroutine monitoring of the patient’s mood state and thoughts of suicide an im-portant aspect of patient care. If antidepressant therapy is begun, it should becontinued for at least a month following the completion of therapy, becauseIFN-α side effects can persist for weeks following drug discontinuation.

Complete abstinence from alcohol during HCV infection and especiallyduring IFN-α treatment is critically important. Alcohol stimulates HCV viralreplication, diminishes immune function, and reduces efficacy of IFN-αtherapy, resulting in poor treatment response (Zhang et al. 2003).

HCV-related medical complications combined with the biological effectsof IFN-α require thoughtful consideration of psychotropic choice. Hypothy-roidism can occur due to IFN-α and may mimic depression. Due to frequenthematological abnormalities in HCV patients receiving IFN-α (i.e., anemia,thrombocytopenia, neutropenia), drugs that can similarly cause or exacerbatethese blood dyscrasias (i.e., mirtazapine, valproate, carbamazepine, clozapine)should be used with care. Anticholinergic TCAs may exacerbate cognitive im-pairment due to HCV and/or IFN-α.

According to a number of case series, case reports, and two clinical trials,SSRIs can be successfully used to treat HCV patients who develop IFN-α–induced depression (Gleason et al. 2005; Hauser et al. 2002; Kraus et al.2008). Prophylactic antidepressant therapy using SSRIs has also been exam-ined in IFN-α–treated melanoma and HCV patients. A majority of findingssuggest that prophylactic treatment is beneficial in reducing the frequencyand severity of IFN-α–induced depression (e.g., Hauser et al. 2000; Raison


et al. 2007); however, findings are not uniformly positive (Morasco et al.2007). SSRIs are generally well tolerated by this patient population, althoughconcerns about the risks of serious bleeding (including GI and retinal hemor-rhages) have been raised (Weinrieb et al. 2003; see also “SSRIs and UpperGastrointestinal Bleeding” later in this chapter). Bupropion can help to alle-viate fatigue, cognitive impairment, and psychomotor retardation associatedwith IFN-α therapy (Malek-Ahmadi and Ghandour 2004). Psychostimulantscan help to manage fatigue, apathy, and cognitive slowing related to IFN-αtreatment but should only be considered for those patients without a historyof substance abuse. Psychosis, mania, and delirium require discontinuation ofIFN-α and treatment with an antipsychotic.

Regarding the question of whether patients with serious preexisting psy-chiatric disorders (e.g., major depression, bipolar disorder, schizophrenia,substance abuse) can safely and successfully undergo IFN-α treatment, mostreports indicate positive results (e.g., Dollarhide et al. 2007; Mauss et al.2004). These patients require close follow-up and coordination between theirmental health and medical providers, which allows for early recognition ofdifficulties. Prompt management of worsening psychiatric symptoms can re-duce the risk of adverse outcomes and premature discontinuation of IFN-αtherapy. For patients with a history of major depression in remission, there isa lack of consensus as to whether prophylactic antidepressant therapy is nec-essary (Loftis and Hauser 2003). Among patients with residual depressivesymptoms, a history of recurrent major depression, or severe depression withsuicidal ideation, prophylactic therapy is a prudent choice.

Gastrointestinal Side Effects of Psychiatric Drugs

Psychopharmacological agents cause a range of GI side effects, from mild-moderate and transient to severe. Persistent and more severe effects are cov-ered here and in Chapter 2, “Severe Drug Reactions,” and are summarized inTable 4–3.

Nausea and Vomiting

Many psychiatric medications, including SSRIs, mood stabilizers, psycho-stimulants, and cognitive enhancers, have nausea as an early side effect(Drossman 2006). In fact, GI distress is arguably the leading cause of acute


Table 4–3. Gastrointestinal adverse effects of psychiatric drugs

Medication Gastrointestinal adverse effect

Anxiolytics/sedative-hypnotics

Buspirone Nausea

Zolpidem Nausea, dyspepsia

Eszopiclone, zopiclone Bitter taste, dry mouth, nausea

Antidepressants

SSRIs

General Nausea, diarrhea

Paroxetine Nausea, diarrhea, constipation

SNRIs and novel action agents

Bupropion, desvenlafaxine, duloxetine, venlafaxine

Nausea, constipation, dry mouth

Mirtazapine Dry mouth, constipation, increased appetite

Nefazodone Dry mouth, nausea, constipation, hepatotoxicity

TCAs Dry mouth, constipation. More severe GI adverse effects with tertiary amine TCAs (e.g., amitriptyline, imipramine, doxepin, clomipramine) than with secondary amine agents (e.g., desipramine, nortriptyline)

Antipsychotics

Atypical agents

General Dry mouth, constipation

Clozapine Hypersalivation, constipation

Low-potency typical agents Dry mouth, constipation, reversible cholestatic hepatotoxicity (especially with chlorpromazine)

Anticholinergics for EPS

Benztropine, biperiden, diphenhydramine, trihexyphenidyl

Dry mouth, constipation

Mood stabilizers

Carbamazepine Nausea, vomiting, dyspepsia, diarrhea, hepatotoxicity

Lamotrigine Nausea, vomiting, dyspepsia, diarrhea

Lithium Nausea, vomiting, diarrhea, decreased appetite


discontinuation of drugs by patients starting treatment with SSRIs. Lithiummay cause nausea and/or vomiting, but changing the formulation to lithiumcitrate often helps (Einarson et al. 2007). Providing divided doses of carba-mazepine throughout the day may be helpful, as can changing sodium val-proate to divalproex sodium (Drossman 2006). Furthermore, the presence ofnausea, vomiting, and diarrhea may herald psychiatric medication toxicity,such as early signs of lithium toxicity or serotonin syndrome. For patients inwhom nausea and vomiting prevent adequate intake of psychiatric medica-tion, alternate routes of administration must be considered (see Chapter 3,“Alternate Routes of Drug Administration”).

Diarrhea

Diarrhea occurs as a side effect of lithium treatment and is an early sign oflithium toxicity. Slow-release formulations of lithium can decrease the likeli-hood of diarrhea as a side effect. Paradoxically, lithium has also been reportedto treat chronic unexplained diarrhea, perhaps by modulating cyclic adeno-

Oxcarbazepine Nausea, vomiting, dyspepsia, diarrhea (less than carbamazepine)

Valproate Nausea, vomiting, dyspepsia, diarrhea, hyperammonemia, hepatotoxicity


Cholinesterase inhibitors Nausea, vomiting, diarrhea, anorexia. Most common with rivastigmine

Memantine Constipation

Psychostimulants

Atomoxetine Nausea, constipation, dry mouth, decreased appetite

Amphetamines, methylphenidate

Stomachache, appetite suppression

Armodafinil, modafinil Nausea, dry mouth, anorexia

Note. EPS=extrapyramidal symptoms; GI=gastrointestinal; SNRI=serotonin-norepinephrinereuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant.

Table 4–3. Gastrointestinal adverse effects of psychiatric drugs (continued)

Medication Gastrointestinal adverse effect


sine monophosphate activity in the gut (Owyang 1984). Valproate, cholines-terase inhibitor cognitive enhancers, and SSRIs can also cause diarrhea (McCainet al. 2007).

Constipation

Constipation is often caused by psychotropic medications, particularly thoseagents with significant anticholinergic activity (e.g., TCAs, paroxetine, low-potency antipsychotics, olanzapine, benztropine). Even among relativelynewer agents, such as venlafaxine, bupropion, and mirtazapine, constipationcan be a problematic side effect. If dietary and medication-oriented remediesdescribed earlier in chapter (see discussion of constipation in “Intestinal Dis-orders”) are ineffective, switching to medications with less risk of constipationshould be considered.

Psychotropic Drug–Induced Gastrointestinal Complications

SSRIs and Upper Gastrointestinal Bleeding

SSRIs may interfere with platelet function and prolong upper GI bleedingtime. No consensus exists as to whether SSRIs raise the risk of upper GIbleeding, with evidence indicating significantly increased risk (e.g., Loke et al.2008), very small risk (e.g., Opatrny et al. 2008), and no increased risk (e.g.,Vidal et al. 2008). Risk of upper GI bleeding appears more likely if the patientis also taking high-dose nonsteroidal anti-inflammatory drugs, is thrombocy-topenic, or has other platelet dysfunction (e.g., von Willebrand disease) (deAbajo and García-Rodriguez 2008). The coadministration of warfarin andSSRIs does not appear to increase risk for GI bleeding, but may increase riskfor non-GI bleeding (Schalekamp et al. 2008).

Psychotropic Drug–Induced Liver Injury

In most cases, psychotropic medication–induced liver injury is idiosyncraticand cannot be predicted from specific risk factors or drug dosage (DeSantyand Amabile 2007) (see also Chapter 2, “Severe Drug Reactions”). Drug-induced liver injury occurs in less than 1 per 1,000 to 1 per 100,000 treatedpatients and is usually not caused by overdose (Russo and Watkins 2004). In


the United States over the past 12 years, fewer than 500 patients with acutedrug-induced liver toxicity developed acute hepatic failure requiring livertransplantation. The majority of these cases of acute toxicity were due toacetaminophen (mostly in overdose); 3% were due to phenytoin, 3% to val-proate, and less than 1% to nefazodone (Russo and Watkins 2004). Thus,even severe drug-induced liver injury is usually reversible and rarely results infatality if the drug is discontinued.

Almost all antidepressants have been implicated in cases of drug-inducedhepatotoxicity, but only duloxetine and nefazodone have received additionalscrutiny. With duloxetine, 1% of patients developed a threefold increase inalanine aminotransferase compared with 0.2% of patients receiving placebo.The risk of duloxetine-mediated hepatotoxicity is primarily a concern inpatients who have preexisting chronic liver disease or who consume largeamounts of alcohol (DeSanty and Amabile 2007). Due to a significant num-ber of nefazodone-induced liver injury cases (1 case of death or transplant per250,000–300,000 patient-years of treatment [Russo et al. 2004]), Bristol-Myers Squibb stopped manufacturing the drug in 2004, although genericnefazodone is still available.

Valproate is associated with an overall 1 in 20,000 incidence of liver tox-icity, although the frequency can be as high as 1 in 600 in certain groups (i.e.,infants younger than 2 years, patients on anticonvulsant polytherapy). Therisk of carbamazepine-induced hepatotoxicity is estimated at 16 cases per100,000 treatment years, and 20 cases of severe lamotrigine-induced liver tox-icity have been reported (Zaccara et al. 2007).

Chlorpromazine, and less commonly other phenothiazines, may cause re-versible cholestatic hepatotoxicity in up to 2% of patients, typically withinthe first 4 weeks of therapy. Because this reaction is believed to be due to im-paired sulfoxidation, patients with primary biliary cirrhosis, who often haveimpaired sulfoxidation, should not be given these drugs (Leipzig 1990).

Despite the potential risk of liver injury, there is no justification to rou-tinely monitor liver enzymes for most psychotropics (with the exception ofvalproate) because hepatic adverse effects are unpredictable and occurabruptly at varying times following drug initiation (Russo and Watkins2004). Routine laboratory monitoring of hepatic enzymes and liver functionsmay be indicated 1) before starting treatment to establish baseline liver en-zymes, 2) in high-risk patients, 3) in patients with impaired ability to com-


municate, or 4) in the presence of early symptoms or prodromal signs of apossible adverse reaction (Zaccara et al. 2007).

Although most episodes of liver injury are asymptomatic, patients can beinstructed on the signs and symptoms of liver injury (e.g., right upper quad-rant pain, dark urine, itching, jaundice, nausea, anorexia) when prescribed amedication that may cause such an adverse effect. Instances of idiosyncratichepatocellular jaundice are almost always associated with minor and asymp-tomatic aminotransferase elevations, exceeding 3 times the upper limits ofnormal in up to 15% of treated patients with drugs capable of causing thesereactions (Russo and Watkins 2004). Inexplicably, the aminotransferase eleva-tions, which reflect liver injury, often reverse even if drug therapy is continued,although a minority of patients will develop progressive liver injury. Neverthe-less, because it is impossible to predict the smaller subset of individuals whoare actually susceptible to progressive injury from the drug, patients who de-velop aminotransferase elevations 2–3 times the upper limit of normal shouldhave the suspected drug discontinued. In most cases, the liver injury sponta-neously resolves upon drug discontinuation, although in some cases, the en-zymes continue to rise for several days. Therefore, clinical symptoms and liverenzymes should be followed closely after the drug is discontinued.

It is unclear if patients with preexisting liver disease are more susceptibleto idiosyncratic drug-induced liver injury, although the manufacturer has rec-ommended that duloxetine be avoided in patients with hepatic dysfunction.Conventional wisdom suggests that these idiosyncratic drug reactions arebased on other factors (e.g., genetics) and are not dependent on dosage orclearance (Russo and Watkins 2004). Nevertheless, caution is recommendedbecause these patients may be less able to handle the additional loss of hepaticfunction caused by drug-induced injury. Another consideration is the chal-lenge of interpreting elevations in hepatic enzyme levels in patients with pre-existing liver dysfunction. If a drug-induced injury occurs in a patient withsignificant cirrhosis, the resulting elevation in aminotransferases may under-estimate the true severity of the insult.

Drug-Induced Pancreatitis

Drug-induced pancreatitis is an infrequent cause of acute pancreatitis, repre-senting only 0.1%–2% of cases within the general population (Dhir et al.2007). Despite this infrequency, prompt recognition is necessary to minimize


the risk of serious consequences, including systemic inflammation, chronicpancreatitis, multiple organ failure, and death. Prompt withdrawal of thedrug usually leads to resolution of the pancreatitis within 10 days. Time ofonset is variable, often occurring within a few weeks to months from startinga particular drug. There is no dose-response relationship for drug-inducedpancreatitis, which can develop over a wide range of drug dosages. Certain pa-tients may be more prone to drug-induced pancreatitis, including those withhuman immunodeficiency virus disease, cancer, Crohn’s disease, and cysticfibrosis, or those taking multiple medications.

Valproic acid is the psychotropic agent that has caused the greatest num-ber of reported cases of drug-induced pancreatitis (Gerstner et al. 2007). Thetrue incidence is considered to be 1 per 40,000 patients, who most oftenpresent with abdominal pain, nausea, vomiting, diarrhea, and anorexia. Tran-sient asymptomatic hyperamylasemia occurs in 20% of adults on valproicacid, but this does not correlate with a greater risk for pancreatitis (Zaccara etal. 2007). Infrequent case reports have linked pancreatitis to other anticon-vulsants, including carbamazepine, lamotrigine, topiramate, levetiracetam,and vigabatrin (Zaccara et al. 2007).

Cases of antipsychotic-induced pancreatitis have been reported, most of-ten occurring within the first 6 months of treatment (Koller et al. 2003). Mostcases have involved clozapine and olanzapine, with fewer instances resultingfrom risperidone and haloperidol (Cerulli 1999; Kahn and Bourgeois 2007).Rarely, ziprasidone, quetiapine, and aripiprazole have been implicated (Grop-per and Jackson 2004; Hanft and Bourgeois 2004; Reddymasu et al. 2006).

Among antidepressants, mirtazapine has been implicated in several casesof drug-induced pancreatitis (Hussain and Burke 2008). Bupropion, ven-lafaxine, and SSRIs have been infrequently involved (Spigset et al. 2003). Re-challenge with the offending drug after an episode of pancreatitis is notadvised, even using lower dosages or a different route of administration, dueto the risk of recurrence. However, substitution with another drug of the sameclass is considered an acceptable option (Dhir et al. 2007).

Colonic Toxicity

A number of medications and substances cause injury to the GI tract. Bar-biturates, chlorpromazine, and TCAs have all been associated with colonicischemia (Gollock and Thomson 1984; Olson et al. 1984). Cocaine is also


well known to induce ischemia after use (Cappell 2004). Drugs that slow thepassage of material through the colon can lead to constipation and pseudo-obstruction. Phenothiazines, which have anticholinergic and antiserotonergicproperties, caused 42% of the cases of pseudo-obstruction in a 1992 series(Jetmore et al. 1992). Pseudo-obstruction can lead to complications includ-ing perforation and ischemia (Cappell 2004). Tricyclic antidepressants arealso associated with pseudo-obstruction. Treatment with physostigmine canimprove motility and relieve the apparent blockade (Cappell 2004). There aresingle case reports of carbamazepine-induced eosinophilic colitis (Antilla andValtonen 1992), lithium causing bowel wall vasculitis and subsequent bowelinfarction (Cannon 1982), and ileus after the addition of bupropion to a sta-ble dose of lithium in an elderly female (Kales and Mellow 1999).

Psychiatric Side Effects of Gastrointestinal Medications

In addition to psychiatric medications causing GI disorders, GI medicationscan have psychiatric side effects. Although much has been written about IFN-α, psychiatrists need to be alert to the potential effects of other GI medica-tions, as they may alter a patient’s clinical presentation and require medica-tion adjustments. Potential adverse psychiatric effects of GI medications arelisted in Table 4–4.

Table 4–4. Psychiatric adverse effects of gastrointestinal drugs

Medication Psychiatric adverse effect

Antidiarrheal agents

Diphenoxylate Preparations contain atropine; sedation, lethargy, insomnia, depression, euphoria, confusion

Loperamide Dizziness

Antiemetics

Aprepitant Dizziness

Corticosteroids (e.g., dexamethasone)

Mania, anxiety, irritability, psychosis (acute), depression (chronic)


Dimenhydrinate Drowsiness, ataxia, disorientation, convulsions, stupor

Diphenhydramine Drowsiness, dizziness, confusion, cognitive impairment

Dolasetron Headache, fatigue, dizziness

Domperidone Acute dystonic reactions (rare)

Dronabinol, nabilone Dizziness, euphoria, paranoid reaction, abnormal thinking, somnolence, confusion

Droperidol Extrapyramidal symptoms

Granisetron Headache, asthenia, somnolence

Metoclopramide Restlessness, drowsiness, fatigue, dystonic reactions

Palonosetron Anxiety

Prochlorperazine Drowsiness, dizziness, and headache are common; extrapyramidal symptoms, seizures, confusion, insomnia, neuroleptic malignant syndrome

Promethazine Drowsiness, confusion, hyperexcitability, extrapyramidal symptoms, seizures, confusion, neuroleptic malignant syndrome

Trimethobenzamide Drowsiness, dizziness, disorientation, depression, seizure, extrapyramidal symptoms

Histamine2 (H2) antagonists

Cimetidine Headache, dizziness

Nizatidine Dizziness, somnolence, anxiety, nervousness

Ranitidine Headache, malaise, dizziness

Irritable bowel drugs

Antispasmodics (dicyclomine, glycopyrrolate, methscopolamine)

Dizziness, blurred vision, drowsiness, weakness, confusion, excitement (especially in the elderly)

Sulfasalazine Headache, anorexia

Proton pump inhibitors

Esomeprazole, lansoprazole, omeprazole, pantoprazole

Dizziness

Table 4–4. Psychiatric adverse effects of gastrointestinal drugs (continued)

Medication Psychiatric adverse effect


Drug–Drug Interactions

Potential interactions between GI and psychotropic medications are sum-marized in Tables 4–5 and 4–6. Drug interactions for antibiotics used forHelicobacter pylori regimens (e.g., metronidazole, tetracycline, clarithromy-cin, amoxicillin) are reviewed in Chapter 12, “Infectious Diseases.” Addi-tional information on corticosteroids is presented in Chapter 10, “Endocrineand Metabolic Disorders.” See Chapter 1 for a discussion of pharmacokinet-ics, pharmacodynamics, and principles of drug–drug interactions.

Conclusion

GI disorders include a wide range of physiological and functional distur-bances that span multiple organ systems, from the mouth to the colorectal re-gion. Often, psychological stress or comorbid psychopathology appears toinfluence the level of GI symptomatology that a patient experiences. Psycho-pharmacological treatment can be beneficial in improving quality of life, re-ducing physical discomfort, and/or controlling anxiety and depression. Theselection of pharmacological agent, however, requires consideration of poten-tial undesirable side effects (e.g., dysphagia, xerostomia, nausea and/or vom-iting), tolerability, and safety.

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Table 4–5. Gastrointestinal drug–psychotropic drug interactions

Medication Interaction mechanism Effect on psychotropic drugs and management

Medications for gastric acidity, peptic ulcers, and GERD

Antacids Increased gastric pH and delayed gastric emptying

Increased sodium excretion

May reduce drug absorption. Take antacids 2–3 hours apart from other drugs.

Sodium bicarbonate may increase renal excretion of lithium.

Cimetidine Inhibits CYP 1A2, 2C9/19, 2D6, 3A4

Inhibits oxidative metabolism of most drugs. Reduce psychotropic dose. Avoid cimetidine or use psychotropics eliminated by conjugation.

Esomeprazole Induces CYP 1A2 Increased elimination and reduced levels of clozapine and olanzapine.

Lansoprazole Induces CYP 1A2 Increased elimination and reduced levels of clozapine and olanzapine.

Omeprazole Inhibits CYP 2C19 Increased levels and toxicity of diazepam, flunitrazepam, phenytoin, and mephenytoin.

Sucralfate Drug binding May reduce drug absorption; take at least 2 hours prior to other drugs.

Antidiarrheal agents

Kaolin/attapulgite Drug binding May bind drugs and reduce absorption. Avoid within 2–3 hours of taking other medications.

Medications for irritable bowel syndrome

Tegaserod Inhibits CYP 1A2 and 2D6 May reduce metabolism and increase levels of atomoxetine, clozapine, chlorpromazine, olanzapine, risperidone, TCAs, maprotiline, mirtazapine, trazodone, and venlafaxine.

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Antispasmodics (clidinium-chlordiazepoxide, dicyclomine, glycopyrrolate, hyoscyamine, methscopolamine)

Additive anticholinergic effects

Increased risk of cognitive impairment and delirium in combination with anticholinergic psychotropics (TCAs, antipsychotics, benztropine, tranylcypromine).

Reduced therapeutic effect of cholinesterase inhibitors and memantine.

Antinauseants/antiemetic agents

5-HT3 antagonists (dolasetron, granisetron, ondansetron, palonosetron, ramosetron)

QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Dimenhydrinate, diphenhydramine




Prochlorperazine, promethazine, trimethobenzamide




Table 4–5. Gastrointestinal drug–psychotropic drug interactions (continued)


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Domperidone, droperidol Dopamine antagonistQT prolongation

Increased risk of EPS when combined with antipsychotics.Increased risk of cardiac arrhythmias with other QT-prolonging agents,

including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Metoclopramide Dopamine antagonist Increased risk of EPS when combined with antipsychotics.

Glucocorticoids Induce CYP 3A4 Increased metabolism and reduced levels of oxidatively metabolized benzodiazepines, buspirone, carbamazepine, quetiapine, ziprasidone, and pimozide. Adjust benzodiazepine dose or consider oxazepam, lorazepam, or temazepam. Monitor carbamazepine levels. Adjust antipsychotic dose or switch to another agent.

Dronabinol, nabilone Additive sympathomimetic effects

Additive hypertension, tachycardia, and possible cardiotoxicity with amphetamines, methylphenidate, and other sympathomimetics.

Additive hypertension, tachycardia, and drowsiness with TCAs.Additive drowsiness and CNS depression with benzodiazepines, lithium,

opioids, buspirone, and other CNS depressants.

Note. CNS = central nervous system; CYP = cytochrome P450; EPS = extrapyramidal symptoms; GERD = gastroesophageal reflux disease; TCA =tricyclic antidepressant.Source. Compiled from Cozza et al. 2003; Wynn et al. 2007; and product monographs.

Table 4–5. Gastrointestinal drug–psychotropic drug interactions (continued)


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Table 4–6. Psychotropic drug–gastrointestinal drug interactions

Medication Interaction mechanism Effect on gastrointestinal drugs and management

Antidepressants

Fluoxetine Inhibits CYP 1A2, 2C19, 2D6, 3A4

Increased levels of aprepitant, granisetron, ondansetron, palonosetron, tropisetron, and corticosteroids including budesonide.

Fluvoxamine Inhibits CYP1A2, 2C9/19, 3A4

Increased levels and toxicity of alosetron. Coadministration is not advised.May increase levels and toxicity of aprepitant, alosetron, granisetron,

ondansetron, palonosetron, and corticosteroids including budesonide.

Nefazodone Inhibits CYP 3A4 Increased levels and toxicity of aprepitant, granisetron, and corticosteroids including budesonide.

Bupropion, duloxetine, moclobemide, paroxetine

Inhibits CYP 2D6 Increased levels and toxicity of tropisetron.

TCAs QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents including domperidone, droperidol, dolasetron, granisetron, ondansetron, palonosetron, and ramosetron.

Antipsychotics

Typical antipsychotics (iloperidone, paliperidone, pimozide, quetiapine, risperidone, ziprasidone)

QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents including domperidone, droperidol, dolasetron, granisetron, ondansetron, palonosetron, and ramosetron.

Gastroin

testinal D

isord

ers137

Mood stabilizers

Carbamazepine, phenytoin, oxcarbazepine

Induces CYP 1A2, 2C9/19, 3A4

Increased metabolism and reduced therapeutic effects of aprepitant, alosetron, ondansetron, palonosetron, granisetron, and corticosteroids including budesonide.

Lithium QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents including domperidone, droperidol, dolasetron, granisetron, ondansetron, palonosetron, and ramosetron.

Psychostimulants

Armodafinil, modafinil Induces CYP 3A4 Increased metabolism and reduced therapeutic effects of aprepitant, granisetron, and corticosteroids including budesonide.

Atomoxetine Inhibits CYP 2D6 Increased levels and toxicity of tropisetron.

Note. CYP=cytochrome P450; TCA=tricyclic antidepressant.Source. Compiled from Cozza et al. 2003; Wynn et al. 2007; and product monographs.

Table 4–6. Psychotropic drug–gastrointestinal drug interactions (continued)

Medication Interaction mechanism Effect on gastrointestinal drugs and management


Key Clinical Points

• Dysphagia secondary to antipsychotic-induced extrapyramidalsymptoms can lead to life-threatening aspiration and pneumo-nia, particularly in the elderly.

• Non-GERD noncardiac chest pain may respond to agents thatmodulate pain sensitivity and pain perception. Trazodone, TCAs,and SSRIs have demonstrated effectiveness; benzodiazepinesare warranted if panic disorder is present.

• With GERD and peptic ulcer disease, beyond conventional ther-apies, TCAs, SSRIs, and sometimes benzodiazepines can be use-ful even without comorbid psychiatric symptoms.

• Nausea and vomiting due to pregnancy, cancer, or cancer treat-ments may respond to antipsychotics or mirtazapine. Patientsshould be monitored for extrapyramidal symptoms with antipsy-chotic agents.

• Gastric bypass and celiac disease may alter drug absorption, re-ducing therapeutic effect. Liquid or orally disintegrating tabletsshould be used instead of extended-release preparations.

• Paroxetine, bupropion, and phenelzine may improve quality oflife in inflammatory bowel disease. Bupropion and phenelzinemay induce disease remission.

• Although the effectiveness of antidepressants for IBS without co-morbid psychopathology is debated, these agents are frequentlyprescribed. If used, SSRIs are preferable for constipation-predom-inant IBS, and TCAs are preferred for diarrhea-predominant IBS.

• Psychotropic dosage may need to be reduced in hepatic impair-ment. The Child-Pugh score, a clinical measure that estimatesthe severity of cirrhosis, can help guide dosing.

• Psychotropic-induced hepatotoxicity is generally idiosyncraticand not readily predictable. Thus, routine monitoring of liver en-zymes is not warranted, except for patients in high-risk groups(e.g., patients with preexisting liver disease) or those demon-strating early signs of possible adverse hepatic reaction.

• Psychotropic-induced liver injury is most often reversible andrarely results in fatality if the drug is discontinued. Use of some


drugs in patients with baseline hepatic dysfunction is not ad-vised (e.g., duloxetine).

• Patients with hepatitis C often develop interferon-alpha–inducedmood changes; however, evidence for antidepressant prophy-laxis is inconsistent, suggesting the need to use this approach ona case-by-case basis (e.g., for patients with history of recurrentmajor depression).

• Patients with hepatitis C with baseline depressive symptomsshould commence antidepressant therapy prior to interferon-alpha treatment.

• Drug-induced pancreatitis, although rare, has been linked tosome antidepressants, anticonvulsants, and both typical andatypical antipsychotics. If a patient develops drug-induced pan-creatitis, rechallenge with the same agent is not recommended.

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5Renal and Urological Disorders



Renal disease and the procedures and medications used to manage renal andurological disorders frequently cause psychiatric symptoms, including depres-sion, anxiety, sleep disorders, and cognitive impairment. Surprisingly, the lit-erature provides little specific guidance on the management of psychiatricsymptoms in patients with renal disease, even though pharmacotherapy isconfounded by disease-related alterations in pharmacokinetics (metabolism,excretion) for both hepatically and renally eliminated drugs, medication ad-verse effects, and drug interactions. Similar issues surround the safe and effec-tive use of psychotropics in patients with urological disorders. The purpose ofthis chapter is to review psychiatric symptoms related to renal and urologicaldisorders, psychopharmacotherapy in renal disease, and interactions betweenpsychiatric drugs and renal and urological drugs.


Differential Diagnosis

Psychiatric Symptoms in Patients With Renal Disease

The diagnosis of psychiatric disorders in patients with end-stage renal disease(ESRD) is complicated because many somatic symptoms are extremely com-mon as a result of renal insufficiency itself or comorbid medical disorders (es-pecially diabetes). A systematic review of symptoms in ESRD found thefollowing weighted mean prevalence rates: fatigue, 71%; pruritus, 55%; con-stipation, 53%; anorexia, 49%; pain, 47%; sleep disturbance, 44%; dyspnea,35%; and nausea, 33% (Murtagh et al. 2007). It is not easy to determine theetiology of a particular symptom, which is often multifactorial in any case.

Depression is the most common psychiatric disorder in patients withESRD. Prevalence estimates vary depending on definitions and methods, butthe prevalence of major depression may be as high as 20%–30% (Kimmel etal. 2007), with minor depression in another 25% of patients. Metabolic, psy-chological, and social factors all contribute to increased risk for depression inESRD. The diagnosis of depression in uremic patients is complicated becauseanorexia, anergia, insomnia, constipation, poor concentration, and dimin-ished libido may all be caused by renal insufficiency. Depression in dialysispatients may be intermittent or chronic (Cukor et al. 2008b).

Significant anxiety is also frequent in almost half of patients with ESRD,intermittent in one-third, and persistent in 15% (Cukor et al. 2008a, 2008b).As with depression, metabolic, psychological, and social factors contribute toetiology. Fluid and electrolyte shifts that are too rapid may physiologicallycause anxiety. Specific phobic anxiety may arise from a fear of needles or thesight of blood, as well as a reaction to removal of blood into a machine andits return to the patient’s body. In one study, the prevalence of posttraumaticstress disorder symptoms was 17%, with most related to the experience of he-modialysis (Tagay et al. 2007).

Acute renal failure with uremia often causes delirium with cognitive dys-function, and at times psychotic symptoms. Acute onset of renal failure ac-companied by hallucinations should lead to consideration of a toxic exposure(e.g., poisonous mushrooms, herbal “remedies,” insecticides). Psychoticsymptoms in patients with ESRD may be due to a primary psychotic disorder(10% of patients at one urban dialysis center; Cukor et al. 2007), electrolyte

Renal and Urological Disorders 151

disturbance, comorbid medical disorder (e.g., stroke, dementia), or toxicityof a renally excreted drug (e.g., acyclovir; Yang et al. 2007).

Subtle cognitive dysfunction is often present in patients with partial renalinsufficiency (Elias et al. 2009). Cognitive disorders are common in patientswith ESRD as a consequence of uremia, electrolyte disturbances, toxicity ofrenally excreted drugs, and comorbid medical disorders (e.g., cerebrovasculardisease). The signs and symptoms of uremia vary in severity, depending onboth the extent and the rapidity with which renal function is lost. Mild orchronic uremia may cause mild cognitive dysfunction, fatigue, and headache.Untreated uremia progresses to lethargy, hypoactive delirium, and coma. Upto 70% of hemodialysis patients over age 55 have moderate to severe chroniccognitive impairment (Murray 2008). Vascular dementia is especially com-mon because of the high prevalence of diabetes, hypertension, and atheroscle-rosis in patients with ESRD.

Sleep disorders, most commonly insomnia, affect 50%–80% of dialysispatients (Novak et al. 2006). Metabolic changes, lifestyle factors, depression,anxiety, and other underlying sleep disorders may all contribute to the devel-opment of chronic insomnia. Restless legs syndrome (RLS) is especially com-mon, affecting 10%–30% of patients on maintenance dialysis (Molnar et al.2006; Murtagh et al. 2007; see “Dopamine Agonists” later in this chapter).

Renal Symptoms of Psychiatric Disorders: Psychogenic Polydipsia

Psychogenic polydipsia (PPD), also called primary polydipsia, occurs in 6%–20% of psychiatric patients, most commonly in patients with schizophrenia(Verghese et al. 1996). Excessive thirst, likely due to abnormal hypothalamicthirst control, causes chronic and excessive fluid intake, often beyond the re-nal ability to excrete dilute urine. Hyponatremia, present in 10%–20% ofcompulsive drinkers, is often mild and asymptomatic, unless accompanied bya syndrome of inappropriate antidiuretic hormone secretion (SIADH) orother impairment of water excretion. PPD can be distinguished from diabetesinsipidus by water restriction. Although both PPD and diabetes insipidushave low urine osmolality before water restriction (<100 mOsm/L), after wa-ter restriction urine becomes very concentrated with PPD (>600 mOsm/L)but remains dilute with diabetes insipidus (<600 mOsm/L) (Dundas et al.


2007). PPD can be managed by water restriction, although compliance isproblematic, or by pharmacotherapy. Case reports suggest efficacy for atypicalantipsychotics (clozapine, risperidone, olanzapine) and beta-blockers. In asmall randomized controlled trial of clonidine or enalapril in chronically psy-chotic patients with PPD, both agents demonstrated improvement of mea-sures reflecting fluid consumption in 60% of patients (Greendyke et al.1998). Demeclocycline was ineffective in randomized controlled trials. A casereport associated the vasopressin V2 antagonist conivaptan with significanthypotension in a patient with PPD (Ghali et al. 2006), suggesting that fluidrestriction should not be combined with vasopressin V2 antagonists whentreating PPD-induced hyponatremia (Hline et al. 2008).

Pharmacotherapy in Renal Disease

Pharmacokinetics in Renal Disease

Although most psychotropic drugs, as the parent compounds, do not dependon the kidney for excretion, renal failure may alter the pharmacokinetics ofpractically all drugs through changes in distribution, protein binding, andmetabolism (see Chapter 1, “Pharmacokinetics, Pharmacodynamics, andPrinciples of Drug–Drug Interactions”). Edema present in ESRD will in-crease the volume of distribution for hydrophilic drugs. Uremic products cir-culating in ESRD may displace highly bound drugs from plasma proteins,increasing the proportion of drug circulating free in plasma. This shift in ratioof free to bound drugs may cause therapeutic drug monitoring methods thatmeasure total drug to suggest lower, possibly subtherapeutic levels. For thosehighly bound drugs for which therapeutic drug monitoring guides dosing(e.g., phenytoin, valproate), clinicians should use drug monitoring methodsthat are selective for free drug (see Chapter 1); otherwise, seemingly lower lev-els might prompt a dosage increase with possibly toxic results. Renal diseasecan also significantly modify Phase I hepatic drug metabolism, although theeffects vary markedly. In general, hepatic metabolism mediated by CYP 2C9,2C19, 2D6, and 3A4 is reduced in chronic renal disease, possibly through re-duced CYP 450 gene expression. Phase II metabolic reactions, includingacetylation, glucuronidation, sulfation, and methylation, are also impaired inchronic renal disease (Pichette and Leblond 2003). The metabolic impact of


renal disease on renal metabolism is often overlooked. Renal metabolism,which ordinarily represents about 15% of hepatic metabolic capacity, is re-duced in renal insufficiency (Anders 1980).

Despite the complexity of pharmacokinetic changes in renal failure, mostpsychotropics do not require drastic dosage adjustment. The exceptions in-clude drugs for which the parent compound or active metabolites undergosignificant renal elimination (lithium, gabapentin, pregabalin, topiramate,paliperidone, risperidone, paroxetine, desvenlafaxine, venlafaxine, and me-mantine) (see Table 5–1). However, many problems associated with use ofpsychotropics in patients with ESRD are related to comorbid illnesses ratherthan to the renal failure per se. Specific dosing guidelines based on creatinineclearance are not available for most psychotropics, but many clinicians use therule of “two-thirds”—that is, for patients with renal insufficiency, use two-thirds of the dosage (except for drugs listed in Table 5–1) used for patientswith normal renal function. Table 5–1 provides recommendations for dosingpsychotropics in patients with renal disease.

Drug clearance may also be influenced by hemodialysis or peritonealdialysis. Most psychotropics are not dialyzable because of their lipophilicityand large volumes of distribution. Dialyzable psychotropics are listed in Table5–2. Significant fluid shifts occur during and several hours after each hemo-dialysis treatment, making dialysis patients more prone to orthostasis. Hence,drugs that frequently cause orthostatic hypotension should ideally be avoided.

Pharmacodynamics in Renal Disease

Electrolyte disturbances associated with renal failure or diuretic therapy mayincrease the risk of cardiac arrhythmias. Significant QT prolongation is ob-served with tricyclic antidepressants (TCAs), lithium (van Noord et al. 2009),and many typical and atypical antipsychotics (for a listing of QT-prolongingdrugs, see Arizona Center for Education and Research on Therapeutics 2009).

Psychotropic Drugs in Renal Disease

Antidepressants

Despite the high prevalence of depression, few studies have been done of theeffectiveness of antidepressants in dialysis patients. One small randomizedcontrolled trial of low-dose paroxetine (10 mg/day) combined with psycho-


Table 5–1. Psychotropic drugs in renal insufficiency (RI)

Medication Effect and management

Antidepressants

SSRIs

Most Mild to moderate RI: no dosage adjustment needed.Severe RI: may need to reduce dosage or lengthen dosing

interval.

Paroxetine Mild RI: no dosage adjustment needed.Moderate RI: 50%–75% of usual dosage.Severe RI: initial dosage of 10 mg/day; increase as needed by

10 mg at weekly intervals to a maximum of 40 mg/day.Controlled-release formulation: initial dosage of 12.5 mg/

day; increase as needed by 12.5 mg at weekly intervals to a maximum of 50 mg/day.

SNRIs and novel agents

Bupropion Water-soluble active metabolites may accumulate. Reduce initial dosage.

Desvenlafaxine Approximately 45% of desvenlafaxine is excreted unchanged in urine. No dosage adjustment is required in mild RI. The dosage should not exceed 50 mg/day in moderate RI, or 50 mg every other day in severe RI, per manufacturer.

Duloxetine Mild RI: population CPK analyses suggest no significant effect on apparent clearance.

No data regarding use in moderate to severe RI.Not recommended for patients with end-stage renal disease.

Mirtazapine Moderate RI: clearance decreased by 30%.Severe RI: clearance decreased by 50%.

Nefazodone No dosage adjustment needed.

Trazodone Mild RI: use with caution. No data regarding use in moderate to severe RI.

Venlafaxine Mild to moderate RI: 75% of usual dosage.Severe RI: 50% of usual dosage.Hemodialysis patients should have dosage reduced by 50%

and be dosed after dialysis session.

MAOIs May accumulate in RI.

Selegiline Active metabolite (methamphetamine) renally eliminated. Use with caution in renal impairment. No dosing guidelines.


TCAs Water-soluble active metabolites may accumulate. No recommended dosage adjustments.

Antipsychotics

Atypical agents

Aripiprazole, asenapine, clozapine, olanzapine, quetiapine

No dosage adjustment needed.

Iloperidone Dosage adjustment not needed in mild to moderate RI, per manufacturer. No recommendations for dosing in severe RI.

Paliperidone Clearance decreased in RI.Mild impairment: start at 3 mg/day, increasing to a maximum

of 6 mg/day.Moderate to severe impairment: start at 1.5 mg/day, increasing

to 3 mg/day, as tolerated.

Risperidone Clearance decreased in RI. Initiate therapy at 0.25–0.5 mg bid.Increases beyond 1.5 mg should be made at intervals of at least

7 days.

Ziprasidone No recommendations made regarding dosage adjustment.

Typical agents

Haloperidol, etc. No dosage adjustment needed.

Anxiolytics and sedative-hypnotics

Benzodiazepines

Most No dosage adjustment needed.

Chlordiazepoxide Severe RI: 50% of usual dosage.

Nonbenzodiazepines

Buspirone Use in severe RI not recommended.

Ramelteon No dosage adjustment needed.

Zaleplon Mild to moderate RI: no dosage adjustment needed.Severe RI: not adequately studied.

Zolpidem Dosage adjustment may not be needed in RI.

Zopiclone, eszopiclone


Table 5–1. Psychotropic drugs in renal insufficiency (RI) (continued)



Anticonvulsant and antimanic agents

Carbamazepine Severe RI: 75% of usual dosage.

Gabapentin Clcr>60 mL/min: 1,200 mg/day (400 mg tid).Clcr 30–60 mL/min: 600 mg/day (300 mg bid).Clcr 15–30 mL/min: 300 mg/day.Clcr<15 mL/min: 150 mg/day (300 mg every other day).Hemodialysis: 300–400 mg loading dose to patients who

have never received gabapentin, then 200–300 mg after each dialysis session.

Lamotrigine Reduced dosage may be effective in significant RI.

Lithium Moderate RI: 50%–75% of usual dosage.Hemodialysis: supplemental dose of 300 mg once after each

dialysis session.

Oxcarbazepine Initiate therapy at 300 mg/day (50% of usual starting dosage).

Pregabalin Clcr 30–60 mL/min: 50% of usual dosage.Clcr 15–30 mL/min: 25% of usual dosage.Clcr<15 mL/min: 12.5% of usual dosage.Hemodialysis: supplemental dose may be needed after each

4-hour dialysis session. See manufacturer’s recommendations.

Topiramate Mild RI: 100% of usual dosage.Moderate RI: 50% of usual dosage.Severe RI: 25% of usual dosage.Supplemental dose may be needed after hemodialysis.

Valproate No dosage adjustment needed in RI, but valproate level measurements are misleading.


Donepezil Limited data suggest no dosage adjustment needed.

Galantamine Moderate RI: maximum dosage 16 mg/day.Severe RI: use not recommended.

Memantine Extensive renal elimination.Mild to moderate RI: no dosage reduction needed.Severe RI: reduce dosage to 5 mg bid.

Rivastigmine Dosage adjustment not recommended.




therapy showed a small benefit in reducing depressive symptoms (Koo et al.2005). Another tiny randomized controlled trial of fluoxetine (Blumenfieldet al. 1997) and a tiny open trial of TCAs (Kennedy et al. 1989) were encour-aging but too small and too brief.

Virtually all antidepressants may be used in patients with renal failure, al-though the greatest amount of experience is with the TCAs. Patients withESRD, however, tend to be more sensitive to the side effects of TCAs, includ-ing sedation, anticholinergic toxicity (urinary retention, dry mouth that en-

Psychostimulants

Atomoxetine No dosage adjustment needed.

Methylphenidate No dosage adjustment needed.

Modafinil, armodafinil


Antiparkinsonian agents

Amantadine Clcr 80 mL/min: 100 mg bid.Clcr 60 mL/min: 100 mg qd alternated with 100 mg bid

every other day.Clcr 40 mL/min: 100 mg/day.Clcr 30 mL/min: 200 mg twice weekly.Clcr 20 mL/min: 100 mg three times weekly.Clcr 10 mL/min: 200 mg alternated with 100 mg every 7 days.

Pramipexole 90% renal elimination: Clearance of pramipexole is 75% lower in severe renal impairment (Clcr 20 mL/min); 60% lower in patients with moderate impairment (Clcr 40 mL/min) compared with healthy volunteers. The interval between titration steps should be increased to 14 days in RLS patients with severe and moderate renal impairment (Clcr 20–60 mL/min).

Note. Mild RI is >50 mL/min; moderate RI is 10–50 mL/min; severe RI is <10 mL/min.bid=twice a day; Clcr=creatinine clearance; CPK=creatine phosphokinase; MAOI=monoamineoxidase inhibitor; qd=once a day; RLS=restless legs syndrome; SSRI=selective serotonin re-uptake inhibitor; TCA=tricyclic antidepressant; tid=three times a day.Source. Cohen et al. 2004; Crone et al. 2006; Jacobson 2002; Periclou et al. 2006; and manu-facturers’ product information.



158C



Table 5–2. Dialyzable psychotropic drugsMedication Conventional hemodialysis High-permeability hemodialysis Peritoneal dialysis

Carbamazepine YesGabapentin Yes LikelyLamotrigine Clearance increased 20%Lithium Yes Yes YesPregabalin Yes LikelyTopiramate Yes LikelyValproate Yes Likely

Note. Likely=no data, but increased clearance likely based on conventional hemodialysis observations; Yes=studies indicate clearance increased by≥30%.Source. Abbott 2009; Bassilios et al. 2001; Israni et al. 2006; Johnson 2009; Lacerda et al. 2006; Ward et al. 1994.


courages excessive drinking), orthostatic hypotension, and QT prolongation.Hydroxylated metabolites have been shown to be markedly elevated in patientswith ESRD and may be responsible for some TCA side effects. Nortriptylineand desipramine are considered preferred TCAs for patients with renal failurebecause these drugs are less likely to cause anticholinergic effects or orthostatichypotension than other TCAs (Gillman 2007). Limited data are available onthe use of newer antidepressants in patients with renal failure. The half-life ofvenlafaxine is prolonged in renal insufficiency; its clearance is reduced by over50% in patients undergoing dialysis. Desvenlafaxine undergoes significant re-nal elimination, requiring dosage reduction in patients with moderate and se-vere renal impairment. Some evidence suggests that dosage adjustments maynot be needed for citalopram (Spigset et al. 2000) and fluoxetine (Levy et al.1996) in those with ESRD. Paroxetine clearance is also reduced in renal insuf-ficiency. Because most antidepressants are metabolized by the liver and ex-creted by the kidney, the prudent action is to initially reduce the dosage for allantidepressants to minimize the potential accumulation of active metabolites.

Antipsychotics

All antipsychotics may be used in patients with renal failure. Paliperidoneclearance, however, is significantly decreased in all degrees of renal impair-ment, requiring a reduction in initial and target dosage. Difficulties arise fromthe complications of renal failure and dialysis or from the chronic diseasecausing renal failure (e.g., diabetes). For example, patients with ESRD whoalso have diabetic autonomic neuropathy will be at higher risk for drug sideeffects, including postural hypotension and bladder, gastrointestinal, and sex-ual dysfunction. Antipsychotics associated with hyperglycemia (e.g., cloza-pine, olanzapine) should be avoided in patients with comorbid diabetes. Inpatients with electrolyte disturbances, risk of cardiac arrhythmias can be min-imized by using antipsychotics with the least QT-prolonging effect (aripipra-zole <1 msec, haloperidol 5 msec, and olanzapine 6 msec; El-Sayeh andMorganti 2006; U.S. Food and Drug Administration PsychopharmacologicalDrugs Advisory Committee 2002).

Anxiolytics and Sedative-Hypnotics

We found no clinical trials of pharmacotherapy for anxiety in patients withESRD. Benzodiazepine and zolpidem use in dialysis patients has been associ-


ated with a 15% increase in mortality, but this may be explained by their in-creased use by those with comorbid chronic obstructive pulmonary disease(Winkelmayer et al. 2007). In Japan, benzodiazepines were associated withhigher mortality in hemodialysis patients with symptoms of depression, mostof whom had not received antidepressants, even after controlling for con-founders (Fukuhara et al. 2006). Fukuhara et al. (2006) suggested that thesebenzodiazepine-related deaths may have been caused by inappropriate use ofbenzodiazepines to treat depression and the drugs’ adverse cognitive and psy-chomotor effects.

Virtually all sedative-hypnotics except barbiturates can be used in patientswith renal failure. Barbiturates should be avoided because they may increaseosteomalacia and because of excessive sedation. Preferred benzodiazepines in-clude those with inactive metabolites, such as lorazepam and oxazepam; how-ever, the half-lives of lorazepam and oxazepam may almost quadruple inpatients with ESRD, and dosage reduction is required. Other benzodiaz-epines with inactive metabolites include clonazepam and temazepam, but lessis known about changes in their half-lives in ESRD.

Mood Stabilizers

Lithium is almost entirely excreted by the kidneys. It is contraindicated in pa-tients with acute renal failure, but not in those with chronic renal failure. Forpatients with stable partial renal insufficiency, clinicians should dose conserva-tively and monitor renal function frequently. For patients on dialysis, lithiumis completely dialyzed and may be given as a single oral dose (300–600 mg) fol-lowing hemodialysis treatment. Lithium levels should not be checked until atleast 2–3 hours after dialysis, because reequilibration from tissue stores occursin the immediate postdialysis period. For patients on peritoneal dialysis, lith-ium can be given in the dialysate. Lithium prolongs QT interval and may in-crease the risk of cardiac arrhythmias in patients with electrolyte disturbances.Dosage adjustment recommendations based on creatinine clearance are avail-able for gabapentin, lithium, topiramate, and carbamazepine (Jacobson 2002).

Cholinesterase Inhibitors and Memantine

It appears, from the limited data available, that dosage adjustment of donepezilis not required. As in patients without renal disease, rivastigmine dosageshould be titrated according to efficacy and individual tolerability. Galan-


tamine should be used cautiously in patients with moderate renal insuffi-ciency; according to the manufacturer, its use in patients with severe renalinsufficiency is not recommended. Memantine undergoes extensive renal elim-ination, requiring a dosage reduction in patients with severe renal insufficiency.

Psychostimulants

No specific dosing recommendations are currently available for psychostim-ulants.

Dopamine Agonists

Dopaminergic therapy has been recommended as first-line treatment for RLS(levodopa or the dopamine receptor agonists pramipexole, ropinirole, per-golide, or cabergoline). Although dopamine agonists have been found effectivein reducing RLS symptoms in the general population, few data are availableregarding their use in patients with ESRD. Side effects can be problematic butare less frequent with dopamine agonists than with levodopa. Alternative treat-ment options for RLS include gabapentin, benzodiazepines (especially clonaz-epam), opioids, and anticonvulsants, but only very limited data are availableon their effectiveness and side-effect profile in patients with ESRD (Molnar etal. 2006). If iron deficiency is present, its repletion will improve RLS.

Psychiatric Adverse Effects of Renal and Urological AgentsDrugs used in the treatment of renal and urological disorders sometimes havepsychiatric adverse effects. The following subsections describe these effects fora variety of drug classes. Psychiatric adverse effects of other medications fre-quently used to treat patients with renal disease are covered elsewhere in thisbook: corticosteroids for autoimmune nephritis in Chapter 10, “Endocrineand Metabolic Disorders”; antihypertensives in Chapter 6, “CardiovascularDisorders”; and immunosuppressants after renal transplant in Chapter 16,“Organ Transplantation.”

Antispasmodics

Anticholinergic agents commonly used to treat overactive bladder are associ-ated with psychiatric adverse effects, including cognitive impairment, confu-


sion, fatigue, and psychosis (see Table 5–3). A large longitudinal cohort studyidentified mild cognitive impairment in 80% of patients receiving anticholin-ergics for overactive bladder compared with 35% of age-matched control sub-jects (Ancelin et al. 2006). Cognitive impairment is well documented andcases of frank psychosis have been reported for first-generation anticholin-ergics, such as oxybutynin (Gulsun et al. 2006; Kay et al. 2006) and tolterod-ine (Salvatore et al. 2007; Tsao and Heilman 2003; Womack and Heilman2003). In contrast, results from three controlled trials suggest that darifenacin,a second-generation muscarinic M3-selective agent, does not impair cognitivefunction in elderly subjects (Kay and Ebinger 2008). To date, no clinical trialsassessing cognitive function with other antispasmodics have been reported.

Diuretics

Thiazide diuretics are the most common cause of hyponatremia (Liamis et al.2008). Psychiatric symptoms of hyponatremia include lethargy, stupor, con-fusion, psychosis, irritability, and seizures.

Alpha-1 Adrenergic Antagonists

Alpha-1 antagonists, including alfuzosin, doxazosin, silodosin, tamsulosin,and terazosin, are used in the treatment of benign prostatic hyperplasia andprostatitis. All alpha-blockers can cause hypotension. Doxazosin and tamsu-losin have also been associated with insomnia and impotence. Increased anx-iety may occur with doxazosin.

5-Alpha Reductase Inhibitors

Dutasteride and finasteride, indicated for benign prostatic hyperplasia, maycause impotence and decreased libido.

Vasopressin Antagonists

Conivaptan, a vasopressin V2-selective receptor antagonist, is associated withconfusion and insomnia in safety and efficacy trials (Astellas 2009). Tolvaptanappears to have a more benign psychiatric adverse-effect profile (Gheorghiadeet al. 2003).

Renal an

d Uro

logical Disord

ers163

Table 5–3. Psychiatric adverse effects of renal and urological drugsMedication Psychiatric adverse effect(s)

Urinary antispasmodics (except possibly darifenacin):flavoxate, oxybutynin, solifenacin, tolterodine, trospium

Cognitive impairment, confusion, fatigue, and psychosis

Thiazide and thiazide-like diuretics:bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, metolazone, trichlormethiazide

Hyponatremia-induced lethargy, stupor, confusion, psychosis, irritability, and seizures

Alpha-1 antagonists:doxazosin Anxiety, insomnia, and impotencetamsulosin Insomnia and impotence

5-alpha reductase inhibitors:dutasteride, finasteride

Impotence and decreased libido

Vasopressin antagonist: conivaptan Confusion, insomnia


Renal and Urological Adverse Effects of Psychotropics

Psychotropic drugs have a variety of renal and urological adverse effects (seeTable 5–4), including hyponatremia or hypernatremia, nephropathy, urinaryretention or incontinence, and sexual dysfunction.

Renal Effects of Psychotropics

Hyponatremia, which can manifest as lethargy, stupor, confusion, psychosis,irritability, and seizures, has many different precipitants, including thiazidediuretics (see Table 5–3), but two have particular psychiatric relevance: 1)SIADH, which can be caused by many psychotropic drugs, especially oxcar-bazepine and carbamazepine, but also selective serotonin reuptake inhibitor(SSRIs), TCAs, and antipsychotics; and 2) psychogenic polydipsia (discussedearlier in this chapter). Hyponatremia is twice as likely with oxcarbazepine(29.9% of patients) as with carbamazepine (14.4% of patients) (Dong et al.2005) and is more common in elderly patients. Acute-onset symptomatic hy-ponatremia may require emergent treatment with hypertonic (3%) saline. Inchronic cases, correction should be gradual to minimize the risk of pontinemyelinolysis, relying on fluid restriction and vasopressin receptor antagonists(Siegel 2008).

Hypernatremia can result in cognitive dysfunction, delirium, seizures,and lethargy, progressing to stupor and coma. Hypernatremia is usuallycaused by dehydration with significant total body water deficits. The onlypsychotropic drug that causes hypernatremia is lithium, via nephrogenic dia-betes insipidus (NDI). Most patients receiving lithium have polydipsia andpolyuria, reflecting mild benign NDI. Lithium-induced NDI sometimes haspersisted long after lithium discontinuation, and varies from mild polyuria tohyperosmolar coma. NDI has been treated with nonsteroidal anti-inflamma-tory drugs, thiazides, and amiloride, as well as sodium restriction (Grunfeldand Rossier 2009; Liamis et al. 2008). Amiloride is considered the treatmentof choice for lithium-induced NDI.

The effect of lithium on renal function is controversial; some studies re-port that longer duration of lithium therapy is predictive of a decrease in es-timated glomerular filtration (“creeping creatinine”), whereas others do not.


Although chronic lithium use may result in altered kidney morphology, in-cluding interstitial fibrosis, tubular atrophy, urinary casts, and occasionallyglomerular sclerosis, in 10%–20% of patients (Bendz et al. 1996), thesechanges are not generally associated with impaired renal function. In a recentmeta-analysis, Paul et al. (2009) concluded that any lithium-induced effecton renal function is quantitatively small and probably clinically insignificant.Although long-term lithium treatment is the only well-established factorassociated with lithium-induced nephropathy, changes in renal function areoften associated with other factors, including age, episodes of lithium toxicity,other medications (analgesics, substance abuse), and the presence of comor-bid disorders (hypertension, diabetes). Lithium dosage is not strongly relatedto nephrotoxic effects (Freeman and Freeman 2006). The progression of lith-ium nephrotoxicity to ESRD is rare (0.2%–0.7%) and requires lithium usefor several decades (Presne et al. 2003). Lithium is so efficacious in bipolardisorder that the risk of renal dysfunction during chronic use is consideredacceptable with yearly monitoring of renal function.

Table 5–4. Renal and urological adverse effects of psychiatric drugs

Medication Renal/urological adverse effects

Mood stabilizersLithium, carbamazepine,

oxcarbazepineNephrogenic diabetes insipidus, hypernatremiaSIADH, psychogenic polydipsia, hyponatremia

AntidepressantsSSRIs or SNRIs Sexual dysfunction

SIADH, psychogenic polydipsia, hyponatremiaTCAs Urinary hesitancy, urinary retention

SIADH, psychogenic polydipsia, hyponatremiaAntipsychotics SIADH, psychogenic polydipsia, hyponatremiaLow-potency typical

antipsychoticsUrinary hesitancy, urinary retention

Anticholinergic agents for EPSTrihexyphenidyl, benztropine,

etc.Urinary hesitancy, urinary retention

Note. EPS=extrapyramidal symptoms; SIADH=syndrome of inappropriate antidiuretic hor-mone secretion; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotoninreuptake inhibitor; TCA=tricyclic antidepressant.


Urological Effects of Psychotropics

Many psychotropics cause disorders of micturition. Urinary retention is asso-ciated with drugs with significant anticholinergic activity, including TCAsand antipsychotics, especially low-potency typical agents but also atypicalagents. Urinary incontinence and other lower urinary tract symptoms (fre-quency, urgency, incomplete emptying) occur in approximately 40% of pa-tients taking clozapine, but in only 15% of the general population (Jeong etal. 2008), and may persist for the duration of treatment. A greater than two-fold increase in urinary incontinence has also been reported in patients fol-lowing initiation of risperidone therapy (Vokas et al. 1997). Treatment ofclozapine-induced urinary incontinence with ephedrine, trihexyphenidyl,oxybutynin, and desmopressin has not proved consistently useful.

SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs) causesexual side effects (delayed or absent orgasm, ejaculation, or reduced libido)in 30%–70% of users. Bupropion is not associated with sexual dysfunction,and mirtazapine, moclobemide, and milnacipran (an SNRI recently approvedby the U.S. Food and Drug Administration for the treatment of fibromyalgia)have less incidence of this side effect than other antidepressants (Baldwin etal. 2008; Serretti and Chiesa 2009). Antidepressant-induced sexual dysfunc-tion can be managed by switching to a less problematic agent or by as-neededuse of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil, which hasbeen shown to be effective in controlled trials in men and women (Nurnberget al. 2003, 2008). Antipsychotics, TCAs, and irreversible monoamine oxi-dase inhibitors (MAOIs) also can impair sexual function.


A number of pharmacodynamic and pharmacokinetic drug interactions fre-quently occur between drugs prescribed for renal and urological disorders andpsychotropic drugs (see Tables 5–5 and 5–6). See Chapter 1 for a discussion ofpharmacokinetics, pharmacodynamics, and principles of drug–drug interactions.

Pharmacodynamic Interactions

A number of urological agents have effects on cardiac conduction (see Table5–5). Thiazides and loop diuretics may cause conduction abnormalities


through electrolyte disturbances, including hypokalemia and hypomag-nesemia. Alfuzosin, indapamide, and vardenafil prolong QT interval (for alisting of QT-prolonging drugs, see Arizona Center for Education and Re-search on Therapeutics 2009). These agents should be used with caution inthe presence of psychotropic drugs with QT-prolonging effects, such asTCAs, low-potency typical antipsychotics, pimozide, risperidone, paliperi-done, iloperidone, quetiapine, ziprasidone, and lithium (Kane et al. 2008;van Noord et al. 2009). The anticholinergic properties of urinary antispas-modics can interact in an additive manner to increase the anticholinergicadverse effects of TCAs and antipsychotics (dry mouth, dry eyes, urinary re-tention, constipation, decreased sweating, and cognitive impairment). Anti-spasmodics may reduce cognitive function and diminish the cognitivebenefits of cholinesterase inhibitors and memantine. The hypotensive adverseeffects of alpha-1 antagonists for benign prostatic hyperplasia (e.g., doxazo-cin) and PDE5 inhibitors (sildenafil, vardenafil, and tadalafil) may exacerbatehypotensive effects of psychotropic agents, including TCAs, antipsychotics,and MAOIs. Hyponatremic effects of thiazide diuretics may be enhanced incombination with oxcarbazepine and carbamazepine, and to a lesser degreewith SSRIs, TCAs, and antipsychotics.

Pharmacokinetic Interactions

Diuretics alter lithium excretion but not in a consistent direction. Thiazidediuretics reduce lithium excretion, giving rise to clinically significant increasesin lithium levels. Acute administration of loop diuretics (furosemide, etha-crynic acid, bumetanide) increases lithium excretion, causing a drop in lith-ium levels; with chronic use of loop diuretics, compensatory changes leavelithium levels somewhat unpredictable but not greatly changed. Carbonic an-hydrase inhibitors (acetazolamide, dichlorphenamide, methazolamide) andosmotic diuretics (e.g., mannitol) reduce lithium levels. Potassium-sparingdiuretics, including both epithelial sodium channel blockers (amiloride,triamterene) and aldosterone antagonists (spironolactone, eplerenone), mayincrease lithium excretion (Eyer et al. 2006; Finley et al. 1995). Furosemideand amiloride are considered to have the least effect on lithium excretion.

Metabolic drug interactions can change the levels of drugs used to treatrenal and urological disorders, thereby increasing the drugs’ toxicity or reduc-ing their therapeutic effect. Many renal and urological agents are CYP 3A4

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Table 5–5. Renal and urological drug–psychotropic drug interactionsMedication Interaction mechanism Effect on psychotropic drugs and management

DiureticsAll Additive hypotensive effect Increased risk of hypotensive effects with antipsychotics, TCAs, and MAOIs.Thiazide diuretics Blocked sodium/lithium

reabsorptionReduced lithium clearance leads to increased lithium levels and risk of toxicity.

Monitor lithium levels.Additive hyponatremia Potential for additive hyponatremic effects when combined with oxcarbazepine,

carbamazepine, and to a lesser degree SSRIs, TCAs, and antipsychotics. Monitor electrolytes.

Electrolyte abnormalities, hypokalemia, hypomagnesemia

Increased risk of cardiac arrhythmias with other QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Indapamide QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Loop diuretics Electrolyte abnormalities, hypokalemia, hypomagnesemia

Increased risk of cardiac arrhythmias with other QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Urine acidification Increased excretion and reduced effect of amphetamine, amitriptyline, imipramine, meperidine, methadone, memantine, and flecainide.

Carbonic anhydrase inhibitors

Urine alkalinization Reduced excretion and prolonged effect of amphetamine, amitriptyline, imipramine, meperidine, methadone, memantine, and flecainide.

Eplerenone, osmotic diuretics, spironolactone

Increased lithium clearance Reduced lithium levels and possible loss of therapeutic effect. Monitor lithium levels. Amiloride has little effect on lithium levels.

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Phosphate bindersCalcium acetate,

calcium carbonate, lanthanum carbonate

Urine alkalinization Reduced excretion and prolonged effect of amphetamine, amitriptyline, imipramine, meperidine, methadone, memantine, and flecainide.

Anticholinergic urinary antispasmodicsDarifenacin,

oxybutynin, solifenacin, tolterodine, trospium


Increased peripheral and central anticholinergic adverse effects of TCAs and antipsychotics. Reduced therapeutic effects of cognitive enhancers. Avoid combination if possible. Darifenacin has less central effect and is preferred.

PDE5 inhibitorsSildenafil, tadalafil Additive hypotensive effect Increased risk of hypotensive effects with antipsychotics, TCAs, and MAOIs.Vardenafil Additive hypotensive effect

QT prolongationIncreased risk of hypotensive effects with antipsychotics, TCAs, and MAOIs.Increased risk of cardiac arrhythmias with other QT-prolonging agents,


Alpha-1 antagonists for BPHAll Additive hypotensive effect Increased risk of hypotensive effects with antipsychotics, TCAs, and MAOIs.Alfuzosin QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents,


Table 5–5. Renal and urological drug–psychotropic drug interactions (continued)


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Vasopressin antagonistsConivaptan Inhibits CYP 3A4 Reduced metabolism of oxidatively metabolized benzodiazepines, buspirone,

carbamazepine, quetiapine, ziprasidone, and pimozide. Midazolam AUC is increased two- to threefold. Adjust benzodiazepine dosage or consider oxazepam, lorazepam, or temazepam. Avoid combination with buspirone or pimozide. Monitor carbamazepine levels. Adjust antipsychotic dosage or switch to another agent.

Note. AUC=area under the concentration–time curve; BPH=benign prostatic hypertrophy; CYP=cytochrome P450; MAOIs=monoamine oxidaseinhibitors; PDE5=phosphodiesterase type 5; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants.

Table 5–5. Renal and urological drug–psychotropic drug interactions (continued)



substrates (see Table 5–6); coadministration of a CYP 3A4 inhibitor (fluox-etine and nefazodone) may increase renal and urological drug bioavailabilityand blood levels and exacerbate toxicity. Inhibition of CYP 3A4 (and likelyP-glycoprotein) has the potential to greatly increase oxybutynin’s bioavailabil-ity (normally only 6%) and exacerbate anticholinergic toxicity. CYP 3A4 in-hibitors increase alfuzosin and vardenafil blood levels and enhance cardiacconduction toxicity (QT prolongation). Severe hypotensive effects have beenreported with sildenafil in the presence of potent CYP 3A4 inhibitors; PDE5inhibitors (sildenafil, tadalafil, and vardenafil) should not be combined withpotent CYP 3A4 inhibitors. Tamsulosin, a substrate for CYP 3A4 and 2D6,may exhibit increased toxicity when combined with CYP 3A4 or 2D6 inhib-itors (e.g., paroxetine). Conversely, the therapeutic effect of these CYP 3A4substrates may be diminished in patients also receiving CYP 3A4 inducers(carbamazepine, etc.). Coadministration of conivaptan, a potent CYP 3A4inhibitor as well as a substrate, increases the systemic exposure (area under thecurve) of midazolam up to threefold (Astellas 2009). Similar effects would beexpected with other oxidatively metabolized benzodiazepines, buspirone, car-bamazepine, quetiapine, ziprasidone, and pimozide.

Changes in urine pH can modify the elimination of those compoundswhose ratio of ionized to un-ionized forms is dramatically altered across thephysiological range of urine pH (4.6–8.2) (i.e., the compound has a pKawithin this pH range). Un-ionized forms of drugs undergo greater glomerularresorption, whereas ionized drug forms have less resorption and greater uri-nary excretion. Thiazide and loop diuretics decrease urine pH and promotethe excretion of amphetamines, and possibly other basic drugs such as ami-triptyline, imipramine, meperidine, methadone (Nilsson et al. 1982), andmemantine (Cadwallader 1983; Freudenthaler et al. 1998). Conversely, car-bonic anhydrase inhibitors and phosphate binders (calcium carbonate, cal-cium acetate, and lanthanum carbonate) alkalinize urine, which may reduceclearance and prolong the effect of these drugs.

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Table 5–6. Psychotropic drug–renal and urological drug interactionsMedication Interaction mechanism Effect on renal/urological drugs and management

AntidepressantsFluoxetine Inhibits CYP 3A4 Increased levels of the following:

Vasopressin antagonists—conivaptan, tolvaptanAlpha-1 antagonists for BPH—alfuzosin, doxazosin, tamsulosin5-alpha reductase inhibitors—dutasteride, finasteridePDE5 inhibitors—sildenafil, tadalafil, vardenafilAnticholinergic urinary antispasmodics—darifenacin, oxybutynin, solifenacinPotassium-sparing diuretics—eplerenone

Avoid concurrent use of CYP 3A4 inhibitors.Inhibits CYP 2D6 Increased levels of tamsulosin, possibly increasing hypotensive adverse effect.

Caution with strong CYP 3A4 or CYP 2D6 inhibitors.Nefazodone Inhibits CYP 3A4 Increased levels of the following:

Vasopressin antagonists—conivaptan, tolvaptanAlpha-1 antagonists for BPH—alfuzosin, doxazosin, tamsulosin5-alpha reductase inhibitors—dutasteride, finasteridePDE5 inhibitors—sildenafil, tadalafil, vardenafilAnticholinergic urinary antispasmodics—darifenacin, oxybutynin, solifenacinPotassium-sparing diuretics—eplerenone

Avoid concurrent use of CYP 3A4 inhibitorsBupropion,

duloxetine, moclobemide, paroxetine

Inhibits CYP 2D6 Increased levels of tamsulosin, possibly increasing hypotensive adverse effect. Paroxetine increased AUC by 1.6-fold. Caution with strong CYP 3A4 or CYP 2D6 inhibitors.

Renal and U

rological Disorders

173

TCAs Additive hypotensive effects

Increased risk of severe hypotension with the following:PDE5 inhibitors—sildenafil, tadalafil, vardenafilAlpha-1 antagonists for BPH—alfuzosin, doxazosin, tamsulosin, terazosin

QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including alfuzosin, indapamide, and vardenafil.

MAOIs Additive hypotensive effects


St. John’s wort Induces CYP 3A4 Decreased conivaptan and tolvaptan levels. Avoid use of CYP 3A4 inducers.AntipsychoticsTypical and

atypical: pimozide, risperidone, paliperidone,iloperidone, quetiapine, ziprasidone

QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including alfuzosin, indapamide, and vardenafil.

Typical and atypical

Additive hypotensive effects


Table 5–6. Psychotropic drug–renal and urological drug interactions (continued)Medication Interaction mechanism Effect on renal/urological drugs and management

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Mood stabilizersCarbamazepine,

oxcarbazepine, phenytoin

Induces CYP 3A4 Decreased conivaptan and tolvaptan levels. Avoid use of CYP 3A4 inducers.

Lithium QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including alfuzosin, indapamide, and vardenafil.

PsychostimulantsArmodafinil,

modafinilInduces CYP 3A4 Decreased conivaptan and tolvaptan levels. Avoid use of CYP 3A4 inducers.

Atomoxetine Inhibits CYP 2D6 Increased levels of tamsulosin, possibly increasing hypotensive adverse effect. Caution with strong CYP 3A4 or CYP 2D6 inhibitors.

Note. AUC=area under the concentration–time curve; BPH=benign prostatic hypertrophy; CYP=cytrochome P450; MAOI=monoamine oxidase in-hibitor; PDE5=phosphodiesterase type 5; TCA=tricyclic antidepressant.

Table 5–6. Psychotropic drug–renal and urological drug interactions (continued)

Medication Interaction mechanism Effect on renal/urological drugs and management


Key Clinical Points

• Unless specific information is available for dosing of psychotro-pic drugs in renal failure, clinicians should start patients withtwo-thirds the dosage recommended for patients with normalrenal function.

• Renal failure alters not only renal elimination of drugs but alsohepatic metabolism. Clinicians should employ therapeutic drugmonitoring (methods selective for free drug) when possible inpatients with renal disease.

• Lithium levels should be regularly monitored in patients receiv-ing diuretic therapy. Furosemide and amiloride are consideredto have the least effect on lithium excretion.

• Disease- and medication-induced electrolyte disturbances in-crease the risk of cardiac arrhythmias. Psychotropics should bechosen for their lack of QT-prolonging effects.

• Many renal and urological drugs are metabolized by CYP 3A4. In-hibitors of CYP 3A4 should be avoided. This is especially relevantfor alfuzosin and vardenafil, which prolong QT interval.

• Amiloride is considered the treatment of choice for lithium-induced diabetes insipidus.

• Lorazepam and oxazepam are preferred benzodiazepines in pa-tients with ESRD because of absence of active metabolites. Be-cause the half-lives of lorazepam and oxazepam may increaseup to fourfold, smaller-than-usual dosages are required.

• Of the anticholinergic urinary antispasmodics, darifenacin hasthe fewest anticholinergic adverse effects on the central nervoussystem.

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6Cardiovascular Disorders

Peter A. Shapiro, M.D.

Comorbidity of psychiatric disorders and heart disease is extremely common.Psychopharmacological treatment for psychiatric disorders in patients withcardiovascular disease has been an important topic of active investigation fromthe beginning of the modern era of psychopharmacology, in the mid-twentiethcentury, when psychoactive agents such as chlorpromazine, tricyclic antide-pressants (TCAs), and lithium were noted to have significant cardiovasculareffects. In the last 20 years, psychiatric disorders, especially depression, havebeen found to be associated with increased cardiovascular morbidity and mor-tality in patients with existing heart disease, spurring even greater interest inthe effects of psychopharmacological treatment in cardiac patients.

The most common psychiatric problems in patients with heart disease areadjustment disorders, anxiety disorders, depressive disorders, and cognitivedisorders (delirium and dementia). In addition, patients who undergo long-term treatment with antipsychotic medications are at risk for heart diseasedue to metabolic side effects. Nicotine dependence, substance use disorders,and sexual dysfunction may also be problems that require intervention.


Most clinical trials in psychopharmacology exclude patients with signifi-cant medical comorbidity, so most psychopharmacotherapy practice for pa-tients with cardiovascular disease is based on inferences from studies ofpatients without heart disease, or on clinical lore alone. More specific evi-dence about treatment in patients with heart disease is needed. Nevertheless,some general guidelines apply.

Differential Diagnostic Considerations

In general, differential diagnosis of psychiatric problems in patients with car-diac disease begins with phenomenological characterization of the psychopa-thology. Next, one must evaluate whether the condition is secondary to ageneral medical condition or substance (including medications used to treatthe medical condition) or is a primary psychiatric problem. Finally, comor-bidity will help to define treatment plans.

Some common errors involve misattribution of symptoms to a primarypsychiatric diagnosis rather than to the cardiac problem. For example, pa-tients with paroxysmal supraventricular tachycardia may appear to be anxiousor to be having panic attacks. Patients with unrecognized congestive heartfailure, pulmonary congestion, and nocturnal dyspnea may complain of in-somnia and receive a diagnosis of depression or panic attacks. These patientswill respond better to effective heart failure management than to psychotro-pics.

The workup of psychiatric symptoms in cardiac patients should includeassessment of cardiac rhythm, blood pressure, fluid and electrolyte status, gly-cemic control, blood gases, blood count, and hepatic, renal, and thyroid func-tion. Hypotension and arrhythmias may reduce cerebral blood flow andperfusion of other vital organs, resulting in organic mental syndromes. Severehyponatremia and anemia may lead to a variety of psychiatric symptoms. He-patic and renal dysfunction often cause mood or cognitive disturbances.Hypothyroidism, which may occur as a complication of amiodarone therapy,causes mood and cognitive problems. The presence of infections and the roleof medications and substance use or withdrawal symptoms should be consid-ered. Consideration should be given to the presence of central nervous system(CNS) disease, including cerebrovascular disease and primary degenerativebrain disorders (e.g., Alzheimer’s disease, Parkinson’s disease). The prevalence

Cardiovascular Disorders 183

of small vessel ischemic cerebrovascular disease is high in patients with is-chemic heart disease, even in patients without a known history of transientischemic attack or stroke (Lazar et al. 2001). Electroencephalograms are oftenuseful to distinguish encephalopathies (hypoactive delirium, dementia, recur-ring seizures and interictal states) from depression with apathy, psychomotorretardation, or apparent cognitive impairment.

Neuropsychiatric Side Effects of Cardiac Medications

Neuropsychiatric side effects of cardiovascular medications should be consid-ered in differential diagnosis (see Table 6–1). Alpha-adrenergic blockingagents may cause depression and sexual dysfunction. The purported associa-tion of beta-adrenergic blocking agents with depression was disproven in aquantitative review of randomized trials (Ko et al. 2002). This study, review-ing 15 trials with a total of more than 35,000 subjects treated for acute myo-cardial infarction, hypertension, or congestive heart failure, found no effectof beta-blocker treatment on reported depressive symptoms. For fatigue andsexual dysfunction, the estimated numbers needed to treat to cause one addi-tional case of these adverse events were 57 and 199 patients per year, respec-tively. Withdrawal of therapy due to fatigue or sexual dysfunction occurred inless than 6 cases per 1,000 patient-years of treatment. Similarly, a comparison

Table 6–1. Selected adverse neuropsychiatric effects of cardiac medicationsCardiac medication Neuropsychiatric effect(s)

Alpha-adrenergic blockers Depression, sexual dysfunction

Amiodarone Mood disorders secondary to thyroid effects

Angiotensin-converting enzyme inhibitors

Mood elevation or depression (rare)

Antiarrhythmic agents Hallucinations, confusion, delirium

Beta-adrenergic blockers Fatigue, sexual dysfunction

Digoxin Visual hallucinations, delirium, depression

Diuretics Anorexia, weakness, apathy secondary to electrolyte disturbances


of post–myocardial infarction patients on beta-blockers to matched patientsnot on beta-blockers found no effect of beta-blocker therapy on incident de-pressive symptoms or cases of depressive disorder (van Melle et al. 2006).However, a trend was noted toward higher depression symptom scores withlong-term use or higher dosages.

Digoxin may produce visual hallucinations, often of colored rings aroundobjects. Some antiarrhythmic agents (especially lidocaine) cause confusion,hallucinations, or delirium. Angiotensin-converting enzyme (ACE) inhibi-tors are occasionally associated with mood elevation or depression. Amio-darone treatment often leads to thyroiditis, with temporary hyperthyroidstatus followed by hypothyroidism; these thyroid disturbances may result inanxiety and/or depression symptoms. Hypokalemia and hyponatremia fromdiuretic therapy may result in anorexia, weakness, and apathy; thiazide diuret-ics sometimes cause erectile dysfunction. More extensive reviews are available(Brown and Stoudemire 1998; Keller and Frishman 2003).

Alterations in Pharmacokinetics in Heart DiseaseFor most patients, heart disease per se does not result in alterations in drugabsorption, distribution, metabolism, and elimination, but there are someimportant exceptions (see Table 6–2). These are severe right-sided heart fail-ure with secondary hepatic congestion, ascites, or marked peripheral edema;severe left-sided heart failure with low cardiac output; and use of diuretics.

Right-sided congestive heart failure may result in elevated central venouspressure and impaired venous drainage from the hepatic venous system andthe gut wall. Resulting gut wall edema may reduce drug absorption. Mild tomoderate hepatic congestion has a limited effect on drug metabolism, but cir-rhosis secondary to hepatic congestion leads to reduced serum albumin, rela-tively increased alpha-1 acid glycoprotein level, and ascites, which may alterdrug distribution and serum levels of free drug. Because the effects of dimin-ished absorption and variable changes in drug distribution may be additive oroffsetting, it is difficult to predict net effects. In general, as serum total proteinand albumin levels fall with more advanced disease, the prudent action is touse smaller than usual dosages of psychotropic agents and increase dosagescautiously. When the ratio of free to protein-bound drug changes, the total

Cardio

vascular Disord

ers185

Table 6–2. Pharmacokinetic changes in heart diseaseCondition Physiological consequences Pharmacokinetic effect(s) Significance

Drug absorption

Right-sided heart failure Hepatic congestion, gut wall edema Decreased absorption Uncertain

Drug distribution

“Cardiac cirrhosis” Reduced albumen, ascites, increased alpha-1 acid glycoprotein

Increased or decreased free drug levels

Uncertain

Drug metabolism

Left-sided heart failure Decreased hepatic artery blood flow, decreased Phase 1 hepatic metabolism

Reduced elimination of parent drug

Important for drugs with low therapeutic index and high hepatic extraction

Drug elimination

Left-sided heart failure Decreased renal artery blood flow, decreased glomerular filtration rate

Reduced elimination of water-soluble molecules

Risk of lithium toxicity


plasma drug level is reduced, even though the amount of free drug, which isthe amount that determines drug activity, remains the same. Therapeuticdrug monitoring that measures only the total drug level would result in alower level, and may mislead the physician to increase drug dosage.

Left-sided heart failure results in reduced cardiac output and reducedblood flow through the hepatic and renal arteries. Decreased hepatic arteryblood flow results in reduced drug metabolism, particularly Phase I pro-cesses—that is, oxidation (e.g., cytochrome P450 [CYP]) and reduction reac-tions. Conjugation reactions (Phase II metabolism) that make drugmetabolites water soluble and subject to excretion through the kidneys are rel-atively spared. Because most psychotropic agents undergo hepatic Phase I me-tabolism, they will tend to accumulate. Even agents that rely on Phase IImetabolism (e.g., lorazepam, oxazepam) tend to accumulate, albeit less thanagents metabolized by Phase I processes (e.g., diazepam, amitriptyline).Again, as cardiac output falls, reduced dosage of most psychotropic agentsmay be necessary. Severe left-sided heart failure results in renal dysfunctiondue to hypotension and reduced renal artery blood flow. Thus, managementof combined left- and right-sided heart failure, with combinations of beta-blockers, ACE inhibitors, or angiotensin II receptor blockers and diuretics, isoften limited by progressive renal dysfunction, requiring inotropic support.Lithium is the most important psychotropic agent eliminated primarily by re-nal excretion—gabapentin, pregabalin, paliperidone, and memantine areothers—and excretion of lithium and these other drugs falls along with crea-tinine clearance.

Diuretic use itself affects excretion of lithium. Thiazide diuretics block so-dium reabsorption in the glomerular proximal convoluted tubule; as serumsodium is depleted, tubular reuptake of lithium from the glomerular filtrateis enhanced. Thus, thiazide diuretics increase serum lithium level and may in-crease risk of lithium toxicity. Loop diuretics (furosemide, ethacrynic acid,bumetanide) have little effect on serum lithium levels (Crabtree et al. 1991;Finley et al. 1995). However, chronic use of any diuretic in patients with heartfailure may reduce creatinine clearance, raising the serum lithium level andincreasing risk of lithium toxicity (Finley et al. 1995). Lithium dosing shouldbe closely monitored or withheld entirely in patients with congestive heartfailure whose fluid and electrolyte status is unstable. Use of hepatically me-tabolized mood stabilizers (e.g., valproate) may be preferred in these patients.


Psychotropic Medication Use in Heart Disease

Mackin (2008) provides a comprehensive discussion of cardiac side effects ofpsychotropic drugs. Some important effects are summarized in Table 6–3.


Relevant Treatment Literature

Although anxiety symptoms are common in patients with heart disease, stud-ies are lacking of benzodiazepine and buspirone treatment efficacy in treat-ment of anxiety in patients with heart disease.

Table 6–3. Cardiac adverse effects of psychotropic drugsMedication Cardiac effect(s)

Antipsychotics Hypotension, orthostatic hypotension, cardiac conduction disturbances, ventricular tachycardia/fibrillation, metabolic syndrome

Antidepressants

Bupropion Hypertension

Monoamine oxidase inhibitors Orthostatic hypotension

Serotonin–norepinephrine reuptake inhibitors

Hypertension

Selective serotonin reuptake inhibitors

Reduced heart rate, occasional clinically significant sinus bradycardia or sinus arrest

Stimulants Hypertension, tachycardia, tachyarrhythmias

Tricyclic antidepressants Hypotension, orthostatic hypotension, Type 1A antiarrhythmic effects: slowed conduction through atrioventricular node and His bundle; heart block; QT prolongation; ventricular fibrillation

Trazodone Orthostatic hypotension

Mood stabilizers

Lithium Sinus node dysfunction

Carbamazepine Type 1A antiarrhythmic effects; atrioventricular block

Phosphodiesterase type 5 inhibitors

Hypotension, myocardial ischemia


Prescribing Principles

Benzodiazepines, compared with buspirone, have the advantage of rapid on-set of effect. Lorazepam, oxazepam, and temazepam may be the safest benzo-diazepines to prescribe in patients with heart disease because these drugs donot undergo Phase I hepatic metabolism, and are therefore relatively unaf-fected by altered metabolism in heart failure. Longer-acting agents and agentswith active metabolites that effectively extend their elimination half-life andduration of action—clonazepam, clorazepate, diazepam, chlordiazepoxide,flurazepam, halazepam, and quazepam—should be used cautiously and atlow dosages, because they may accumulate to a higher than expected steady-state level due to slowed elimination. Cognitive dysfunction or delirium canresult when the CNS depressant effect of benzodiazepines is superimposed ona brain already compromised by microvascular disease, which may co-occurwith atherosclerotic cardiovascular disease.

Desirable Secondary Effects

Benzodiazepines have no significant effects of their own on heart rate andblood pressure, but reduction in acute anxiety can lead to reduction in anxi-ety-associated tachycardia, myocardial irritability, and myocardial work(Huffman and Stern 2003). Effects on autonomic nervous system activity andon the balance of parasympathetic to sympathetic tone are uncertain; bothparasympathetic withdrawal and a shift in sympathovagal balance toward in-creased parasympathetic predominance have been described in response tobenzodiazepines (Marty et al. 1986; Vogel et al. 1996). Buspirone has no car-diovascular effects.

Antidepressants


Many studies have examined treatment of depression in patients with heartdisease. Initial investigations of TCAs demonstrated their efficacy and theirsignificant cardiovascular side-effect profile, which was particularly pro-nounced in patients with heart disease: increased heart rate, orthostatic hypo-tension, and cardiac conduction disturbances. First-, second-, or third-degreeheart block may develop, and a pacemaker may be necessary to avoid syncope,particularly in patients with a prolonged PR interval at baseline. A series of


studies on depressed patients with impaired left ventricular function sug-gested that nortriptyline, titrated to a blood level between 50 and 150 ng/mL,is relatively well tolerated in patients with impaired left ventricular function(Roose and Glassman 1989). In overdose, TCAs can cause lethal ventriculararrhythmias associated with QRS and QT interval prolongation. TCAs haveType 1A (quinidine-like) antiarrhythmic properties (Giardina et al. 1986).Type 1A antiarrhythmic agents are associated with increased mortality in pa-tients with ischemic heart disease (Morganroth and Goin 1991). TCA usersalso had increased risk of incident myocardial infarction, compared with non-antidepressant users and with users of selective serotonin reuptake inhibitors(SSRIs), in a cohort of over 50,000 workers, with a median 4.5-year follow-up (Cohen et al. 2000).

Cardiovascular effects of SSRIs in patients who do not have heart diseaseare limited to slowing of heart rate, usually by no more than two to three beatsper minute, but occasionally to a clinically significant extent. Sinus bradycar-dia and syncope have been reported (Glassman et al. 1998). A head-to-headcomparison of paroxetine and nortriptyline in patients with impaired leftventricular function showed similar efficacy but a substantially lower rate ofcardiovascular adverse events and dropout in patients treated with paroxetine(Roose et al. 1998b; Yeragani et al. 2002). Two other small trials utilizing flu-oxetine, one in patients with impaired left ventricular function and one in pa-tients who had had an acute myocardial infarction, demonstrated tolerabilityof fluoxetine but also found low efficacy rates (Roose et al. 1994, 1998a; Striket al. 2000).

Two large-scale randomized, placebo-controlled, double-blind trials ofSSRIs in heart disease have been reported. The first, the Sertraline Antide-pressant Heart Attack Randomized Trial (SADHART), enrolled 369 patientswithin 30 days of an acute coronary syndrome (Glassman et al. 2002, 2006).Patients were randomized to 24 weeks of treatment with sertraline or placebo.Sertraline was dosed in a range from 50 to 200 mg/day (mean 71 mg/day).Sertraline was more effective than placebo overall, as measured by the ClinicalGlobal Impressions Improvement scale; planned subgroup analyses demon-strated that sertraline efficacy was limited to patients with recurrent depres-sion, depression onset before the index cardiac event, or severe depressionwith Hamilton Rating Scale for Depression (Ham-D) scores above 20. Pa-tients with first-episode onset of depression after the index cardiac event had


a high placebo response rate, and sertraline showed no advantage over pla-cebo. Sertraline treatment did not have significant effects on heart rate, bloodpressure, cardiac conduction intervals, left ventricular ejection fraction, orarrhythmias. Results were similar for patients with left ventricular ejectionfraction above or below 35%. The study was not designed to have sufficientsample size to test for a difference in rates of major adverse cardiac events, buta trend toward a reduction in events in patients treated with sertraline wasnoted. (In another study, the Enhancing Recovery in Coronary Heart Disease[ENRICHD] trial for treatment of depression and low social support aftermyocardial infarction, open treatment with sertraline, which was prescribedin a nonrandomized fashion, was also associated with reduced major adversecardiac events and reduced mortality [Taylor et al. 2005].)

The second study, the Canadian Cardiac Randomized Evaluation of Anti-depressant and Psychotherapy Efficacy (CREATE) trial, enrolled 281 patientswith stable coronary disease, and randomized patients simultaneously tocitalopram versus placebo and to clinical management alone versus clinicalmanagement supplemented by interpersonal psychotherapy (Lespérance et al.2007). Citalopram dosing ranged from 20 to 40 mg/day (mean 33.1 mg/day). Patients were followed for 12 weeks. Clinical management plus inter-personal psychotherapy had no advantage over clinical management alone,but citalopram demonstrated superior antidepressant efficacy over placebo.There were no differences between treatment groups in cardiovascular effectsand adverse event rates.

A retrospective case-control comparison study in patients hospitalized foracute coronary syndromes found a reduction in in-hospital recurrent is-chemic events, heart failure, and asymptomatic cardiac enzyme elevation inpatients taking SSRI antidepressants during the hospital stay, and also anincrease in minor bleeding complications, but no effect of SSRIs on eithermajor cardiac event rates or major bleeding complications (Ziegelstein et al.2007). Almost all of the patients in this study were also on aspirin and full-dose antiplatelet therapy.

Although controlled studies in patients with heart failure are lacking, aprospective, naturalistic follow-up study of 204 outpatients with heart failurefound that both symptoms of depression and antidepressant use were associ-ated with a trend toward an increase in deaths over a median of 3 years follow-up (antidepressant-associated hazard ratio 1.79, 95% confidence interval [CI]


0.96–3.34; P=0.07) as well as a significant increase in combined mortalityand cardiovascular hospitalizations (hazard ratio 1.75, 95% CI 1.14–2.68;P=0.01) (Sherwood et al. 2007).

Orthostatic hypotension is a known side effect of mirtazapine in patientswho do not have heart disease. Mirtazapine was tested in a randomized, pla-cebo-controlled trial on 94 patients (Honig et al. 2007), nested within thelarger Myocardial INfarction and Depression–Intervention Trial (MIND-IT)(van Melle et al. 2007). Mirtazapine dosing ranged from 30 to 45 mg/day. Atweek 8, the effect of mirtazapine on patients’ Ham-D scores was not signifi-cantly different from that of placebo, but mirtazapine was more efficacious asmeasured by the Depression scale of the Symptom Checklist–90 and by theBeck Depression Inventory. Patients with inadequate response at 8 weekswere offered alternative treatment, whereas the subset of patients with ade-quate response at 8 weeks continued with maintenance treatment to 24-weekfollow-up (n=40). This small subset of patients demonstrated efficacy of mir-tazapine treatment on all measures at 24-week follow-up. Mirtazapine waswell tolerated.

Limited data are available about other antidepressants for treatment of pa-tients with heart disease. Hypertension sufficient to cause treatment discon-tinuation occurred in 2 of 40 patients in an open-label study of bupropion inpatients with heart disease (Roose et al. 1991). Hypertension is also a knownadverse effect of venlafaxine; no studies have been reported of venlafaxine inpatients with cardiac disease, but an open-label study in patients older than60 years found significant rates of increased blood pressure and orthostatichypotension and several instances of palpitations, dizziness, or QT prolonga-tion (E.M. Johnson et al. 2006). Venlafaxine (but not paroxetine) treatmentreduced laboratory measures of heart rate variability (an undesirable effect) ina cohort of depressed subjects who were free of heart disease (Davidson et al.2005). Monoamine oxidase inhibitors have not been studied in patients withheart disease; their use is not appealing in view of their strong risk of ortho-static hypotension, the risk of interaction with pressors, and the risk of hyper-tensive reactions to dietary indiscretions.

Duloxetine did not appear to be associated with significant cardiovascularrisks in the subjects in 42 placebo-controlled trials, 3 of which were in pa-tients with diabetic neuropathy (Wernicke et al. 2007). The medication hasnot been studied, however, in patients with significant heart disease.


In a small open-label study in patients with congestive heart failure anddepression, nefazodone produced a significant reduction in heart rate but nochanges in heart rate variability (Lespérance et al. 2003).

In a small placebo-controlled trial in patients with cardiac disease, trazo-done was without significant adverse cardiac effects except postural hypoten-sion (Bucknall et al. 1988). Numerous case reports have described QTprolongation and ventricular arrhythmias after trazodone overdose (e.g., Ser-vice and Waring 2008).

Hierarchy of Drug Choice

Based on the available evidence as of July 2009, citalopram, escitalopram, andsertraline appear to be the first-line pharmacotherapy treatment options for de-pression in patients with heart disease. The relative absence of CYP interactionsassociated with escitalopram and citalopram (and, to a lesser degree, with lower-dose sertraline) is an advantage in patients taking other medications. Patientswho cannot tolerate or have failed to respond to these agents might logically beoffered second-line treatment with mirtazapine, bupropion, venlafaxine, or du-loxetine, with special attention to blood pressure response during treatment.TCAs remain the gold standard of antidepressant efficacy; however, especiallyin patients with ischemic heart disease, they have a substantial side-effect bur-den and carry increased mortality risk. Nortriptyline might be a reasonablethird-line option in patients who have failed to respond to adequate trials ofother first- and second-line treatments and who are sufficiently impaired by de-pression that the additional adverse-effect risks are worth incurring.


The agent of choice depends on the factors described above, the patient’s co-morbid conditions, and the patient’s other medications. Medication shouldbe started at a low dose—possibly below the lowest therapeutic dose—andsubjective tolerability and relevant electrocardiographic effects, vital signs,physical examination, and laboratory parameters reassessed before increasingthe dose. Dosage increases should be followed by reassessment for adverse ef-fects. For patients in heart failure, with hepatic or renal dysfunction, targetdosages may need to be reduced to lower than normal levels due to prolongedmetabolism. However, if a patient is tolerating medication well but not re-sponding adequately, it is worthwhile to consider a dosage increase.


Desirable Secondary Effects

Antihistaminic agents (TCAs, trazodone, mirtazapine) may increase appetiteand promote weight gain in patients with cardiac cachexia, and sedating ef-fects may help patients with insomnia. Bupropion is one of the few psycho-tropic agents associated with weight loss and therefore may help patients whoneed to lose weight as part of their cardiac treatment program. Bupropion isalso indicated as pharmacotherapy for smoking cessation (although the pe-riod of acute treatment of a depressive episode is probably an unfavorabletime to attempt smoking cessation). Several SSRIs have been demonstrated toreduce the overactivation of platelets associated with depression; whether thisplatelet effect is clinically valuable in patients with ischemic heart disease is asyet unknown (Pollock et al. 2000; Serebruany et al. 2003b).

Antipsychotics


Delirium is frequently treated with antipsychotic medication, although suchtreatment is off-label. Heart disease patients with other psychiatric disordersmay also require antipsychotic drug therapy. No controlled studies have beenreported of the benefits of antipsychotic medications specifically in cardiacpatients.

All antipsychotic agents may cause hypotension, especially orthostatichypotension (Mackin 2008). The effect is particularly marked for low-potency agents such as chlorpromazine. Olanzapine, clozapine, and quetia-pine may be associated with higher rates of orthostatic hypotension thanother second-generation agents. Complaints of dizziness may occur even inthe absence of hypotension or orthostatic hypotension. Increased heart rate iscommon in patients treated with clozapine, but bradycardia can also occurwith clozapine and other second-generation antipsychotics. In a review ofU.S. Food and Drug Administration (FDA) data, syncope due to orthostatichypotension occurred in up to 1% of patients treated with quetiapine and upto 6% of patients treated with clozapine. Most of the patients in these samplesdid not have heart disease. Tolerance to the blood pressure–lowering effects ofantipsychotics may develop over time; initiating treatment with low dosagesreduces the risk. Salt supplements, alpha-adrenergic agonists such as mido-drine, and mineralocorticoids such as fludrocortisone can reduce the risk, but


these agents may not be suitable for some cardiac patients; support stockingsmay be an acceptable alternative.

Metabolic syndrome—comprised of dyslipidemia, glucose intolerance,hypertension, and abdominal obesity—is an important side effect of second-generation antipsychotics, especially olanzapine and clozapine, and a risk factorfor coronary artery disease (Bobes et al. 2007; Correll et al. 2006; Newcomerand Hennekens 2007). Aripiprazole and ziprasidone are less likely to lead tothese effects than other second-generation antipsychotic medications. Currentrecommendations for prevention of metabolic side effects associated with sec-ond-generation antipsychotics emphasize exercise and dietary modification(Newcomer and Sernyak 2007) (see also Chapter 2, “Severe Drug Reactions”).

All antipsychotic medications may prolong the QT interval, with the pos-sible exception of aripiprazole. Haloperidol, droperidol, thioridazine, sertin-dole, and ziprasidone tend to produce greater magnitude QT prolongationthan other agents (Glassman and Bigger 2001; Harrigan et al. 2004; Stöll-berger et al. 2005). QT interval prolongation (QTc above 440 msec, and es-pecially above 500 msec) is associated with increased risk of polymorphicsustained ventricular tachycardia (torsade de pointes), which can degenerateinto ventricular fibrillation. First-generation phenothiazine antipsychoticsmay also cause QT interval prolongation and torsade de pointes. Neverthe-less, there are case reports of patients with delirium treated in intensive careunits with intravenous haloperidol in dosages up to 1,000 mg/day withoutharm (Tesar et al. 1985), and low dosages of aripiprazole, quetiapine, andolanzapine are commonly used to treat psychotic symptoms in hospitalizedpatients, including cardiac patients. Women, patients with chronic heavy al-cohol consumption, and patients with anorexia nervosa are at increased riskof torsade de pointes. Other easily noted risk factors for torsade de pointes in-clude severe heart disease, hypokalemia, hypomagnesemia, and concurrenttreatment with one of the myriad other drugs that prolong the QT interval(see Table 6–4) (Justo et al. 2005; Stöllberger et al. 2005).

Based on Danish registry data, the risk of sudden death associated withantipsychotic medication is estimated to be only about 2–4 per 10,000 per-son-years of exposure in otherwise medically healthy subjects (Glassman andBigger 2001). However, reviews of treatment studies addressing use of bothfirst- and second-generation antipsychotic medications in behaviorally dis-turbed elderly patients have concluded that antipsychotic medications are as-


sociated with about a 1.9% absolute increase in short-term mortality in thispatient population (4.5% vs. 2.6%, or about a 70% increase in adjusted rel-ative risk), due mostly to cardiovascular events and infections. This resultedin an FDA-mandated black-box warning about off-label treatment of agita-tion and psychotic symptoms in behaviorally disturbed elderly patients withdementia (Gill et al. 2007; Kuehn 2008; Liperoti et al. 2005; Rochon et al.2008). A review of Tennessee Medicaid data found that nonusers of antipsy-chotic drugs had a sudden death rate of 0.0014 deaths per person-year,whereas antipsychotic drug users had a sudden death rate of 0.0028–0.0029deaths per person-year. Thus, antipsychotic drugs were associated with an ap-proximate doubling of risk for sudden death, but the absolute risk was onlyabout 0.0015 deaths per person-year, yielding a number needed to treat tocause one additional sudden death in 1 year of 666 persons (Ray et al. 2009).The degree to which these findings apply in the treatment of delirium andacute psychotic symptoms in patients with cardiac disease is unknown.

Clozapine is associated with a risk of myocarditis, which has been vari-ously estimated to occur in 1 in 10,000 to 1 in 500 to over 1% of exposedpatients (Merrill et al. 2005). Generally, clozapine-associated myocarditis oc-curs within the first few weeks of treatment. The mechanism of inflammationis uncertain, but an immune hypersensitivity reaction is suspected. Patientsexposed to clozapine also have an increased incidence of cardiomyopathy,even in the absence of an acute myocarditis process; onset may occur monthsto a few years after starting treatment (Mackin 2008).

Table 6–4. Risk factors for torsade de pointes

Familial long QT syndrome

QT prolongation

Female sex

Chronic heavy alcohol use

Anorexia nervosa

Low ejection fraction

Hypokalemia

Hypomagnesemia

Concurrent treatment with multiple drugs that prolong QT interval or inhibit metabolism of a QT-prolonging drug


Hierarchy of Drug Choice

In light of its relative freedom from metabolic problems and QRS prolonga-tion, aripiprazole deserves consideration as first-line treatment for psychoticsymptoms in patients with heart disease or with significant coronary arterydisease risk factors. However, few data are available to definitively support thisimpression. Olanzapine and aripiprazole are available as orally disintegratingtablets, which may be a convenient route of administration for patients whocannot swallow medications, and many medications are available for intra-muscular administration. Intravenous haloperidol, in widely variable dosages,has been in use (off-label) for decades.


Before antipsychotic drugs are prescribed, heart patients should be evaluatedfor risk factors for sudden cardiac death. Risk factors include history of syn-cope or cardiac arrest, family history of sudden death, familial long QT syn-drome (Roden 2008), long QT interval, low ejection fraction, treatment withother drugs that may prolong the QT interval either directly or through druginteractions, hypokalemia, and hypomagnesemia. Vital signs and electrocar-diograms should be reviewed. For patients with congestive heart failure, lowerthan normal dosages may be adequate.

Mood Stabilizers

No studies have been reported of mood stabilizers as treatment for depressionor bipolar disorder in heart patients. Lithium can cause sinus node dysfunc-tion, manifesting in sinus bradycardia or sinus arrest. Lithium excretion is al-most entirely through the kidney and is sensitive to the effects of diuretics (see“Alterations in Pharmacokinetics in Heart Disease” earlier in this chapter),ACE inhibitors, and angiotensin II receptor blockers. Long-term lithium usemay cause impaired renal function, which may complicate heart failure man-agement. Valproic acid has no cardiovascular effects; however, it may causethrombocytopenia, which may be important for patients taking anticoagulantsor on antiplatelet therapy. It may increase plasma warfarin levels, but this hasnot been shown to be of clinical significance. An interaction with aspirin hasbeen described that results in decreased protein binding, inhibited metabolism,and elevated free valproic acid level in blood. Lamotrigine does not have signif-icant cardiac effects. It undergoes only Phase II hepatic metabolism, which may


make it easier to dose in heart failure. Carbamazepine appears to be relativelyfree of cardiac effects in healthy patients (Kennebäck et al. 1995), but someelectrocardiographic abnormalities have occurred in patients with heart disease(Kennebäck et al. 1991). Both carbamazepine and oxcarbazepine are associatedwith hyponatremia, especially in elderly women (see “Drug Interactions” laterin this chapter). Gabapentin and pregabalin have no known cardiac effects.

Psychostimulants


Despite clinical lore supporting the value of stimulants to improve mood, in-crease energy, and improve subjective well-being in patients who are medi-cally ill (Emlage and Semla 1996), including patients with heart disease (e.g.,Kauffmann et al. 1984), no clinical trials have been reported of the risks andbenefits of stimulants for depressed cardiac patients. A recent Cochrane re-view of a number of small trials of psychostimulant treatment of depression,including several trials in subjects who are medically ill, found no associationbetween stimulant use and adverse cardiac effects, but noted significant lim-itations in the quantity and quality of evidence available (Candy et al. 2008).Low dosages of stimulants (e.g., methylphenidate 5–30 mg/day; dextroam-phetamine 5–20 mg/day) used as treatment for depression in medical patientshave minimal effects on heart rate and blood pressure (Masand and Tesar1996). A review of data from five clinical trials of stimulant and nonstimulantdrugs for treatment of attention-deficit disorder in adults concluded that am-phetamine and methylphenidate both raise systolic and diastolic blood pres-sure by about 5 mmHg; the dosages of stimulants were not described in thisreport (Wilens et al. 2005).


Contraindications to stimulant use in manufacturers’ package inserts gener-ally include broadly construed “serious heart problems,” “structural cardiacabnormalities,” “serious cardiac rhythm abnormalities,” cardiomyopathy, andcoronary artery disease. Interpreting this language may require clinical judg-ment and consultation with a cardiologist. Stimulant treatment should not bestarted, without a medical consultation, in a patient with history of heart dis-ease or hypertension; symptoms of chest pain, palpitations, or shortness ofbreath; or physical exam findings of tachycardia, elevated blood pressure, or


irregular heart rhythm. Stimulant treatment should be avoided in patientswith acute ischemia, unstable angina, frequent ventricular premature contrac-tions, or tachyarrhythmias. However, with concurrent medical supervision, ininpatient settings with cardiac monitoring, I have employed stimulants in thetreatment of numerous patients within days after coronary artery bypass graftsurgery, myocardial infarction, heart transplantation, and admission for dec-ompensated heart failure and acute coronary events. Even ill patients can startwith methylphenidate at dosages of 5 mg/day, increasing over a few days upto 20–30 mg/day. Vital signs and heart rhythm should be assessed with dosagechanges. Benefit from stimulant medications for depressed cardiac patientsshould be observable within several days.

With respect to newer agents, such as modafinil and atomoxetine, almost nodata are available. Potential hemodynamic effects, especially increased systolicblood pressure, could be problematic for patients with heart failure or coronaryartery disease (Heitmann et al. 1999; Shibao et al. 2007; Taneja et al. 2005).

Cognitive Enhancers

Cognitive enhancers have not been studied in trials for patients with heart dis-ease. The cholinesterase inhibitors donepezil, rivastigmine, and galantaminehave modest benefit for treatment of mild to moderate dementia. Theirprocholinergic effects reduce heart rate and may rarely result in sinus brady-cardia, heart block, and syncope. Clinical trials of cholinesterase inhibitorshave largely excluded patients with cardiovascular disease, although there issome evidence of increased mortality and treatment discontinuation due tocardiovascular side effects in elderly patients with heart disease treated withcholinesterase inhibitors (Malone and Lindesay 2007). For the N-methyl-D-aspartate receptor antagonist memantine, which is indicated for treatment ofmoderate dementia, the manufacturer reported hypertension as a rare event inpremarketing trials.

Other Agents

Varenicline, a nicotinic receptor partial agonist, was introduced in 2006 as amedication to aid smoking cessation, with data from two studies showingshort-term cessation rates significantly better than those achieved with bupro-pion or placebo (Gonzales et al. 2006; Jorenby et al. 2006). A third studydemonstrated that for patients who achieved abstinence during 12 weeks of


acute treatment, adding an additional 12 weeks of maintenance treatmentimproved abstinence at 24 and 52 weeks (Tonstad et al. 2006). Importantside effects of varenicline are nausea and worsening of depression. Vareniclinedoes not have significant cardiac effects. Varenicline should be titrated froma starting dosage of 0.5 mg once daily to 1 mg twice daily over 7 days.

Naltrexone hydrochloride, an opioid antagonist, is sometimes used to reducecraving and help prevent relapse in patients with a history of alcohol dependence.This may be useful for patients with alcoholic cardiomyopathy, in concert withother measures to promote and maintain abstinence. Naltrexone has no cardio-vascular effects in this situation. Intravenous naloxone, given as a competitiveopioid receptor inhibitor in patients with opioid intoxication or overdose, maycause hypertension, hypotension, pulmonary edema, and cardiac arrest.

Acamprosate is indicated for maintenance of abstinence in patients withalcohol dependence. Acamprosate has no cardiovascular effects.

Topiramate was recently reported to improve maintenance of abstinencefrom alcohol (B.A. Johnson et al. 2007). Topiramate has no cardiovascularside effects. Hydrochlorothiazide increases topiramate blood levels. Topira-mate reduces digoxin blood levels slightly.

The phosphodiesterase type 5 (PDE5) inhibitors sildenafil, vardenafil,and tadalafil, used for the treatment of erectile dysfunction, cause vasodilata-tion and increased blood flow into the penile corpus cavernosum. PDE5 in-hibitors are also systemic and pulmonary arterial vasodilators and interactwith numerous other agents that lower blood pressure. PDE5 inhibitors arealso useful for treatment of pulmonary hypertension (Wilkins et al. 2008).Concurrent use of nitrates is contraindicated due to severe hypotension, andextreme caution must be used when combining alpha-blocking agents withPDE5 inhibitors. PDE5 inhibitor use in patients with cardiovascular diseasehas resulted in syncope, chest pain, myocardial infarction, tachycardia, anddeath, usually in conjunction with sexual activity.

Drug–Drug InteractionsThe discussion of drug interactions in this section is based on several compre-hensive reviews (Robinson and Owen 2005; Strain et al. 1999, 2002; Williamset al. 2007). Interactions between psychotropic and cardiac medications aredue to pharmacodynamic properties of the drugs (i.e., they have overlapping


and additive or offsetting effects) or pharmacokinetic effects (i.e., one drug af-fects metabolism, distribution, or elimination of the other), including but notlimited to effects on hepatic metabolism by the CYP system (see Tables 6–5and 6–6). (For a complete review of drug–drug interactions, including cardiacmedications, see Chapter 1, “Pharmacokinetics, Pharmacodynamics, andPrinciples of Drug–Drug Interactions.”)

Common pharmacodynamic interactions are additive effects on heartrate, blood pressure, and cardiac conduction. Many psychotropic drugs re-duce blood pressure, and combining them with antihypertensive medicationswill increase the hypotensive effect. SSRI antidepressants tend to reduce heartrate; combining them with beta-blockers may exacerbate the bradycardic ef-fect. TCAs and mirtazapine suppress the centrally mediated antihypertensiveeffects of clonidine; the combination of TCA or mirtazapine with clonidinemay result in severe hypertension. Drugs that prolong cardiac conduction—TCAs, phenothiazines, and atypical antipsychotics—may interact withamiodarone, Type 1A antiarrhythmic drugs, and ibutilide, resulting in atrio-ventricular block or prolonged QT interval. Several antibiotics, antifungalagents, methadone, tacrolimus, and cocaine also prolong the QT interval.Trazodone combined with amiodarone has resulted in QT prolongation andventricular tachycardia.

Lithium clearance is an important example of a pharmacokinetic interac-tion that does not involve the hepatic CYP system. Thiazide diuretics, nifedi-pine, verapamil, lisinopril, ACE inhibitors, and angiotensin II receptorblockers all reduce lithium clearance and raise serum lithium levels. Aceta-zolamide and osmotic diuretics such as mannitol increase lithium clearance.Lithium toxicity may occur even when serum levels are not elevated in pa-tients also taking diltiazem or verapamil.

Hyponatremia, a common side effect of SSRIs, oxcarbazepine, and carba-mazepine, can be significantly exacerbated by interaction with the addedhyponatremic effect of diuretics (Dong et al. 2005; Jacob and Spinler 2006;Ranta and Wooten 2004; Rosner 2004).

Many benzodiazepines, fluoxetine, paroxetine, and nefazodone can in-crease blood levels of digoxin, by an unknown mechanism.

SSRIs reduce platelet activation in patients with ischemic heart disease anddepression, and when combined with nonsteroidal anti-inflammatory drugshave been linked to a modest increased risk of gastrointestinal bleeding (see


Chapter 4, “Gastrointestinal Disorders”). However, sertraline did not increasebleeding, even in patients taking antiplatelet therapy, in the SADHART study,or in other cohorts of patients with congestive heart failure and coronary arterydisease (Glassman et al. 2002; Serebruany et al. 2003a, 2003b).

Donepezil, rivastigmine, and galantamine have systemic and CNSprocholinergic effects; these may be antagonized by medicines with anticho-linergic activity, including disopyramide, procainamide, quinidine, isosor-bide dinitrate, digoxin, and furosemide, resulting in cognitive worsening.Cholinesterase inhibitors plus beta-blockers have additive bradycardic effectsand could cause syncope.

Numerous pharmacokinetic interactions involve inhibition or inductionof CYP isoenzymes involved in the metabolism of psychotropic and cardiacmedications (see Chapter 1, “Pharmacokinetics, Pharmacodynamics, andPrinciples of Drug–Drug Interactions”). The following discussion is limitedto a few specific interactions of clinical importance.

Most beta-blockers, including carvedilol, propranolol, and metoprolol,are mainly metabolized by CYP 2D6, which is strongly inhibited by fluoxet-ine, paroxetine, and bupropion. Significant bradycardia could result. Mostantiarrhythmic drugs are also metabolized by CYP 2D6.

Warfarin is metabolized mainly by CYP 2C9 and to a lesser extentthrough several other CYP isozymes. Fluvoxamine inhibition and carbamaz-epine induction of CYP 2C9 may cause clinically significant increase or de-crease, respectively, in the international normalized ratio (INR). Clopidogrel,argatroban, and heparin have not been reported to have interactions with psy-chotropic medications.

Most statins are metabolized by CYP 3A4. Myopathy and hepatic injuryas a result of statin toxicity may theoretically result from interaction with flu-voxamine, nefazodone, or other strong CYP 3A4 inhibitors.

Although added QT prolongation could occur if metabolism of an anti-psychotic drug were inhibited by a second agent, the clinical significance ofthis effect is uncertain. Cautious electrocardiographic monitoring would beespecially appropriate in patients who begin with a QT interval near the up-per limits of normal (Harrigan et al. 2004).

The combination of beta-blockers and phenothiazines results in increasedblood levels of both due to mutual metabolic inhibition. Heart rate and bloodpressure effects, as well as CNS effects, may be increased.

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Table 6–5. Clinically relevant cardiac drug–psychotropic drug interactionsCardiac drug Mechanism of interaction Clinical effect(s) and management

ACE inhibitors Reduced lithium clearance Elevated lithium levels. Monitor serum lithium levels.

Angiotensin II receptor blockers Reduced lithium clearance Elevated lithium levels. Monitor serum lithium levels.

Antianginals

Isosorbide dinitrate Anticholinergic activity Impaired cognition. Reduced therapeutic effect of cholinesterase inhibitors and memantine.

Antiarrhythmics

Amiodarone Inhibition of CYP 2C9, 2D6, 3A4

Increased levels of phenytoin, TCAs, opiates, risperidone, aripiprazole, atomoxetine, benzodiazepines, buspirone, alfentanil, zopiclone, eszopiclone, modafinil. Impaired activation of codeine to morphine.

Disopyramide Anticholinergic activity Impaired cognition. Reduced therapeutic effect of cholinesterase inhibitors and memantine.

Mexiletine CYP 1A2 inhibition Increased levels of olanzapine and clozapine.

Procainamide Anticholinergic activity Impaired cognition. Reduced therapeutic effect of cholinesterase inhibitors and memantine.

Propafenone CYP 1A2 inhibition Increased levels of olanzapine and clozapine.

Quinidine CYP 2D6 inhibition Increased levels of TCAs, opiates, risperidone, aripiprazole, atomoxetine. Impaired activation of codeine to morphine.

Anticholinergic activity Impaired cognition. Reduced therapeutic effect of cholinesterase inhibitors and memantine.

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Antihyperlipidemics

Fluvastatin, gemfibrozil, lovastatin, simvastatin

CYP 2C9 inhibition Increased levels of phenytoin. Monitor phenytoin levels.

Calcium channel blockers

Diltiazem CYP 3A4 inhibition Increased levels of benzodiazepines, buspirone, alfentanil, zopiclone, eszopiclone, modafinil.

Nifedipine, verapamil Reduced lithium clearance Elevated lithium levels. Monitor serum lithium levels.

Cardiac glycosides

Digoxin Anticholinergic activity Impaired cognition. Reduced therapeutic effect of cholinesterase inhibitors and memantine.

Diuretics

Acetazolamide, osmotic diuretics Increased lithium clearance Reduced lithium levels. Monitor serum lithium levels.

Furosemide Anticholinergic activity Impaired cognition. Reduced therapeutic effect of cholinesterase inhibitors and memantine.

Thiazides Reduced lithium clearance Elevated lithium levels. Monitor serum lithium levels.

Note. ACE=angiotensin-converting enzyme; CYP=cytochrome P450; TCA=tricyclic antidepressant.

Table 6–5. Clinically relevant cardiac drug–psychotropic drug interactions (continued)Cardiac drug Mechanism of interaction Clinical effect(s) and management

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Table 6–6. Clinically relevant psychotropic drug–cardiac drug interactionsPsychotropic drug Mechanism of interaction Clinical effect(s) and management

Antidepressants

Bupropion CYP 2D6 inhibition Increased beta-blocker levels→decreased heart rate.Increased levels of many antiarrhythmics with possible conduction

abnormalities.

Duloxetine CYP 2D6 inhibition Increased beta-blocker levels→decreased heart rate.Increased levels of many antiarrhythmics with possible conduction

abnormalities.

Fluoxetine CYP 3A4 inhibition Increased statin levels→myopathy, hepatic injury.Increased calcium channel blocker levels→hypotension.

Fluvoxamine CYP 2C9 inhibition Increased warfarin levels, increased INR→possible increased bleeding risk.Fluvoxamine contraindicated in patients receiving warfarin.

Mirtazapine Unknown Possible severe hypertension with clonidine; avoid this combination.

Moclobemide CYP 2D6 inhibition Increased beta-blocker levels→decreased heart rate.Increased levels of many antiarrhythmics with possible conduction

abnormalities.

Nefazodone CYP 3A4 inhibition Increased statin levels→myopathy, hepatic injury.Increased calcium channel blocker levels→hypotension.

Paroxetine CYP 2D6 inhibition Increased beta-blocker levels→decreased heart rate.Increased levels of many antiarrhythmics with possible conduction

abnormalities.

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Trazodone Type 1A antiarrhythmic effects

QT prolongation, AV block with amiodarone, ibutilide, and Type 1A antiarrhythmic agents. Monitor QT interval. Avoid trazodone in conjunction with antiarrhythmic therapy.

MAOIs MAO inhibition increases monoamine effect

Increased pressor effects of epinephrine and dopamine—hypertension.

SSRIs/SNRIs Pharmacodynamic synergism: SIADH plus sodium wasting

SSRI/SNRI-induced SIADH and hyponatremia. Exacerbated with thiazide diuretic–induced sodium wasting. Monitor sodium levels. Consider nonthiazide diuretics.

TCAs Type 1A antiarrhythmic effects

QT prolongation, AV block with amiodarone, ibutilide, and Type 1A antiarrhythmic agents. Monitor QT interval. Avoid TCAs in conjunction with antiarrhythmic therapy.

Unknown Possible severe hypertension with clonidine; avoid this combination.

Antipsychotics

Atypical and typical antipsychotics

Type 1A antiarrhythmic effects

QT prolongation, AV block with amiodarone, ibutilide, and Type 1A antiarrhythmic agents. Monitor QT interval. Use antipsychotics with minimal QT-prolonging effect (olanzapine, aripiprazole).

Table 6–6. Clinically relevant psychotropic drug–cardiac drug interactions (continued)Psychotropic drug Mechanism of interaction Clinical effect(s) and management

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Mood stabilizers

Carbamazepine Pan-inducer of CYP 450 metabolic enzymes

Increased metabolism and lower levels of most cardiac medications, including warfarin, beta-blockers, antiarrhythmics, statins, calcium channel blockers, etc. Avoid carbamazepine if possible. Monitor cardiovascular function. Increase cardiac agent dosage as necessary.

Pharmacodynamic synergism: SIADH plus sodium wasting


Oxcarbazepine Pharmacodynamic synergism: SIADH plus sodium wasting


Phenytoin Pan-inducer of CYP 450 metabolic enzymes

Increased metabolism and lower levels of most cardiac medications, including warfarin, beta-blockers, antiarrhythmics, statins, calcium channel blockers, etc. Avoid phenytoin if possible. Monitor cardiovascular function.

Cholinesterase inhibitors Pharmacodynamic synergism: increased vagal tone

Increased beta-blocker effect on heart rate. Monitor heart rate. Reduce beta-blocker dosage as necessary.

Note. AV=atrioventricular; CYP=cytochrome P450; INR=international normalized ratio; MAOI=monoamine oxidase inhibitor; SIADH=syndrome of inappropriate antidiuretic hormone secretion; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant.

Table 6–6. Clinically relevant psychotropic drug–cardiac drug interactions (continued)Psychotropic drug Mechanism of interaction Clinical effect(s) and management


Key Clinical Points

• Hypotension and QT interval prolongation should be monitored,particularly with TCAs and antipsychotic medications.

• Serum lithium levels need to be closely monitored.• Many relevant cardiac medications are metabolized through CYP

2D6; bupropion, fluoxetine, duloxetine, moclobemide, and par-oxetine are CYP 2D6 inhibitors.

• Many relevant cardiac medications are metabolized through CYP3A4; nefazodone, fluoxetine, fluvoxamine, and diltiazem arestrong CYP 3A4 inhibitors.

• Carbamazepine, phenytoin, and barbiturates are strong inducersof multiple CYP 450 enzymes and increase metabolism of manycardiac drugs.

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7Respiratory Disorders

Wendy L. Thompson, M.D.

Yvette L. Smolin, M.D.

The modern era of treatment for depression was ushered in by the serendip-itous discovery in 1952 that iproniazid, a potential antitubercular agent, causedan elevation of mood in patients with tuberculosis (Lieberman 2003). Ipro-niazid was a poor antitubercular drug, but its secondary activity as a monoam-ine oxidase inhibitor (MAOI) opened the door to the use of drugs to treatdepression.

In this chapter, we focus on asthma, chronic obstructive pulmonary dis-ease (COPD), cystic fibrosis, tuberculosis, obstructive sleep apnea, vocal corddysfunction, and pulmonary embolus. For both psychological and physiolog-ical reasons, each of these disorders may present with symptoms that are afocus of psychopharmacological treatment (see Table 7–1). Most illnesses dis-cussed (except cystic fibrosis, or if the patient smokes) do not alter the metab-olism of pulmonary or other drugs. The main concern is to avoid medicationsthat decrease respiratory drive or otherwise adversely affect ventilation. Psy-


chiatric side effects of the medications used to treat pulmonary disease anddrug–drug interactions are also reviewed.

Differential Diagnostic Considerations

All respiratory disorders discussed in this chapter are frequently associatedwith psychiatric symptoms that may require psychotropic medication. Diag-nosis may be difficult when the symptoms of respiratory disease and those ofthe psychiatric disorder overlap. Furthermore, patients often get into a cycli-cal pattern with their psychiatric and respiratory symptoms such that the rootcause is difficult to define, with multiple ongoing contributing factors.

Anxiety

Dyspnea, chest tightness, and the sensation of choking are common in bothanxiety disorders and respiratory diseases (Shanmugam et al. 2007). Somaticanxiety symptoms may be due to a comorbid anxiety disorder, an anxious re-sponse to a respiratory disorder, or the respiratory disorder itself. Differentia-

Table 7–1. Psychiatric symptoms often associated with respiratory diseasesRespiratory illness Psychiatric symptoms

Asthma Anxiety, depression, substance abuse (marijuana, crack cocaine), sleep disturbance

Chronic obstructive pulmonary disease

Anxiety, depression, nicotine dependence, cognitive impairment, sleep disturbance, sexual dysfunction, fatigue

Cystic fibrosis Depression, anxiety, eating disorder

Functional respiratory disorders

Vocal cord dysfunctionHyperventilation syndrome

Stress, anxiety, depression, conversion disorderAnxiety, depression, pseudoseizure

Sleep apnea Somnolence, sleep disturbance, irritability, depression, cognitive impairment

Tuberculosis Psychosis, sleep disturbance, substance abuse, cognitive impairment, fatigue, lethargy, mania, delirium

Respiratory Disorders 215

tion is important whenever possible; if the symptoms have a physiologicalbasis (e.g., hypoxia), then this must be treated, either independently or inconjunction with treatment of the associated anxiety. For example, pulmo-nary embolus may present with dyspnea and hyperventilation in the absenceof chest pain, and be mistaken for a panic attack (Mehta et al. 2000). Anxietydisorders, especially panic disorder, are included in the differential diagnosisfor vocal cord dysfunction (VCD) (Hicks et al. 2008). Anxiety disorders oc-cur in almost one-third of patients with asthma in primary care, and anxietymay precipitate asthma attacks (Cooper et al. 2007; Goodwin et al. 2003;Roy-Byrne et al. 2008; Scott et al. 2007). Theophylline and many beta-ago-nists may induce or exacerbate anxiety (Thompson and Sullivan 2006). Anx-iety frequently accompanies VCD and pulmonary embolus. There is also anincreased incidence of anxiety disorders, especially panic disorder with agora-phobia, in patients with COPD (Vögele and von Leupoldt 2008).

Depression

Patients with asthma, COPD, and cystic fibrosis also experience depressivesymptoms more commonly than the general population (Cooper et al. 2007;Riekert et al. 2007; Zielinski et al. 2000). Diagnosis of major depression maybe difficult in patients with chronic respiratory disease, because many of thesymptoms overlap, including fatigue, poor sleep, anergy, weight loss, and an-orexia. Tuberculosis may present with vegetative signs suggestive of depres-sion, such as weight loss, lethargy, sleep disturbance, lack of interest in usualactivities, and confusion, confounding the diagnosis.

Sleep Disturbance

Sleep disturbance may be caused by sleep apnea, nocturnal cough, nocturnalasthma attacks, and medication side effect, as well as by comorbid anxiety ordepression. More than 50% of patients with COPD have pronounced sleepcomplaints (George and Bayliff 2003). Many COPD patients are found tohave obstructive sleep apnea (OSA), resulting in excessive daytime sleepiness,insomnia, and very frequently irritability and depressive symptoms (Baranand Richert 2003). Such patients may have significant difficulty with concen-tration, attention, and recall (Doghramji 2006).


Cognitive Deficits

Cognitive dysfunction occurs frequently in patients with COPD, even thosewithout chronic hypoxia or hypercapnia (Zheng et al. 2008). Patients with se-vere COPD may have irreversible cognitive deficits and subclinical encepha-lopathy due to repeated episodes of hypoxia or chronic hypoxia (Lima et al.2007; Ortapamuk and Naldoken 2006). Oxygen therapy may help to mini-mize cognitive deficits in patients with mild hypoxia (Kozora et al. 1999).Other patients may have potentially reversible causes of cognitive deficits,such as hypercapnia or exacerbation of coexisting cardiac disease.

Neuropsychiatric Side Effects of Respiratory Drugs

Medications used to treat respiratory illnesses often cause neuropsychiatricside effects. These drugs and side effects are discussed in detail in this sectionand summarized in Table 7–2.

Corticosteroids

Although side effects are uncommon with inhaled corticosteroids, oral corti-costeroids (e.g., prednisone, prednisolone, dexamethasone) can cause a varietyof side effects, which include depression, mania, lability, anxiety, insomnia,psychosis, hallucinations, paranoia, and personality changes. These drugs arediscussed in more detail in Chapter 10, “Endocrine and Metabolic Disorders.”

Bronchodilators

The most common side effects of the beta-adrenergic bronchodilators are ner-vousness and tremor. Albuterol can also cause insomnia. (See Table 7–2 forfurther information about the specific drugs.) Over-the-counter inhalers con-tain epinephrine or ephedrine, which are nonselective alpha- and beta-ago-nists; they may cause anxiety and, when taken in high dosages, psychosis.

Mixed Alpha- and Beta-Agonists

Mixed alpha- and beta-agonists are often used in over-the-counter asthmamedications. Epinephrine, ephedrine, phenylephrine, and phenylpropanola-mine can cause anxiety, insomnia, tremor, and psychosis.


Table 7–2. Neuropsychiatric side effects of drugs used to treat respiratory diseasesDrug Neuropsychiatric side effects

Anticholinergics

Atropine Paranoia; tactile, visual, and auditory hallucinations; memory loss; delirium; agitation

Beta-agonists

Albuterol, levalbuterol Anxiety, insomnia, paranoia, hallucinations, tremor, palpitations

Formoterol, arformoterol Insomnia, anxiety, tremor, palpitations

Isoproterenol Anxiety, insomnia tremor

Metaproterenol Anxiety, insomnia

Pirbuterol Anxiety, tremor

Salmeterol Anxiety, tremor, palpitations

Bronchodilator—other

Aminophylline, theophylline Anxiety, insomnia, tremor, restlessness, withdrawal, hyperactivity, psychosis, delirium, mutism

Corticosteroids

Inhaled Uncommon

Oral (e.g., prednisone, prednisolone, dexamethasone)

Depression, mania, lability, anxiety, insomnia, psychosis, hallucinations, paranoia, personality changes

Leukotriene inhibitors

Montelukast Fatigue, asthenia, suicidal ideation

Mixed alpha- and beta-agonists

Epinephrine Anxiety, tremor, psychosis

Phenylephrine Depression, hallucinations, paranoia

Phenylpropanolamine Restlessness, anxiety, insomnia, psychosis, hallucinations, aggressiveness

Miscellaneous

Acetazolamide Confusion, malaise

Modafinil Nervousness, depression, anxiety

Source. American Thoracic Society et al. 2003; Breen et al. 2006; Flume et al. 2007; Polosa 2008; Thompson and Sullivan 2006.


Theophylline

Theophylline preparations may cause jitteriness, insomnia, anxiety, restless-ness, and irritability, which can mimic a primary anxiety disorder or akathisia.Theophylline-induced symptoms tend to be dose related and in close prox-imity to time of administration. Management involves tapering to minimallyeffective dosage, altering dose timing, and/or switching to other asthma med-ications. The patient with anxiety can often be managed without oral theo-phylline, if inhaled cromolyn, ipratropium, or steroids are added (Thompsonand Sullivan 2006).

Theophylline toxicity is characterized by marked anxiety, severe nausea,headache, and insomnia, and may cause a delirium with severe agitation andpsychosis. Theophylline should be stopped until the symptoms abate and theblood level returns to the therapeutic range. Theophylline may induce tremoror exacerbate essential tremor. If theophylline cannot be discontinued, tremormay be managed by beta-blockers or benzodiazepines. Although beta-block-ers have been relatively contraindicated in COPD and asthma due to theirbronchoconstricting effects, highly cardioselective beta-blockers, such as ace-butolol, atenolol, celiprolol, metoprolol, and practolol, may be used in pa-tients with mild to moderate reactive airways disease and those with COPD(Salpeter et al. 2002, 2005).

Antibiotics and Antitubercular Drugs

Antibiotics used to treat infections associated with asthma or COPD usuallyhave minimal side effects. However, antitubercular drugs are associated withmore frequent and severe side effects, including depression, anorexia, anxiety,insomnia, delusions, hallucinations, and toxic psychosis. Antibiotics andantitubercular drugs are discussed in more detail in Chapter 12, “InfectiousDiseases.”

Anticholinergics

Atropine, an anticholinergic that is used rarely for the treatment of asthma,can cause paranoia; tactile, visual, and auditory hallucinations; memory loss;delirium; and agitation. Inhaled ipratropium and tiotropium are anticholin-ergics that have not been found to cause significant psychiatric side effects.


Leukotriene Inhibitors

Montelukast, a leukotriene inhibitor, can cause dizziness, fatigue, asthenia,and suicidal ideation, but has not been associated with increased suicide at-tempts. Another leukotriene inhibitor, zafirlukast, does not appear to causesignificant psychiatric side effects.

Obstructive Sleep Apnea Drugs

Acetazolamide may cause confusion and malaise. Modafinil, approved by theU.S. Food and Drug Administration (FDA) for excessive daytime sleepiness,may cause nervousness, depression, and anxiety (Qureshi and Lee-Chiong2005).

Alteration of Pharmacokinetics

For the most part, respiratory illnesses do not have an impact on pharmaco-kinetics, with two major exceptions: cystic fibrosis and smoking. Cystic fibro-sis may alter drug pharmacokinetics due to abnormalities in the ion transportfunction of the cell membrane. The rate of drug absorption is slowed, but theextent of absorption is generally unchanged and bioavailability stays the same.Volume of distribution is unaffected. Cystic fibrosis increases oxidative he-patic metabolism, but only for drug substrates of cytochrome P450 (CYP)1A2 and 2C8; metabolism by other cytochromes is unchanged (Rey et al.1998). Little has been published about the use of lithium in patients with cys-tic fibrosis, and the data that exist are contradictory. Brager et al. (1996) re-ported that renal clearance is reduced, resulting in higher lithium levels.However, in a case report by Turkel and Cafaro (1992), lithium level was notaltered with standard dosages. The prudent course would be to start cysticfibrosis patients on a low dosage of lithium, with careful monitoring to avoidtoxicity.

Smoking, in addition to causing respiratory diseases, affects both thepharmacodynamics and pharmacokinetics of many drugs. Smoking-inducedbronchoconstriction is countertherapeutic, resulting in a poorer response tobronchodilators. Smoking induces CYP 1A2, which enhances the metabo-lism of drug substrates of this hepatic enzyme, including clozapine, olan-zapine, duloxetine, and theophylline. Unless drug dosage is increased


accordingly, lower, possibly subtherapeutic drug levels will result. If thepatient stops smoking, a week or more is required before CYP 1A2 activitydeclines to normal (Kroon 2007). In this case, substrate drugs may require adosage reduction to prevent toxicities. These effects are further discussed inChapter 1, “Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions.”

Prescribing Psychotropic Medications in Respiratory Disease

Antidepressants

Antidepressants are frequently used to treat anxiety and depression in patientswith chronic respiratory disease. Most reported studies have examined the useof these drugs in patients with asthma and COPD; almost no information ex-ists on the use of antidepressants in patients with cystic fibrosis or tuberculo-sis, and sparse evidence is available about their use in patients with OSA.

Brown et al. (2005) compared citalopram to placebo in a randomized,double-blind trial in 82 patients with asthma and major depression. Remis-sion rates for depression were numerically but not statistically significantlyhigher in the citalopram group, and the citalopram group tended toward sus-tained remission from depression. Citalopram was well tolerated, and thisgroup had a significant decrease in corticosteroid use. Changes in asthma-related symptoms were similar in the two groups despite the decreased use ofsteroids in the citalopram group. Depressed asthmatic patients receivingopen-label bupropion experienced improvement in depressive and asthmaticsymptoms (Brown et al. 2007), as did depressed and nondepressed patientstreated with sertraline (Smoller et al. 1998). Mirtazapine may be an effectivetreatment for OSA in stroke patients but may worsen central and mixed sleepapnea (Brunner 2008). One randomized, crossover, double-blind study ofmirtazapine in patients with OSA found it to reduce the apnea-hypopnea in-dex and to reduce sleep fragmentation (Carley et al. 2007). However, this andtwo follow-up studies with negative OSA outcomes (Marshall et al. 2008)documented high dropout rates due to increased daytime lethargy and weightgain. Mirtazapine should therefore be avoided in patients with OSA. In smallrandomized controlled trials, paroxetine and protriptyline (one of two stud-


ies) improved apnea-hypopnea index scores relative to placebo, with multipleother antidepressants yielding negative results (Smith et al. 2006).

Attention is required when combining sedating antidepressants and othersedating drugs such as anxiolytics and sedative-hypnotics in patients with se-vere COPD or OSA; the additive sedating effects may reduce respiratorydrive. Because very few studies have examined the safety and efficacy of anti-depressants in patients with pulmonary disease, their safety can only be im-plied by the lack of published reports of drug–disease interactions.

Formerly, anticholinergic drugs were thought to be contraindicated inbronchospastic conditions, but now an inhaled anticholinergic, tiotropium,is often part of the regimen. Thus, although no data have been reported, it isconceivable that the anticholinergic effect of a tricyclic antidepressant (TCA)might reduce bronchoconstriction. One might also expect that an anticholin-ergic TCA’s drying effect would be beneficial in an asthmatic patient with co-pious thin secretions, but aggravate the condition in a patient whose airwaysare plugged with inspissated mucus. TCAs should be avoided in patients withcystic fibrosis because the anticholinergic drying effect would exacerbate thedifficulty these patients have in clearing secretions. The TCA nortriptylinewas found to be safe and effective for depression and functional outcomes inCOPD (Borson et al. 1992).

Other than concern about drug interactions, antidepressants can be safelyused in patients with tuberculosis. Monoamine oxidase inhibitors have notbeen studied in the treatment of patients with respiratory disease and are amajor concern due to drug–drug interactions, which are addressed later in thechapter.


Benzodiazepines

The respiratory depressant effects of benzodiazepines can significantly reducethe ventilatory response to hypoxia. This may precipitate respiratory failurein a patient with marginal respiratory reserve and contraindicates the use ofbenzodiazepines in patients with carbon dioxide retention. Patients with se-vere bronchitis, severe restrictive lung disease, and sleep apnea are the mostvulnerable to the adverse effects of benzodiazepines. However, benzodiaz-epines are not contraindicated for use in all patients with COPD and asthma.


Anxiety can often reduce respiratory efficiency, and benzodiazepines may ac-tually improve respiratory status in some patients with asthma or emphysema.In contrast, benzodiazepine-induced respiratory suppression occurs whenpatients with OSA are awake as well as asleep, potentially prolonging sleepapneic episodes, with dangerous consequences. Benzodiazepines can be usedto terminate a severe episode of VCD (Hicks et al. 2008). If a benzodiazepineis prescribed, reduced dosages of a shorter-acting benzodiazepine (e.g.,lorazepam) should be used so that adverse effects are mild and rapidly revers-ible with drug discontinuation.

Nonbenzodiazepines

Several nonbenzodiazepine agents are useful for promoting sleep in patientswith respiratory disease. On an acute basis, zolpidem has been shown to pro-mote sleep in patients with severe OSA without disturbing the efficiency ofcontinuous positive airway therapy (Berry and Patel 2006). It also does notimpair respiratory drive or pulmonary function tests in patients with COPD(Girault et al. 1996). In patients with mild to moderate sleep apnea, zopiclonehas been found to improve sleep while not worsening breathing (Rosenberget al. 2007). No research has been reported on trazodone in this population.

Two small studies have reported inconsistent effects of melatonin on pul-monary function in patients with asthma; melatonin increased inflammationand decreased lung function in one study (Sutherland et al. 2003), but pro-duced no change in asthma symptoms while improving sleep in the other(Campos et al. 2004). In patients with COPD or sleep apnea, the melatoninagonist ramelteon improved length of sleep with no worsening of patients’pulmonary function (Kryger et al. 2007).

Due to its lack of respiratory depression, buspirone should be the firstanxiolytic considered in respiratory patients with chronic anxiety. Buspironemay improve the respiratory status of patients with sleep apnea (Mendelsonet al. 1991) and can improve exercise tolerance and the sensation of dyspneain patients with chronic lung disease (Argyropoulou et al. 1993). Buspironeis reported to be effective and well tolerated in combination with bronchodi-lators (Kiev and Domantay 1988).

The use of barbiturates should be avoided in patients with impaired respi-ratory drive or for alcohol withdrawal in patients with severe COPD or OSA.An exception could be chronic treatment of epilepsy with phenobarbital.


Antipsychotics

Despite a paucity of research, clinical experience suggests that atypical andtypical antipsychotics can be employed in patients with respiratory disorders,with a few cautionary notes related to the effects of extrapyramidal symptoms,weight gain, and tardive dyskinesia on respiratory function, as well as the riskfor aspiration pneumonia in elderly patients with dementia.

Laryngeal dystonia, presenting as acute dyspnea, is an extremely rare formof acute dystonic reaction. It is usually associated with high-potency typicalantipsychotics, but two cases have been reported with ziprasidone (Mellach-eruvu et al. 2007). It generally occurs, like other dystonic reactions, within 24–48 hours after antipsychotic therapy is initiated or, in a small number of cases,when dosage is increased. Laryngeal dystonia can be life threatening but usu-ally responds dramatically to intramuscular injection of anticholinergic agents.Tardive dyskinesia affecting the respiratory musculature (Jann and Bitar 1982)is rare, generally occurs with long-term typical antipsychotic use, and can se-verely impede breathing in patients with reduced respiratory capacity.

Weight gain with olanzapine, quetiapine, and other atypical antipsychot-ics is particularly problematic in patients with OSA; the additional weightwill worsen the sleep apnea. Likewise, weight gain may further impair respi-ratory capacity in patients with decreased respiratory function, especially inrestrictive lung disease. Several reports also suggest that olanzapine and per-haps risperidone may be associated with increased risk for pulmonary embo-lism (Borras et al. 2008; Waage and Gedde-Dahl 2003).

Patients using atypical antipsychotics were found in a Canadian study (Jo-seph et al. 1996) to have a significantly greater risk of death or near-deathfrom asthma. Patients who had recently discontinued antipsychotic use wereat a particularly high risk. Patients with asthma (De Bruin et al. 2003) andCOPD are particularly susceptible to cardiac arrhythmias. If antipsychoticmedications are used, those most likely to cause QTc prolongation (ziprasi-done, thioridazine) should be avoided, or the patients should be monitored.Abrupt discontinuation of antipsychotics with significant anticholinergicactivity, such as clozapine, may cause cholinergic rebound, impairing theeffectiveness of anticholinergic asthma medication (Szafranski and Gmur-kowski 1999). These drugs should be discontinued slowly to prevent cholin-ergic rebounds.


Finally, an FDA black-box warning on antipsychotic medications cau-tions against their use in elderly patients with dementia, due to increased riskfor death secondary to cardiovascular complications and infection, particu-larly pneumonia. The pneumonia is likely to involve aspiration of secretionssecondary to sedation and dysphagia.

Mood Stabilizers

In a small number of case reports, carbamazepine has been associated withpulmonary eosinophilia, diffuse parenchymal lung disease, and respiratoryfailure. Carbamazepine has also been found to be an effective treatment forasthma (Lomia et al. 2006). In a single case study of lithium treatment for bi-polar mania in a patient with cystic fibrosis, mood improved with no appar-ent impact on pulmonary function (Turkel and Cafaro 1992).

Psychostimulants

Chronic respiratory illnesses often lead to insomnia and daytime sleepiness.The few studies of stimulants have been in patients with sleep apnea. Modafi-nil (and also armodafinil, the R-enantiomer of modafinil) was found to in-crease daytime wakefulness when used as an adjunct treatment for patientswith OSA who were benefiting from continuous positive airway therapy butwho still experienced daytime sleepiness. Behavioral alertness and functionalimpairment also improved, and sleep architecture remained intact (Hirsh-kowitz et al. 2007). Atomoxetine improved wakefulness in patients with mildto moderate obstructive sleep apnea without worsening the respiratory dis-tress index (Bart et al. 2008). However, because this literature is limited, andbecause of the increased risk for cardiac arrhythmia in chronic respiratory dis-ease, psychostimulants should be used with caution.

Cognitive Enhancers

Scant literature exists on the use of cognitive enhancers in patients with respi-ratory illnesses. Two small randomized, double-blind, placebo-controlled stud-ies found that donepezil improved sleep apnea, increased rapid eye movementsleep, and improved cognition in patients with Alzheimer’s disease (Moraes etal. 2006, 2008). However, because of their cholinomimetic effects, cholinest-erase inhibitors increase acetylcholine levels and may cause bronchoconstric-


tion. Also, they are likely to block the therapeutic effects of bronchodilators,especially anticholinergic agents such as ipratropium and tiotropium. Frequentpulmonary side effects that have been reported with these drugs are dyspneaand bronchitis, and infrequent side effects include pneumonia, hyperventila-tion, pulmonary congestion, wheezing, hypoxia, pleurisy, pulmonary collapse,sleep apnea, and snoring. Thus, cholinesterase inhibitors should be used cau-tiously, if at all, in patients with asthma and COPD. As an alternative, meman-tine may be preferred because it is devoid of respiratory adverse effects.

Opioids

When dyspnea in patients with advanced pulmonary disease cannot be man-aged by treating the underlying disease, a number of pharmacological agentshave been tried, including opioids. A meta-analysis of 18 small studies inCOPD showed a statistically significant positive effect of opioids on the sen-sation of dyspnea, especially when administered orally or parenterally ratherthan nebulized (Jennings et al. 2002). No evidence indicated a deleterious ef-fect on arterial blood gases or oxygen saturation. The use of low-dose oral orparenteral opioids to treat dyspnea associated with end-stage pulmonary dis-ease has been confirmed in other studies (Abernethy et al. 2003; Lorenz et al.2008). A retrospective chart survey found that sedatives, hypnotics, and mor-phine were frequently used in patients with terminal malignant and nonma-lignant pulmonary disease (Kanemoto et al. 2007). Although these drugswere useful and effective, this study emphasized the need to weigh comfortagainst the potential shortening of life due to respiratory depression. Opioids(usually morphine) and sometimes benzodiazepines are also used in terminalweaning from ventilatory support (Campbell 2007).

Effects of Psychotropic Drugs on Pulmonary Diseases

Some psychotropic medications adversely affect pulmonary function (sum-marized in Table 7–3). Respiratory depression resulting from sedative-hyp-notics and opioids is the most common adverse effect (discussed above).Methylphenidate has been reported to cause dyspnea, asthma, pulmonary in-filtrates, idiopathic pulmonary fibrosis, respiratory failure, and pulmonary

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Table 7–3. Respiratory side effects of psychotropic medicationsPsychotropic drug Cough Dyspnea Asthma PIE IPF ARDS RF PE PVD RD

Benzodiazepines + + +Butyrophenones + + +Carbamazepine + + + +Methylphenidate + + + + + +Phenothiazines +Phenytoin + + + + +Trazodone + + +Tricyclic antidepressants + + + +Venlafaxine/desvenlafaxine + +Note. ARDS=adult respiratory distress syndrome; IPF=interstitial pneumonitis and/or fibrosis; PE=pulmonary edema; PIE=pulmonary infiltrate,with or without eosinophilia: PVD=pulmonary vascular disease including pulmonary embolus; RD=respiratory depression; RF=respiratory failure.Source. Ben-Noun 2000.


vascular disease (Ben-Noun 2000). Carbamazepine may cause cough, dys-pnea, pulmonary infiltrates, and idiopathic pulmonary fibrosis, and benzo-diazepines may precipitate cough. Acute pulmonary edema has been reportedwith phenothiazine overdose (Li and Gefter 1992), and typical and atypicalantipsychotics have been associated with an increase in pulmonary embolism.High-potency antipsychotics, such as haloperidol, have also been associatedwith laryngeal dystonia (Chakravarty 2005) and tardive dyskinesia of the res-piratory musculature causing respiratory distress (Kruk et al. 1995). Trazo-done overdose may cause eosinophilic pneumonia and respiratory failure.TCAs are associated with Loeffler’s syndrome (pulmonary eosinophilia), andoverdose may result in pulmonary edema leading to adult respiratory distresssyndrome (Ben-Noun 2000). Individual cases have been reported of eosino-philic pneumonia associated with other antidepressants, but this appears tobe a very rare adverse event.

Drug–Drug InteractionsA number of pharmacokinetic and pharmacodynamic drug interactions mayoccur between drugs prescribed for chronic respiratory disease and psychotro-pic drugs. A brief summary is provided in Table 7–4.

It is important to note that smoking, a cause or contributor to multiplerespiratory illnesses, can enhance the metabolism of multiple psychotropicdrugs via induction of CYP 1A2, 2B6, and 2D6 (Kroon 2007). These drugsinclude benzodiazepines, zolpidem, antipsychotics (notable exceptions arearipiprazole, quetiapine, risperidone, and ziprasidone), and antidepressants,including fluvoxamine, duloxetine, TCAs, and mirtazapine. Reduction or ces-sation of smoking may necessitate reduction in dosage of psychotropic medi-cations whose metabolism has been induced.

Many anti-infective agents, including macrolide and fluoroquinoloneantibacterials and conazole antifungals, are potent inhibitors of one or moreCYP isoenzymes, whereas several rifamycins, such as rifampin, induce multi-ple CYP enzymes. Anti-infective drugs can cause significant psychotropicdrug toxicities or loss of therapeutic effect unless the psychotropic drug dos-age is suitably adjusted (see Chapter 1, “Pharmacokinetics, Pharmacodynam-ics, and Principles of Drug–Drug Interactions,” and Chapter 12, “InfectiousDiseases,” for further discussion of antibiotic drug interactions).

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Table 7–4. Respiratory drug–psychotropic drug interactionsDrug Mechanism of interaction Clinical effect

Anticholinergics

Atropine (systemic) Additive anticholinergic effect Additive anticholinergic effects with TCAs, antipsychotics, and other anticholinergic agents. Countertherapeutic effects with cholinesterase inhibitor cognitive enhancers.

Beta-agonists

Albuterol QT prolongation Increased QT interval; avoid QT-prolonging drugs (TCAs, antipsychotics [pimozide, quetiapine, risperidone, ziprasidone]).

Bronchodilators

Theophylline Increased renal clearance Increased clearance and lower levels of renally eliminated drugs (lithium, gabapentin, pregabalin, paliperidone, memantine, desvenlafaxine).

Leukotriene inhibitors

Zafirlukast Moderate inhibitor of CYP 2C9, 2C8, 3A4

Possible increased levels of carbamazepine, phenytoin, benzodiazepines, pimozide, quetiapine, ziprasidone.

Note. TCAs=tricyclic antidepressants.Source. Wynn et al. 2009.


Isoniazid, a weak MAOI, is potentially problematic when used withTCAs, serotonin–norepinephrine reuptake inhibitors (SNRIs), selective sero-tonin reuptake inhibitors (SSRIs), and other MAOIs, due to the potential forhypertensive crisis and serotonin syndrome. Although when isoniazid is usedalone, its MAOI effects do not require dietary precautions, dietary tyraminerestriction should be used when isoniazid is combined with an antidepressant(DiMartini 1995). Patients taking isoniazid should avoid sympathomimeticagents such as epinephrine, ephedrine, and pseudoephedrine, which are espe-cially common in many over-the-counter cold, cough, and sinus preparations(Dawson et al. 1995), and oral beta-agonists should only be used with extremecaution. Inhaled beta-agonists appear safe to use, because little is absorbed sys-temically. SSRI and SNRI antidepressants are safe to use with the selectivebeta2-agonists (e.g., terbutaline, metaproterenol, albuterol, isoetharine).

Theophylline can lower alprazolam and possibly other benzodiazepinelevels (Tuncok et al. 1994) and may counteract the therapeutic effects of ben-zodiazepines by exacerbating anxiety and insomnia. Theophylline may alsoincrease lithium clearance (Cook et al. 1985; Holstad et al. 1988; Perry et al.1984); lithium levels should be monitored when coadministering these drugs.

Several psychotropic medications, including TCAs, low-potency typicalantipsychotics, and anticholinergic agents for extrapyramidal symptoms, haveanticholinergic effects that may enhance the bronchodilator effects of atro-pine and inhaled anticholinergic bronchodilators such as ipratropium andtiotropium.

Respiratory disease drugs are also susceptible to pharmacokinetic interac-tions from psychotropic drugs. Fluvoxamine inhibits CYP 1A2 and can sig-nificantly increase theophylline levels (Dawson et al. 1995). Carbamazepineand phenobarbital, both general metabolic inducers, significantly reduceblood levels of many drugs, including theophylline and doxycycline. St.John’s wort is also a CYP 1A2 inducer and can lower theophylline levels tosubtherapeutic values (Hu et al. 2005). Drug interactions are discussed inmore detail in Chapter 1, “Pharmacokinetics, Pharmacodynamics, and Prin-ciples of Drug–Drug Interactions.”


Key Clinical Points

• Most antidepressants have little or no effect on respiratory sta-tus; however, anticholinergic antidepressants may have func-tional and bronchodilating benefits.

• Generally, avoid sedating agents in carbon dioxide retainers. Ifnecessary, short-acting benzodiazepines with no active metabo-lites, prescribed at low dosage, are best tolerated.

• Polypharmacy contributes to unwanted drug–drug interactionsand increases risk for respiratory side effects.

• Drugs known to cause QTc prolongation should be avoided inpatients with asthma and COPD. If used, cardiac status shouldbe carefully monitored.

• Smoking induces CYP 1A2, 2B6, and 2D6, thereby lowering thelevels of many psychotropic medications. When smoking is re-duced or stopped, psychotropic side effects and blood levelsshould be monitored and dosages adjusted as necessary.

• Rifampin induces metabolism of some psychiatric drugs. Higherdosages of these psychiatric medications may be required foradequate response in patients treated for tuberculosis.

• Isoniazid is a weak irreversible MAOI that may cause serotoninsyndrome or hypertensive crisis when combined with SSRIs andsympathomimetic psychotropics and agents used to treat pul-monary diseases.

• Theophylline has multiple activating psychiatric side effects. Itslevels can be reduced by CYP 1A2 inducers, such as carbamaz-epine, and increased by CYP 1A2 inhibitors, such as fluvoxamine.

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8Oncology



Psychiatric symptoms are common in many cancer patients, especially inthose with advanced cancer. Several factors, including the emotional stress ofthe cancer diagnosis, the effects of central nervous system (CNS) tumors,neurotoxicity from immune reactions to non-CNS tumors, and the adverseeffects of cancer chemotherapy or radiotherapy, may contribute to psychiatriccomorbidity. In most situations, psychiatric symptoms can be safely managedwith psychotropics; however, psychotropic agents must be carefully selectedto avoid adverse interactions with chemotherapeutic agents, including inter-actions that potentially limit the therapeutic efficacy of chemotherapy. In thischapter, we review psychiatric symptoms related to cancer and cancer treat-ment, psychopharmacological treatment of psychiatric comorbidity, and in-teractions between psychiatric and oncological drugs.


Differential Diagnosis of Psychiatric Manifestations of CancersCancer-Related Depression and Fatigue

Emotional distress accompanies the diagnosis of cancer and adversely affectsthe patient’s quality of life. Surveys suggest about 50% of patients with ad-vanced cancer meet criteria for a psychiatric disorder, most commonly adjust-ment disorder (11%–35%), major depression (5%–26%), and anxietydisorders (6%–8%) (Miovic and Block 2007). Pancreatic, oropharyngeal, andbreast cancers are often associated with symptoms of depression (McDaniel etal. 1995). The diagnosis of cancer may also exacerbate preexisting psychiatricdisorders. Depression and fatigue are frequent adverse effects of cancer che-motherapy and radiation therapy (discussed later in this chapter in “Neuro-psychiatric Adverse Effects of Oncology Treatments”).

Differentiating transient adjustment-related depression and anxiety war-ranting short-term pharmacotherapy (e.g., benzodiazepines) from major de-pression or generalized anxiety disorder requiring ongoing pharmacotherapycan be challenging. Furthermore, differentiating neurovegetative symptomsof depression and anxiety, such as appetite disturbance or fatigue, from thoseproduced by cancer or its treatment is often impossible. Addressing potentialunderlying causes, such as anemia, and close monitoring of these symptomsduring pharmacotherapy is warranted. These symptoms may be amelioratedwith pharmacotherapy; however, if residual neurovegetative symptoms per-sist, adjunctive treatment should be initiated.

Psychiatric Symptoms of Brain Tumors

Brain tumors typically cause generalized or focal neurological symptoms andsigns. However, some tumors, especially in neurologically silent areas, maygive rise only to psychiatric symptoms, such as depression, anxiety disorders,mania, psychosis, personality changes, anorexia, or cognitive dysfunction.Despite attempts in the past to categorize psychiatric symptoms according totumor location or histological type, a recent review indicates a lack of associ-ation (Madhusoodanan et al. 2007). Brain imaging should be considered forall patients presenting with atypical psychiatric symptoms, onset of psychiat-ric symptoms after age 40, or a change in the clinical presentation of existingpsychiatric symptoms (Gupta and Kumar 2004; Hollister and Boutros 1991;

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Moise and Madhusoodanan 2006; see also Chapter 9, “Central Nervous Sys-tem Disorders”).

Paraneoplastic Limbic Encephalitis

Paraneoplastic limbic encephalitis (PLE) is a consequence of CNS damagefrom antineuronal antibodies expressed as an immune response to a non–ner-vous system cancer. Symptoms include rapidly progressive confusion andshort-term memory deficits, depression, visual and auditory hallucinations,delusions, paranoia, and seizures (Voltz 2007). PLE occurs most often in pa-tients with small-cell lung cancer (40%) and testicular seminoma (20%), butalso in those with lymphoma or with tumors of the breast or thymus (Gulte-kin et al. 2000). In most cases of PLE, neuropsychiatric symptoms precedecancer diagnosis, often by several years. PLE is identified by characteristicfindings on magnetic resonance imaging, with supporting evidence from en-cephalographic and cerebrospinal fluid antibody studies. Symptoms havelimited response to psychopharmacotherapy (Foster and Caplan 2009). Al-though antipsychotics and anticonvulsants have been tried, treatment shouldfocus on eradication of the tumor and immunosuppressant therapy.

Psychopharmacological Treatment of Psychiatric Disorders in Cancer PatientsThe research literature on psychopharmacological treatment of psychiatric dis-orders in cancer is relatively sparse and is focused primarily on depression andsomatic symptoms, including pain, nausea, and fatigue (for general clinical re-views of major psychotropic drug classes in cancer, see Berney et al. 2000;Buclin et al. 2001; Mazzocato et al. 2000; Stiefel et al. 1999). Psychophar-macological treatment of pain and nausea are covered in Chapter 17, “PainManagement,” and Chapter 4, “Gastrointestinal Disorders,” respectively. Psy-chopharmacological treatments of depression, anxiety, and cancer-related fa-tigue and cognitive impairment are covered in the following subsections.

Depression

Depression has a median point prevalence of 24% in cancer patients. Multi-ple case series and case reports suggest effectiveness of tricyclic antidepressants(TCAs) and selective serotonin reuptake inhibitors (SSRIs) in a range of can-


cers; however, a relatively small number of randomized controlled trials(RCTs) have been conducted. Most RCTs have included predominantlywomen with breast and gynecological malignancies, many RCTs have beenrelatively brief in duration (5–6 weeks), and several have been underpoweredto detect drug–drug or drug–placebo differences.

Cyclic Antidepressants

In depressed women with breast cancer, the tetracyclic antidepressant mian-serin (up to 60 mg/day) has been reported by two groups to be superior toplacebo for improving both depression and quality of life (Costa et al. 1985;van Heeringen and Zivkov 1996). Mianserin was well tolerated, and dropoutswere greater in placebo-treated patients due to lack of response. In a clinicalsample, patients with gynecological malignancies and depression who wereadherent to imipramine treatment (minimum 150 mg/day for 4 weeks) hadsignificantly decreased depressive symptoms when compared with patientswho did not adhere to the treatment (Evans et al. 1988).

Selective Serotonin Reuptake Inhibitors

A 5-week RCT of fluoxetine (n=45) versus placebo (n=46) for depression incancer patients failed to find a difference in the primary depression endpointon the Montgomery-Åsberg Depression Rating Scale; however, fluoxetineyielded greater reduction in general distress as measured by the SymptomChecklist–90 (Razavi et al. 1996). In a 6-week multisite RCT comparing flu-oxetine (20–40 mg/day, n=21) and desipramine (25–100 mg/day, n=17) indepressed women with breast, colorectal, and gynecological malignancies,both treatments yielded significant improvements in depression, anxiety, andquality-of-life endpoints (Holland et al. 1998). However, 29% of fluoxetine-treated and 41% of desipramine-treated patients withdrew due to adverseevents. The results of both of these studies are hampered by their brief dura-tion. In two large RCTs of treatment for depressive and/or fatigue symptomsin women with breast cancer actively undergoing chemotherapy, paroxetine20 mg/day initiated just after starting chemotherapy and discontinued a weekafter ending chemotherapy was more effective than placebo in reducing de-pressive symptoms, but not more effective in reducing fatigue (Morrow et al.2003; Roscoe et al. 2005). A small multicenter RCT comparing paroxetine(n=13) to desipramine (n=11) and placebo (n=11) showed no group differ-

Oncology 241

ences, likely a result of high placebo response and lack of statistical power(Musselman et al. 2006).

Fluoxetine was superior to placebo in an oncologist-driven RCT for thetreatment of nonmajor depression and diminished quality of life in advancedcancer patients (with 3–24 months estimated survival) (Fisch et al. 2003);however, this effect was accounted for by improvement in the patients withthe most severe depression at baseline. Nausea and vomiting were also morecommon in the fluoxetine group. In another oncologist-driven RCT compar-ing sertraline 50 mg/day to placebo for the amelioration of mild depression,anxiety, and other quality-of-life symptoms, sertraline showed no benefit overplacebo and was associated with a higher dropout rate (Stockler et al. 2007).This study was stopped due to higher mortality in the sertraline group at thefirst interim analysis on a subset of the patients; however, survival did not dif-fer between the treatment groups when all enrolled patients were analyzedwith a longer duration of follow-up.

Other Antidepressants

In a 6-week, unblinded, randomized trial in advanced cancer patients withmultiple somatic and psychiatric symptoms, mirtazapine (7.5–30 mg/day),but not imipramine (5–100 mg/day) or a no-medication control, was foundto reduce depression and anxiety, as well as insomnia (Cankurtaran et al.2008). Similarly, in a group of depressed patients with lung, breast, and gas-trointestinal cancers experiencing nausea/vomiting and sleep disturbance,open-label treatment with mirtazapine (orally dissolving, 15–45 mg/day) wasassociated with improvement in depressive and somatic symptoms and qual-ity of life within 7 days (Kim et al. 2008). Excessive sleepiness occurred in36% of patients early in treatment but generally abated within 2 weeks.

Sustained-release bupropion (100–300 mg/day) was effective in an open-label trial for depressive symptoms in cancer patients where fatigue was theprimary endpoint (Moss et al. 2006).

Psychostimulants

Methylphenidate and dextroamphetamine have also been found effective incase series and small open-label trials of depression in patients with advancedcancer, with onset of action generally within 2–5 days (Homsi et al. 2001;Olin and Masand 1996; Sood et al. 2006). Methylphenidate (10 mg/day) and


modafinil (200–400 mg/day) have been found to improve depression inRCTs in which cancer-related fatigue was the primary endpoint (Kaleita et al.2006; Meyers et al. 1998).

Cholinesterase Inhibitors

In a small clinical trial with irradiated brain tumor patients, donepezil 10 mg/day demonstrated limited improvements in acute fatigue, depression, andcognitive impairment (Shaw et al. 2006).

Conclusion

In sum, the limited clinical trial literature generally supports the use of stan-dard antidepressants for the treatment of moderate to severe depression incancer patients, although those who are currently receiving chemotherapyand/or who have widespread disease are likely to be sensitive to adverse effectssuch as nausea. In patients with advanced malignancies and limited life ex-pectancies, a psychostimulant should be considered due to rapid onset of re-sponse and benefit for accompanying symptoms such as fatigue and cognitiveimpairment.

Anxiety

Anxiety is also prevalent in patients with cancer and is often comorbid withdepression, in which case antidepressant treatment is effective in alleviatinganxiety symptoms (see previous section). No studies of antidepressants haveconsidered anxiety as the primary endpoint.

Benzodiazepines are often used clinically to treat acute anxiety-relatedsymptoms and nausea. Alprazolam (0.5–3.4 mg/day) and placebo were foundto decrease anxiety symptoms within 1 week in 36 patients with mixed can-cers enrolled in an RCT (Wald et al. 1993). Similarly, in a 10-day multicenterRCT that included 147 inpatients and outpatients with mixed cancers, alpra-zolam 0.5 mg three times daily and progressive muscle relaxation were foundto reduce anxiety symptoms (Holland et al. 1991). Alprazolam producedgreater and more rapid symptom relief on some but not all outcome mea-sures. In both studies, the structure and attention received by the patients wasthought to be instrumental in alleviating symptoms.

In clinical practice, clinicians often use lorazepam in cancer patients dueto its favorable pharmacokinetics, multiple routes of administration, and pu-

Oncology 243

tative efficacy for treating nausea and other distressing symptoms (Buzdar etal. 1994). Clonazepam is also employed due to its longer half-life. In usingbenzodiazepines in cancer patients, excessive sedation, cognitive impairment,rebound/withdrawal, and other adverse effects should be monitored closely(Stiefel et al. 1999).

Fatigue

Cancer-related fatigue affects a majority of cancer patients at some point dur-ing the course of illness. The most common disease-related correlates are activechemotherapy and anemia. Fatigue is often comorbid with anxiety and depres-sion; however, it also occurs alone and can be a residual symptom even if theseare effectively treated. Anemia-related fatigue is ameliorated by treatment witherythropoietin or darbepoetin (for a review, see Minton et al. 2008).

Psychostimulants and modafinil are the most commonly prescribed psy-chotropic agents for cancer-related fatigue. Methylphenidate 10–50 mg/dayin divided doses has been studied in RCTs in palliative care patients (Brueraet al. 2006) and in breast cancer patients actively undergoing chemotherapy(Fleishman et al. 2005). In palliative care patients, fatigue improved after1 week in both methylphenidate and placebo groups, the latter attributed tothe powerful effects of research nurse support. Effects were sustained up to36 weeks during open-label methylphenidate treatment. In breast cancer pa-tients undergoing chemotherapy, fatigue improved more with methylpheni-date than with placebo at the 8-week study endpoint. Concerns regardingstimulant-induced symptoms of excessive activation and anorexia were notsupported by these studies.

Modafinil has been studied in four open-label trials of cancer-related fa-tigue in patients with lung cancer (Spathis et al. 2009), cerebral tumor, andbreast cancer, and in one RCT of patients with mixed cancers receiving che-motherapy (Cooper et al. 2009). Modafinil 200 mg/day was more efficaciousthan placebo in treating fatigue and excessive daytime sleepiness, but not de-pressive symptoms, in the RCT with 642 patients receiving concurrent che-motherapy. Patients with the highest levels of fatigue at the beginning of theirsecond cycle of chemotherapy benefited most. Adverse effects reported inthese trials included headache, nausea, and activation symptoms such as in-somnia and anxiety.


As discussed in the “Depression” section above, two RCTs of paroxetine 20mg/day (Morrow et al. 2003; Roscoe et al. 2005) and one of donepezil 10 mg/day failed to show superiority of these agents over placebo in the treatment ofcancer-related fatigue. Paroxetine improved depression but not fatigue.

Although potential etiological factors for cancer-related fatigue (e.g., ane-mia, depression) should be addressed whenever possible, methylphenidateand modafinil appear to be effective treatments for cancer-related fatigue. Be-cause many patients have residual symptoms of fatigue, which diminish theirquality of life, adjunctive treatment should not be unduly delayed. Excessiveactivation and anorexia are not major clinical concerns, but these potentialadverse effects should be monitored.

Cognitive Impairment

Although cognitive dysfunction is documented in patients with brain tumorsand in patients with breast cancer following adjuvant chemotherapy, pharma-cological treatment data are relatively lacking. For patients with brain tumorsundergoing radiation therapy, donepezil 5–10 mg/day was modestly benefi-cial for cognitive dysfunction (Shaw et al. 2006). Whereas one open-labelstudy indicated benefit of methylphenidate for brain tumor patients under-going radiation (Meyers et al. 1998), two small RCTs, one in a similar popu-lation (Butler et al. 2007) and one in breast cancer patients undergoingchemotherapy (Mar Fan et al. 2008), yielded negative results.

Adverse Oncological Effects of Psychotropics

Concerns have been raised that psychotropic drugs may increase cancer risk.This issue has bee the focus of several surveys of cancer risk in patients receiv-ing antipsychotics, anxiolytics, mood stabilizers, or antidepressants.

Antipsychotics

Evaluation of cancer risk with antipsychotic medications is confounded bythe association in patients with schizophrenia of several risk factors for cancer,including alcohol abuse, obesity, smoking, and inactive lifestyle. Antipsy-chotic-induced hyperprolactinemia is also considered a risk factor for pitu-itary, breast, and endometrial cancers (see also Chapter 10, “Endocrine and

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Metabolic Disorders”). However, certain phenothiazines, especially chlorpro-mazine, may have anticancer properties (Jones 1985).

A number of epidemiological studies have reported both increased anddecreased rates of cancer in patients taking (mostly typical) antipsychotics(Dalton et al. 2006; Hippisley-Cox et al. 2007; Mortensen 1987, 1992;Wang et al. 2002). No findings have been clearly replicated.

Because of the relatively recent introduction of atypical antipsychotics,few studies have explored the cancer risk of these medications. Risperidone,and possibly its major metabolite paliperidone, may be associated with pitu-itary tumors. A retrospective pharmacovigilance study employed the U.S.Food and Drug Administration’s Adverse Event Reporting System databasethrough March 2005 to assess the association of pituitary tumors with atypi-cal antipsychotics. Risperidone was associated with pituitary tumors at 18.7times the expected rate (Szarfman et al. 2006). A survey of the World HealthOrganization’s Adverse Drug Reactions database supports this relationshipbetween risperidone and pituitary neoplasms (Doraiswamy et al. 2007).

Reluctance to prescribe antipsychotics because of fear of increasing cancerrisk is not supported by available studies, with the possible exception ofincreased risk for pituitary tumors with risperidone. Animal studies suggest arelationship between pituitary tumor growth and hyperprolactinemia second-ary to dopamine D2 receptor antagonism (Szarfman et al. 2006). It wouldseem prudent to avoid antipsychotics with a high incidence of hyperprolac-tinemia (risperidone, paliperidone, ziprasidone, haloperidol, aripiprazole) inpatients with a present or past history of pituitary endocrine tumors. Evi-dence that antipsychotics may reduce cancer risk is inconclusive.

Anxiolytics

Studies support the lack of cancer risk with benzodiazepine use for severalcancers. These include breast, large bowel, lung, endometrium, ovary, testis,thyroid, and liver cancer; malignant melanoma; non-Hodgkin’s lymphoma;and Hodgkin’s disease (Halapy et al. 2006; Rosenberg et al. 1995).

Mood Stabilizers

Lithium salts frequently cause leukocytosis, which raised a concern that lith-ium may act as an inducer or reinducer of acute and chronic monocytic leu-


kemia (Swierenga et al. 1987). However, no association of lithium andleukemia was observed in two retrospective studies of leukemia patients(Lyskowski and Nasrallah 1981; Resek and Olivieri 1983). A third retrospec-tive study observed a significant inverse trend for nonepithelial cancers withlithium dose (Cohen et al. 1998). This report suggested that psychiatric pa-tients have lower cancer prevalence than the general population and that lith-ium may have a protective effect.

Valproate, similar to other short-chain fatty acids, has been known tohave anticancer effects on a variety of malignant cells in vitro. Several clinicaltrials have confirmed the efficacy of valproate in acute myeloid leukemia andmyelodysplastic syndromes (Kuendgen and Gattermann 2007). No humanstudies of carbamazepine carcinogenicity have been reported.

Antidepressants

A relationship between antidepressant use and cancer risk has been suggested,but early epidemiological studies yielded inconsistent results. Serotonin-enhancing antidepressants elevate prolactin levels, and hyperprolactinemiahas been associated with increased risk of postmenopausal breast cancer. Sev-eral large population-based case control surveys reported no association be-tween the risk of breast cancer and the use of antidepressants overall, or byantidepressant class or individual agent (Chien et al. 2006; Coogan et al.2005; Fulton-Kehoe et al. 2006). Similar methodologies have been used toexamine the risk of ovarian, prostate, lung, and colorectal cancer with SSRIsand TCAs. No evidence of increased risk of ovarian cancer was observed withantidepressants in general or with SSRIs (Moorman et al. 2005). SSRI use didnot increase the risk of prostate cancer (Tamim et al. 2008) and was relatedto a decreased risk of lung cancer (Toh et al. 2007) and colorectal cancer (Xuet al. 2006). A marginally elevated risk of lung and prostate cancer, possiblydue to experimental bias, was observed among TCA users.

Conclusion

Studies to date do not support withholding any psychiatric medications basedon fear of increasing cancer risk, and no conclusions can be drawn regardingtheir potential for reducing cancer risk. The one exception appears to be in-creased risk for pituitary tumors with risperidone. The prudent action wouldbe to avoid antipsychotics with a high incidence of hyperprolactinemia (ris-

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peridone, paliperidone, ziprasidone, haloperidol, aripiprazole) in patientswith present or past history of pituitary endocrine tumors.

Neuropsychiatric Adverse Effects of Oncology Treatments

Radiotherapy

Fatigue is the most common neuropsychological acute reaction to brain radi-ation, often occurring within several weeks of initiating therapy and generallylasting 1–3 months. Delayed reactions, including decreased energy, depres-sion, and cognitive dysfunction, occur months or years postradiotherapy andare generally irreversible.

The psychostimulants methylphenidate (Meyers et al. 1998) and modafi-nil (Kaleita et al. 2006) and the cholinesterase inhibitor donepezil (Shaw etal. 2006) have demonstrated limited improvements in acute fatigue, depres-sion, and cognitive impairment in small clinical trials with irradiated braintumor patients.

Chemotherapy

Delirium

Delirium is common in cancer, with many possible causes, including adverseeffects of chemotherapy as well as infection, brain metastases, and terminaldelirium. Delirium occurs frequently with chemotherapeutic agents associ-ated with CNS toxicity and those able to cross the blood–brain barrier, suchas 5-fluorouracil, ifosfamide, asparaginase, chlorambucil, cytarabine, metho-trexate, interferons, interleukins, vincristine, and vinblastine (Fann and Sul-livan 2003). Corticosteroids (see also Chapter 10, “Endocrine and MetabolicDisorders,” for full discussion), antihistamines, and opioids are a few support-ive medications also contributing to an acute confusional state (Agar andLawlor 2008). Medication-related delirium often responds to dosage reduc-tion or a change of drug. The incidence of delirium and other psychiatricsymptoms may be exacerbated by the interaction of tumor-related factors andtreatment-induced neurotoxicity. No RCTs of psychotropic drugs for cancer-related delirium have been published. Treatment of delirium is discussedmore fully in Chapter 15, “Surgery and Critical Care.”


Adverse Effects of Chemotherapeutic Agents

Table 8–1 lists the psychiatric adverse effects of a variety of chemotherapeuticagents. Some of the agents listed in the table are discussed in the followingparagraphs.

Nitrogen mustards. Ifosfamide encephalopathy, characterized by seizures,drowsiness, confusion, and hallucinations, occurs in 15%–30% of patientsand is often dose limiting. Case reports suggest a lack of efficacy of psychoac-tive agents for ifosfamide-induced neurotoxicity and delirium. Symptomsusually resolve after drug withdrawal and treatment with oral or intravenousmethylene blue (Dufour et al. 2006). Although methylene blue is widely usedto treat ifosfamide delirium, its efficacy has not been confirmed in controlledclinical trials, and many patients experience positive outcomes withoutmethylene blue (Alici-Evcimen and Breitbart 2007; Brunello et al. 2007).

Nonclassic alkylating agents. Neuropsychiatric adverse events have beenreported with procarbazine and altretamine. Several case reports identify psy-chosis as a side effect of procarbazine chemotherapy (Carney et al. 1982; vanEys et al. 1987). Other psychiatric adverse effects, including hallucinations,anxiety, depression, confusion, and nightmares, are also associated with pro-carbazine use (Sigma-Tau Pharmaceuticals 2004). Altretamine was associatedwith fatigue (63%) and anxiety/depression (29%) of mild to moderate sever-ity during a 6-month Phase 2 trial (Rothenberg et al. 2001).

Interferons and interleukins. The immunomodulatory agents interferon-alpha (IFN-α) and interleukin-2 are often associated with psychiatric adverseeffects, including apathy, fatigue, cognitive impairment, depression with sui-cidal ideations, and psychosis. Preexisting psychiatric illness increases vul-nerability to psychiatric adverse effects. (See Chapter 4, “GastrointestinalDisorders,” for a more thorough discussion of psychiatric symptoms associ-ated with IFN-α.)

Interleukin-2 therapy is reported to cause severe depressive symptoms in>20% of cancer patients (Capuron et al. 2000) and moderate to severe cog-nitive and behavioral changes (aggression, combative behavior) and halluci-nations in >50% of cancer patients (Denicoff et al. 1987). Neuropsychiatricsymptoms may lead to treatment discontinuation.

On

cology

249Table 8–1. Psychiatric adverse effects of oncology drugsMedication Psychiatric adverse effect

Alkylating agentsNitrogen mustards

Ifosfamide Seizures, drowsiness, confusion, hallucinationsNonclassic alkylators

Altretamine Fatigue, anxiety, depressionProcarbazine Psychosis, hallucinations, anxiety, depression, confusion, nightmares

AntimetabolitesPyrimidine analogs

Cytarabine (cytosine arabinoside) Confusion, somnolence, personality changes (high dose) (Baker et al. 1991; Pfizer Canada 2008)EnzymesAsparaginase Depression, somnolence, fatigue, coma, seizures, confusion, agitation, hallucinations (Merck

2005)Monoclonal antibodiesBortezomib 35% incidence of psychiatric disorders: agitation, confusion, mental status change, psychotic

disorder, suicidal ideation (Millennium Pharmaceuticals 2009)Interferons/interleukinsInterferon-alpha-2A Depression, suicidal behaviors, agitation, mania, psychosesInterferon-alpha-2B Depression, suicidal behaviors, confusion, maniaInterleukin-2 (aldesleukin) Confusion, sedation, anxiety, psychosisRetinoic acid compoundsTretinoin Anxiety, insomnia, depression, confusion, agitation, hallucinations


Several psychotropic agents have been suggested to improve neuropsychi-atric symptoms related to IFN-α in cancer patients. In a small open-labelwithin-subjects trial of IFN-α treatment with and without adjuvant naltrex-one therapy, naltrexone improved cognitive and emotional scores in five ofnine patients (Valentine et al. 1995). A case report suggested that methyl-phenidate may improve symptoms of depression and apathy resulting fromIFN-α administration (Capuron et al. 2002).

Depression induced by IFN-α in cancer patients is responsive to anti-depressant treatment in controlled trials with paroxetine (Capuron et al.2002; Musselman et al. 2001), but symptoms of fatigue and anorexia are lessresponsive to SSRI treatment (Capuron et al. 2002). Use of an adjunctiveantidepressant was associated with better adherence to IFN-α therapy (Mus-selman et al. 2001).

Retinoic acid compounds. Retinoic acid compounds that are commonlyused to treat acne are also employed systemically for acute promyelocytic leu-kemia (tretinoin) and brain and pancreatic cancer (isotretinoin). Tretinoinfrequently causes psychiatric symptoms, including anxiety (in 17% of pa-tients), insomnia (14%), depression (14%), confusion (11%), agitation(9%), and hallucinations (6%) (Roche Pharmaceuticals 2004). Several stud-ies also suggest an association between isotretinoin use and depression, sui-cide, and psychosis. (See Chapter 13, “Dermatological Disorders,” for addi-tional discussion of isotretinoin and depression and suicide.)

Hormone therapy. Tamoxifen has been reported to impair verbal memoryin several clinical trials (Jenkins et al. 2004; Schilder et al. 2009). Despiteearly concerns, a large placebo-controlled retrospective cohort study ofwomen with breast cancer indicated that tamoxifen administration does notincrease the risk for developing depression (Lee et al. 2007). These resultssupport those of an earlier multicenter placebo-controlled chemopreventiontrial, which showed that tamoxifen does not increase risk for or exacerbateexisting depression in women (Day et al. 2001).

The effect of the aromatase inhibitor anastrozole on memory is unclear.Studies variably show a greater impairment with anastrozole than withtamoxifen (Bender et al. 2007) or little or no impairment with anastrozole(Jenkins et al. 2008).

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Vinca alkaloids. Some references cite the vinca alkaloids as causing neuro-psychiatric symptoms. Although neuropathy is a widely recognized adverseeffect, there appears to be only a single case report of a psychiatric reaction(hallucinations) associated with vincristine (Ghosh et al. 1994).


Drug interactions are common in cancer therapy because of the use of multi-ple medications, including cytotoxic chemotherapy, hormonal agents, andadjunctive medications for supportive care and preexisting medical problems.Because most cancer patients are elderly (Yancik 2005), the drug burden fromother medical conditions can be considerable.

A number of complex pharmacokinetic and pharmacodynamic inter-actions can occur between cancer drugs and psychotropic drugs. Pharmaco-kinetic interactions due to cancer chemotherapy occur at several levels:inhibition of metabolic enzymes (cytochrome P450 [CYP] enzymes,monoamine oxidase), reduction of metabolism and excretion through cyto-toxic effects on hepatic and renal function, altered distribution (hypoalbu-minemia), and absorption (increased P-glycoprotein [P-gp] activity) (seeTables 8–2 and 8–3). Many cancer agents are prodrugs, compounds that re-quire metabolic activation for clinical effect, and many of these utilize CYPenzymes for their activation (see Table 8–4). Interactions from adjunctivemedications, including psychotropics, can enhance or impair the metabolicactivation of these prodrugs and affect their therapeutic benefit and adverseeffects. Although clinicians should be vigilant regarding potential drug inter-actions, many are theoretical in nature. Also, because oncological drug inter-actions are rarely reported, their clinical impact is uncertain. (For furtherdiscussion, see Chapter 1, “Pharmacokinetics, Pharmacodynamics, and Prin-ciples of Drug–Drug Interactions.”)


Interactions Affecting Drug Distribution

Asparaginase reduces serum albumin by approximately 25% (Petros et al.1992; Yang et al. 2008). Reductions in serum albumin can have variable clin-ical effects on serum levels and clearance of highly protein-bound drugs,

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Table 8–2. Oncology drug–psychotropic drug interactionsMedication Interaction mechanism Effect on psychotropic drugs and management

Alemtuzumab, arsenic trioxide, cetuximab, daunorubicin, denileukin, etoposide, homoharringtonine, idarubicin, mitoxantrone, nilotinib, rituximab, tamoxifen, tretinoin (systemic)

QT prolongation Increased QT prolongation in combination with other QT-prolonging drugs, such as TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Asparaginase Hypoalbuminemia Therapeutic drug monitoring of total (free + bound) drug may give misleading results. Use methods selective for free drug levels (see Chapter 1).

Cisplatin Nephrotoxicity Reduced elimination of renally eliminated drugs, such as lithium, paliperidone, desvenlafaxine, gabapentin, pregabalin, and memantine. Monitor lithium levels.

Unknown Decreased levels of carbamazepine, phenytoin, and valproate.Carboplatin,

ifosfamide, methotrexate

Nephrotoxicity: acute and chronic reduction in GFR

Reduced elimination of renally eliminated drugs, such as lithium, paliperidone, desvenlafaxine, gabapentin, pregabalin, and memantine. Monitor lithium levels.

Dasatinib Inhibits CYP 3A4 Increased levels and toxicities for pimozide, quetiapine, ziprasidone, iloperidone, fentanyl, meperidine, and tramadol.

Capecitabine, 5-fluorouracil

Reduced synthesis of CYP 2C9

Reduced phenytoin metabolism with increased toxicity.

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Imatinib Inhibits CYP 2C9, 2D6, 3A4

Increased levels and toxicities for phenytoin, pimozide, quetiapine, risperidone, ziprasidone, iloperidone, TCAs, bupropion, paroxetine, venlafaxine, fentanyl, meperidine, tramadol, atomoxetine, and benzodiazepines except oxazepam, lorazepam, and temazepam (see Chapter 1 for expanded listing).

Interleukin-2 (aldesleukin)

QT prolongation

Nephrotoxicity and reduced renal function

Reduced hepatic and renal function

Increased QT prolongation in combination with other QT-prolonging drugs, such as TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Reduced elimination of renally eliminated drugs, such as lithium, paliperidone, desvenlafaxine, gabapentin, pregabalin, and memantine. Monitor lithium levels.

Reduced hepatic metabolism and renal elimination of most drugs.

Interferon-alpha General CYP inhibition

QT prolongation

P-gp inhibition

Increased levels and adverse effects for oxidatively metabolized drugs, especially those metabolized by CYP 1A2, 2C19, and 2D6.

Increased QT prolongation in combination with other QT-prolonging drugs, such as TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Possible increased oral bioavailability of P-gp substrates (e.g., carbamazepine, phenytoin, lamotrigine, olanzapine, risperidone, quetiapine).

Nilutamide Inhibits CYP 1A2, 2D6, 3A4

Increased levels and toxicities for clozapine, olanzapine, pimozide, quetiapine, risperidone, ziprasidone, iloperidone, TCAs, bupropion, paroxetine, venlafaxine, fentanyl, meperidine, tramadol, atomoxetine, and benzodiazepines except oxazepam, lorazepam, and temazepam (see Chapter 1 for expanded listing).

Table 8–2. Oncology drug–psychotropic drug interactions (continued)Medication Interaction mechanism Effect on psychotropic drugs and management

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Procarbazine MAO inhibition Serotonin syndrome with SSRIs, SNRIs, TCAs, lithium, opiates (fentanyl, meperidine, methadone, tramadol, dextromethorphan, and propoxyphene), etc.

Hypertensive reaction with TCAs, sympathomimetics, psychostimulants, etc.Tamoxifen Inhibits CYP 2C9 Reduced phenytoin metabolism with increased toxicity.

Note. CYP=cytochrome P450; GFR=glomerular filtration rate; MAO=monamine oxidase; P-gp=P-glycoprotein; SNRI=serotonin-norepinephrine re-uptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant.

Table 8–3. Psychotropic drug–oncology drug interactionsMedication Pharmacokinetic effect Effect on oncological drug and management

Armodafinil, carbamazepine, modafinil, oxcarbazepine, phenytoin, St. John’s wort

Induction of CYP 3A4 and other CYP enzymes

Increased metabolism and reduced exposure and therapeutic effect of CYP 3A4 substrates, including bexarotene, dasatinib, docetaxel, doxorubicin, etoposide, gefitinib, imatinib, lapatinib, methotrexate, paclitaxel, sorafenib, sunitinib, teniposide, topotecan, toremifene, vinblastine, vincristine, and vinorelbine.

Increased metabolism of cyclophosphamide and thioTEPA and increased exposure to the toxic active metabolites. Reduce dosage to avoid excessive toxicity.

Increased metabolic activation of prodrugs ifosfamide and procarbazine increases toxicity and shortens duration of effect.

Increased metabolic inactivation of prodrug irinotecan reduces therapeutic effect.

Table 8–2. Oncology drug–psychotropic drug interactions (continued)Medication Interaction mechanism Effect on psychotropic drugs and management

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Fluoxetine, nefazodone

Inhibition of CYP 3A4 Reduced metabolism and increased exposure and toxicities of CYP 3A4 substrates, including bexarotene, dasatinib, docetaxel, doxorubicin, etoposide, gefitinib, imatinib, lapatinib, methotrexate, paclitaxel, sorafenib, sunitinib, teniposide, topotecan, toremifene, vinblastine, vincristine, and vinorelbine.

Reduced metabolism of cyclophosphamide and thioTEPA and reduced exposure to toxic active metabolites.

Reduced metabolic activation of prodrugs ifosfamide, irinotecan, and procarbazine.

Atomoxetine, bupropion, duloxetine, fluoxetine, moclobemide, paroxetine

Inhibition of CYP 2D6 Reduced bioactivation of prodrug tamoxifen. Decreased therapeutic effect.

Carbamazepine Downregulation of folate carrier Reduced methotrexate cancer treatment efficacy.

Valproate Inhibition of UGT 1A1 Reduced metabolism of irinotecan active metabolite (SN-38) and increased toxicity.

Possible reduced metabolism of sorafenib.

Note. CYP=cytochrome P450; UGT=uridine diphosphate glucuronosyltransferase.

Table 8–3. Psychotropic drug–oncology drug interactions (continued)Medication Pharmacokinetic effect Effect on oncological drug and management


including carbamazepine, phenytoin, and valproate (see Chapter 1, “Pharma-cokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions”).When asparaginase and psychotropic drugs are coadministered, the psycho-tropic drug levels should be monitored using methods selective for free drug;otherwise, lower total (free+bound) drug levels may prompt an inappropriatedosage increase.

Inhibition of Drug Metabolism by Chemotherapeutic Agents

The protein kinase inhibitors imatinib and nilotinib and the antiandrogennilutamide inhibit several CYP isozymes. Imatinib inhibits CYP 2D6 and3A4 (Novartis Pharmaceuticals 2009), whereas the second-generation com-pound nilotinib has greater scope, inhibiting CYP 2C8, 2C9, 2D6, and 3A4,as well as P-gp (Deremer et al. 2008). The drug interaction profile of niluta-mide suggests inhibition of CYP 1A2, 2C9, and 3A4 (Sanofi-Aventis Canada2006). In the presence of one of these anticancer agents, many drugs, includ-ing many psychotropics, may experience increased bioavailability and re-duced metabolism. Similarly, introduction of dasatinib, a CYP 3A4 inhibitor(Bristol-Myers Squibb 2009), may increase the bioavailability and plasma lev-els of several psychotropics, including pimozide, quetiapine, ziprasidone, ilo-peridone, desvenlafaxine, oxidatively metabolized benzodiazepines, fentanyl,and methadone.

Interferons and interleukins can give rise to drug interactions through in-hibition of one or more CYP isozymes or the P-gp efflux transporter. Smallstudies have shown interferons to significantly inhibit CYP 1A2 and 2D6 im-mediately after the first interferon dose (Islam et al. 2002; Williams et al.1987), with inhibition of CYP 1A2, 2C19, and 2D6 over the course of treat-ment. However, by a similar method, other investigators found no consistentchanges in CYP 1A2 and 3A4 (Pageaux et al. 1998) or in CYP 2D6 and 3A4(Becquemont et al. 2002). The reason for this variable effect is unclear. How-ever, given the wide scope of interferon’s potential effects on CYP metabo-lism, the introduction of IFN-α may require a dosage reduction of narrow-therapeutic-range drugs metabolized by CYP isozymes.

A similar reduction in CYP activity has been observed with interleukin-2administration. Research findings suggest that high-dose (≥9×106 units/m2)interleukin-2 therapy may reduce metabolism of drugs metabolized by CYP1A2 (olanzapine, clozapine) and CYP 3A4 (benzodiazepines, pimozide, que-

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tiapine, ziprasidone, iloperidone, modafinil, etc.) (Elkahwaji et al. 1999;Vanda Pharmaceuticals 2009).

Procarbazine inhibits monoamine oxidase and could trigger serotonin syn-drome in combination with TCAs, SSRIs, serotonin–norepinephrine reuptakeinhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), or opiates withserotonin reuptake inhibiting activity (meperidine, fentanyl, tramadol, metha-done, dextromethorphan, and propoxyphene). Psychostimulants and othersympathomimetics should be avoided, and the patient should be placed on atyramine-restricted diet.

Inhibition of Renal Elimination by Chemotherapeutic Agents

Several cancer agents are nephrotoxic, including the platinating agents cis-platin and carboplatin, methotrexate, ifosfamide, and aldesleukin (Kintzel2001) (see Table 8–2). A 20%–40% reduction in glomerular filtration rate(GFR) following cisplatin therapy is common. Surprisingly, little evidencesuggests that these drugs alter renal drug elimination. In case reports of pa-tients receiving lithium, the introduction of cisplatin led to a transient de-crease—not the expected increase—in lithium levels in two cases (Beijnen etal. 1992, 1994) and no change in a third (Pietruszka et al. 1985). Ifosfamidehas been shown to cause an average reduction in GFR by about 30% in a sur-vey of 123 children and adolescents (Skinner et al. 2000). Caution is advisedwhen administering a nephrotoxic agent with a drug that is primarily renallyeliminated, including lithium, paliperidone, desvenlafaxine, gabapentin, pre-gabalin, and memantine.

Intentional Pharmacokinetic Interactions

Although drug–drug interactions are generally avoided in pharmacotherapy,some interactions are purposely used to increase therapeutic efficacy. Forexample, the oral bioavailability of the anticancer agent paclitaxel can be in-creased 10-fold by coadministering cyclosporine, a CYP 3A4 and P-gpinhibitor (Helgason et al. 2006). The pharmacokinetic effect of drugs coad-ministered for their interacting properties must also be considered for othermedications, including psychotropics.

Interactions of Psychotropic Drugs With Chemotherapeutic Agents

Drug interactions causing changes in oncology drug levels may increase tox-icity or reduce therapeutic effect and survival rate. Many chemotherapeutic


agents are CYP 3A4 substrates; coadministration of a CYP 3A4 inhibitor (flu-oxetine, fluvoxamine, nefazodone) may increase chemotherapeutic drug bio-availability and blood levels and exacerbate toxicity (see Table 8–3).

Psychotropic induction of chemotherapeutic metabolism. Concurrentuse of the general CYP enzyme–inducing anticonvulsants carbamazepine,phenytoin, and phenobarbital with antileukemic therapy has been shown tocompromise the efficacy of the chemotherapy (Relling et al. 2000). Patientsreceiving long-term anticonvulsant therapy had significantly worse event-freesurvival (odds ratio 2.67) than the anticonvulsant-free group. Systemic clear-ance of teniposide and methotrexate was shown to be faster in the anticon-vulsant group. Other studies confirm the increased clearance of imatinib(Pursche et al. 2008), irinotecan (Mathijssen et al. 2002a, 2002b), and gefi-tinib (Swaisland et al. 2005) in the presence of CYP enzyme inducers.

Psychotropic inhibition of chemotherapeutic prodrug bioactivation.Many anticancer agents are administered as prodrugs; cyclophosphamide,dacarbazine, ifosfamide, procarbazine, tamoxifen, and trofosfamide undergobioactivation by the CYP system (see Table 8–4). Drug interactions that re-duce the bioactivation of oncology prodrugs may reduce therapeutic effectand survival rate.

Tamoxifen is metabolized in a two-step process involving CYP 2D6 and3A4 to the active metabolite endoxifen (Briest and Stearns 2009). In womenwith breast cancer taking tamoxifen, plasma levels of endoxifen were reducedfollowing the strong CYP 2D6 inhibitor paroxetine (>70%) or the mild CYP2D6 inhibitor sertraline (>40%). Conversion of tamoxifen was also reducedwith even mild CYP 3A4 inhibition (Jin et al. 2005). In women with breastcancer receiving tamoxifen therapy, concurrent use of a CYP 2D6 inhibitorincreased the recurrence of breast cancer 1.9-fold (Aubert et al. 2009). Parox-etine, fluoxetine, sertraline (CYP 2D6 inhibition at >200 mg/day), dulox-etine, bupropion, moclobemide, atomoxetine, and other CYP 2D6 inhibitorsshould be avoided during tamoxifen therapy (Goetz et al. 2007). Citalopram,escitalopram, venlafaxine, and mirtazapine are preferred because of their lackof effect on CYP metabolism.

Irinotecan has complex metabolism; it is metabolized to the active cyto-toxic compound SN-38 by carboxylesterases but inactivated by CYP 3A4.Drugs that induce CYP 3A4, including carbamazepine, phenytoin, pheno-

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barbital (Kuhn 2002), and St. John’s wort (Mathijssen et al. 2002b), producesignificant reductions in SN-38 levels, as does valproate (de Jong et al. 2007).Dosage adjustment may be required in the presence of these and other psy-chotropic drugs that induce (armodafinil, modafinil) or inhibit (fluoxetine,fluvoxamine, nefazodone) CYP 3A4.

Cyclophosphamide is converted by CYP 2B6 to the active anticanceragent 4-hydroxycoumarin (4-OHC). Two case reports suggest that CYP en-zyme induction by phenytoin (de Jonge et al. 2005) or carbamazepine (Ek-hart et al. 2009) enhances conversion to 4-OHC and may increase toxicity.Inhibitors of CYP 2B6 would be expected to reduce 4-OHC levels and de-crease therapeutic effect. Paroxetine, fluoxetine, and fluvoxamine are alsoCYP 2B6 inhibitors and should be avoided.

Ifosfamide and trofosfamide (an ifosfamide prodrug), in contrast to cy-clophosphamide, are bioactivated by CYP 3A4 and inactivated by CYP 2B6and 3A4. One study suggests that CYP 3A4 inhibitors and inducers shouldbe avoided with ifosfamide, and possibly trofosfamide, therapy (Kerbusch etal. 2001).


A wide variety of anticancer drugs prolong QT interval (see Table 8–2) (Arbelet al. 2007; Slovacek et al. 2008; Yeh 2006; see also Arizona Center for Edu-cation and Research on Therapeutics 2009). These agents should be usedwith caution in the presence of other drugs with QT-prolonging effects, such

Table 8–4. Oncology prodrugs activated by cytochrome P450 (CYP) metabolism

Prodrug Activating enzymes

Cyclophosphamide CYP 2B6

Dacarbazine CYP 1A2

Ifosfamide CYP 3A4

Procarbazine Unidentified CYPs

Tamoxifen CYP 2D6, 3A4

Trofosfamide CYP 3A4

Note. Refer to Chapter 1, “Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions,” for a listing of relevant CYP metabolic inhibitors and inducers.


as TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperi-done, quetiapine, ziprasidone, and lithium (Kane et al. 2008; van Noord etal. 2009).

Hypotension is associated with etoposide, denileukin, systemic tretinoin,alemtuzumab, cetuximab, rituximab, IFN-α, and interleukin-2 (aldesleukin).These agents may exacerbate hypotensive effects of psychotropic agents, in-cluding TCAs, antipsychotics, and MAOIs.

Antiemetics are often used to manage chemotherapy-induced nausea andvomiting. Antiemetic drug interactions are discussed in Chapter 4, “Gas-trointestinal Disorders.”

Drug Interaction Summary

Clinically significant drug interactions are rarely reported in the literature,and many are speculative in nature; however, several interactions deserve at-tention. The use of multiple QT-prolonging drugs should be avoided. Severalchemotherapeutic agents inhibit metabolism of psychotropic drugs and mayincrease psychotropic toxicities. In this event, psychotropic clinical responseand therapeutic drug level monitoring should guide dosage adjustments.SSRIs, SNRIs, TCAs, MAOIs and other agents known to precipitate seroto-nin syndrome should be used cautiously with procarbazine. Because manyoncological drugs are CYP 3A4 substrates, inducers and inhibitors of thisenzyme should be avoided. Reduced therapeutic efficacy of oncological pro-drugs may occur in the presence of drugs that inhibit their metabolic bio-activation. Prodrug interactions that reduce therapeutic efficacy are becomingincreasingly recognized. Conversely, oncological prodrug adverse effects maybe exacerbated by metabolic inducers, especially pan-inducers such as car-bamazepine, phenytoin, and phenobarbital.

Key Clinical Points

• Psychiatric comorbidities of cancer or cancer therapy are oftenundertreated. Anxiety, depression, and fatigue can be effectivelytreated with psychotropics.

• Neuropsychiatric symptoms of chemotherapy—especially de-pression that occurs with interferon and interleukin—may lead to

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treatment discontinuation. Use of an adjunctive antidepressantenhances adherence to chemotherapy.

• Studies to date do not support withholding any psychiatric med-ications based on fear of increasing cancer risk, with the possibleexception of antipsychotics with a high incidence of hyperpro-lactinemia in patients with present or past history of pituitaryendocrine tumors.

• Many chemotherapeutic agents prolong QT interval. Coadminis-tration of other QT-prolonging drugs, including many psychotro-pics, should be avoided.

• Many chemotherapy agents are metabolized by CYP 3A4. Coad-ministration of a CYP 3A4 inhibitor may exacerbate chemother-apy toxicity and should be avoided.

• Use of psychotropics that do not inhibit metabolism is preferredwhen in combination with oncology prodrugs such as tamoxifen(see Table 8–4).

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9Central Nervous System

Disorders

Saeed Salehinia, M.D.

Vani Rao, M.D.

Many patients with diseases of the central nervous system (CNS) have psy-chiatric disturbances in addition to their neurological symptoms (Lyketsos etal. 2008). Underlying brain disease may predispose patients to adverse effectsof psychotropic medications, including lowering of the seizure threshold (e.g.,clozapine, bupropion), worsening of cognitive dysfunction (e.g., anticholin-ergic drugs), development of neuropsychiatric symptoms (e.g., disinhibitionwith sedative-hypnotic medications), movement disorders (e.g., antipsychot-ics), and autonomic dysfunction (e.g., antiadrenergic and anticholinergicdrugs).

In this chapter, treatment of cognitive dysfunction, depression, mania,anxiety, and psychotic disorders is described for key neurological conditions.Neuropsychiatric disturbances such as apathy, fatigue, sleep disturbances, and


behavioral dysregulation that are often seen across CNS diseases are describedunder a common subheading.

DementiaDementia is a clinical syndrome characterized by cognitive decline, psychiatricdisturbances, and impairments in activities of daily living. The most commontype of dementia is Alzheimer’s disease, which accounts for 60%–70% of allpatients with dementia who are 65 years and older, followed by vascular de-mentia, dementia with Lewy bodies, frontotemporal dementia, dementias ofthe lenticulostriatal system (e.g., Parkinson’s disease), dementia due to im-mune diseases (e.g., multiple sclerosis), dementia due to brain injury (e.g.,traumatic brain injury, hypoxia), and dementia due to infectious diseases (e.g.,human immunodeficiency virus). Guidelines for the treatment of Alzheimer’sdisease and other dementias have been written by the American Psychiatric As-sociation Work Group on Alzheimer’s Disease and Other Dementias (2007).We provide an outline of the salient features related to pharmacotherapy.

Alzheimer’s Disease

Cognitive Deficits

Medications for the treatment of memory problems in Alzheimer’s diseaseinclude the cholinesterase inhibitors donepezil, galantamine, and rivastig-mine, and the N-methyl-D-aspartate (NMDA) receptor antagonist meman-tine. Cholinesterase inhibitors have modest cognitive, functional, andbehavioral benefits (Hansen et al. 2008; Rodda et al. 2009). Side effects aregenerally mild and include symptoms of cholinergic excess, such as nausea,vomiting, and diarrhea. Donepezil appears to have the lowest side-effect bur-den and rivastigmine the highest (Hansen et al. 2008). Side effects of meman-tine are relatively benign, with isolated reports of delirium.

Depression

Depression is the most common comorbid condition in dementia and is asso-ciated with worsening of cognitive deficits, a poorer quality of life, rapid rateof institutionalization, and increased caregiver burden. Selective serotonin re-uptake inhibitors (SSRIs) are usually considered first-line agents because oftheir benign side-effect profile. Sertraline, citalopram, and escitalopram are

Central Nervous System Disorders 273

preferred because they have fewer drug interactions than other SSRIs. Lyketsoset al. (2003) reported improvement of mood and reduction in functional de-cline in a 12-week randomized controlled trial (RCT) with sertraline, with nodifferences in adverse effects between medication and placebo. If SSRIs are notefficacious, other agents can be considered, including mirtazapine, venlafax-ine, secondary amine tricyclic antidepressants (TCAs), or monoamine oxidaseinhibitors (MAOIs). However, patients on these agents should be carefullymonitored for anticholinergic and antihistaminergic side effects.

Anxiety

Anxiety is common in patients with Alzheimer’s disease and often presents aseither a symptom of depression or a comorbid disorder. SSRIs are first-lineagents. Benzodiazepines or atypical antipsychotics should be used only forshort-term management of severe anxiety until SSRIs take effect. Buspironemay be useful because it is less sedating than benzodiazepines.

Psychosis and Agitation

In April 2005, the U.S. Food and Drug Administration (FDA) added a black-box warning for the use of atypical antipsychotics in elderly patients with de-mentia-related psychosis (Kuehn 2005; see Chapter 2, “Severe Drug Reac-tions”). The National Institute of Mental Health’s Clinical AntipsychoticTrials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD) studywas designed to better understand the effectiveness of the different antipsy-chotics for the treatment of behavioral disturbances in patients with Alzhei-mer’s disease (Schneider et al. 2003). In this multicenter RCT, outpatientswith Alzheimer’s disease and psychosis, aggression, or agitation received olan-zapine, quetiapine, risperidone, or placebo. Results of CATIE-AD Phase 1 in-dicated no significant differences among the medications and placebo withregard to time to discontinuation of treatment and overall improvement as as-sessed by the Clinical Global Impression of Change scale. The median timefor discontinuation of treatment due to poor efficacy favored risperidone andolanzapine, but the median time to discontinue secondary to side effects fa-vored only placebo. The authors concluded that adverse effects of the atypicalantipsychotics outweigh the benefits.

On examining the effects of antipsychotics on behavioral and psychiatricsymptoms, the CATIE-AD researchers found that antipsychotics such as


olanzapine and risperidone may be effective for the treatment of anger, ag-gression, and paranoid ideas but not for cognitive symptoms or improvingquality of life (Sultzer et al. 2008). As part of the same study, Zheng et al.(2009) found increased weight gain in females, with the odds of weight gainincreasing as the duration of treatment increased. Olanzapine was also associ-ated with increases in waist circumference and decreases in high-density lipo-protein cholesterol. These findings underscore the importance of carefullyweighing the indications, risks, and benefits of the atypical antipsychotics andusing them only when nonpharmacological approaches have failed and/or thebehavioral disturbances are severe. The CATIE-AD study focused only on pa-tients with Alzheimer’s disease living in the community; thus, it is unclear ifthese results can be extrapolated to inpatient settings, where the behavioraldisturbances may be more severe.

Other classes of psychotropics, such as typical antipsychotics, benzodiaz-epines, and mood stabilizers, have been used for the treatment of behavioralproblems, but studies are limited. In an RCT, Pollock et al. (2002) found cit-alopram to be superior to both perphenazine and placebo for the treatmentof agitation in 85 hospitalized patients with dementia. Sink et al. (2005) con-ducted a systematic review to evaluate the efficacy of all medications in thetreatment of neuropsychiatric symptoms associated with dementia. Their al-gorithm (p. 606) suggested the use of cholinesterase inhibitors first, with anSSRI for depressed patients or followed by an SSRI in nondepressed but stillagitated patients, followed by antipsychotics, followed by mood stabilizers.Mood stabilizers, however, have not been found to be efficacious for agitationin Alzheimer’s disease.

Dementia With Lewy Bodies

Patients who have dementia with Lewy bodies (DLB) have significant cholin-ergic deficits, surpassing those in patients with Alzheimer’s disease (Tarawnehand Galvin 2007). In randomized placebo-controlled trials of rivastigmine,patients with DLB have shown improvement, specifically in cognitive vigi-lance, working memory, episodic memory, attention, and executive function(Wesnes et al. 2002). Open-label studies of donepezil and galantamine havealso shown similar beneficial effects (Simard and van Reekum 2004).

The treatment of noncognitive symptoms of DLB is similar to that ofAlzheimer’s disease. Open-label trials of donepezil and galantamine revealed


that the neuropsychiatric symptoms most responsive to therapy are hallucina-tions, paranoid delusions, daytime somnolence, apathy, aggression, and agi-tation (Simard and van Reekum 2004). Because patients with DLB arehypersensitive to the extrapyramidal side effects of antipsychotics, these drugsshould be used with extreme caution, if at all.

Frontotemporal Dementia

Patients with frontotemporal dementia often have abnormalities in the sero-tonin and dopamine neurotransmitter systems, while the acetylcholine sys-tem is relatively intact (Huey et al. 2006). Open-label studies of SSRIs inpatients with frontotemporal dementia revealed improvement in compulsivebehaviors, depression, disinhibition, and carbohydrate craving, and reductionin caregiver burden (Moretti et al. 2003).

Vascular Dementia

The most important therapy in vascular dementia is stroke preventionthrough smoking cessation and tight control of hypertension, hyperlipi-demia, and diabetes mellitus. A meta-analysis of controlled trials in patientswith vascular dementia indicates that donepezil, galantamine, rivastigmine,and memantine are superior to placebo for cognitive outcomes on the Alzhei-mer’s Disease Assessment Scale (Kavirajan and Schneider 2007).

StrokeStroke patients are at significant risk for neuropsychiatric disturbances. Theseinclude dementia, depression, mania, anxiety, psychosis, disinhibition, apa-thy, and fatigue.

Cognitive Deficits

The psychopharmacology of poststroke cognitive disorders is similar to thatfor vascular dementia, as discussed earlier in this chapter.

Depression

The prevalence of poststroke depression ranges from 20% to 60% (Lenzi etal. 2008). Compared with nondepressed stroke patients, patients with post-stroke depression have increased rates of morbidity and mortality. Several


clinical trials have demonstrated the efficacy of TCAs, SSRIs, and mirtazapinefor minor or major poststroke depression; however, no clear guidelines areavailable on the optimal drug, dosage, or duration of therapy (Paolucci 2008).Nortriptyline was found to be superior to both placebo and fluoxetine in oneRCT (Robinson et al. 2000). A randomized, open-label trial found that mir-tazapine given prophylactically and acutely after stroke may be beneficial inpreventing poststroke depression (Niedermaier et al. 2004). It remains un-clear if prophylactic antidepressants prevent poststroke depression or decreasepoststroke mortality.

Mania

Although no systematic treatment studies of poststroke mania have been con-ducted, valproic acid, carbamazepine, and lithium have been reported to beuseful (Bernardo et al. 2008). Antipsychotics may also be useful; however,caution is advised considering the 2005 FDA warning about antipsychoticuse in older adults. Case reports support the effectiveness of valproate(Himelhoch and Haller 1996), lamotrigine (Ramasubbu 2003), and olanza-pine (Morris et al. 1996) for the treatment of poststroke mood lability.

Anxiety

Anxiety disorder is a major comorbid condition of poststroke depression andresponds well to antidepressants. In an RCT, nortriptyline was superior toplacebo in treating poststroke anxiety comorbid with poststroke depression(Kimura et al. 2003). Benzodiazepines should be avoided because they mayworsen cognitive deficits, and increase the risk for falls.

Traumatic Brain InjuryTraumatic brain injury (TBI) may produce a variety of neuropsychiatricsymptoms, including impaired cognition, depression, mania, affective labil-ity, irritability, anxiety, and psychosis (Warden et al. 2006). However, fewRCTs have been reported that guide treatment decisions.

Cognitive Deficits

TBI is associated with impairments in one or more cognitive domains ofarousal, attention, concentration, memory, language, and executive function.


Small case series and anecdotal reports have suggested that stimulants (dex-troamphetamine, methylphenidate, modafinil) and dopamine agonists(amantadine, levodopa/carbidopa, bromocriptine) may be useful in the treat-ment of post-TBI cognitive deficits (Warden et al. 2006). Cholinesterase in-hibitors are also effective treatment for global cognitive deficits post-TBI(Tenovuo et al. 2005). In an RCT, donepezil improved memory and concen-tration (Zhang et al. 2004a), and studies of galantamine and rivastigminehave also noted modest improvement in memory deficits, inattention, and in-formation processing (Tenovuo et al. 2005; Silver et al. 2009a).

Depression

SSRIs are usually the first-line medications for post-TBI depression. In asmall open-label trial of sertraline for depression in patients with mild TBI,significant improvement was seen in depressive symptoms (Fann et al. 2000).An open-label trial of citalopram in patients with post-TBI depression re-ported a response rate of 28% at 6 weeks and 46% after 10 weeks (Rapoportet al. 2008). However, sertraline was not superior to placebo in an RCT ofpatients with moderate to severe TBI and depression (Ashman et al. 2009).The serotonin–norepinephrine reuptake inhibitors (SNRIs) venlafaxine andduloxetine also appear to be effective (Silver et al. 2009b). Psychostimulantsand dopamine agonists can be used to augment the effect of antidepressants.Bupropion should be used with caution because of its potential to reduce sei-zure threshold.

Mania

Some patients with TBI experience mania. Anecdotal reports and small caseseries suggest the effectiveness of mood stabilizers, such as lithium, carbamaz-epine, and valproic acid, in reducing mania (Kim and Humaran 2002).

Psychosis and Agitation

Limited literature is available on the treatment of post-TBI psychosis. Atypi-cal antipsychotics are preferred to typical agents because of lower rates of neu-rological side effects. Olanzapine was effective in a few case reports (Guerreiroet al. 2009; Umansky and Geller 2000). Clozapine was found to be mildlyeffective, but two of the nine TBI patients developed seizures (Michals et al.


1993). Schreiber et al. (1998) reported on the successful use of risperidone forsleep disturbance and delusions in a patient with brain injury. Psychosis resis-tant to treatment with antipsychotics or anticonvulsants (e.g., valproate, car-bamazepine) may be a manifestation of subclinical seizures.

RCTs have demonstrated the effectiveness of beta-blockers such as pro-pranolol for agitation in TBI patients (Fleminger et al. 2006).

Multiple SclerosisMultiple sclerosis includes motor, cognitive, and psychiatric disturbances,which can occur together or independently (for a full review, see Ghaffar andFeinstein 2007).

Cognitive Deficits

Over 40% of patients with multiple sclerosis have cognitive impairments, in-cluding attention deficits, reduced speed of information processing, memorydeficits, executive dysfunction, and dementia. Disease-modifying drugs(drugs that alter the disease course), such as interferon-beta-1a, have beenfound to prevent or reduce the progression of cognitive dysfunction in mul-tiple sclerosis (Fischer et al. 2000). Cholinesterase inhibitors have been shownto improve memory. In an RCT, patients with multiple sclerosis treated withdonepezil significantly improved on both objective and subjective memorymeasures (Christodoulou et al. 2006). Dopamine agonists, such as amanta-dine, have not been found to be beneficial (Geisler et al. 1996).

Depression

The lifetime incidence of affective disorder is 50% among patients with mul-tiple sclerosis, and they have an elevated rate of suicide (Siegert and Abernethy2005). The somatic symptoms of depression, especially fatigue, are often con-founded by the symptoms of multiple sclerosis. The SSRIs escitalopram,citalopram, and sertraline are first-line agents because of few drug–drug in-teractions (Kaplin 2007).

Only two RCTs have been reported for the treatment of depression inmultiple sclerosis. The first found desipramine to be more effective than casemanagement control (Schiffer and Wineman 1990). The second comparedsertraline to two types of psychotherapy: individual cognitive-behavioral ther-


apy and supportive-expressive group therapy (Mohr et al. 2001). Responsewas greater in the individual cognitive-behavioral therapy group (50%) thanthe sertraline group (24%), but both were superior to supportive-expressivetherapy (14%). The sertraline group had the highest attrition rate. The resultsfrom these studies suggested that although antidepressants may be useful inthe treatment of depressive symptoms, treatment response is not uniform.Furthermore, patients with multiple sclerosis may be particularly susceptibleto SSRI-induced sexual dysfunction due to spinal cord involvement (Kaplin2007). Bupropion may therefore be a prudent choice due to its relative lackof sexual side effects and its activating effects, which can be helpful for fatigue.TCAs may be helpful in depressed multiple sclerosis patients with inconti-nence. TCAs and duloxetine may benefit neuropathic pain. Psychostimulantsmay help depression, as well as fatigue (discussed later in this chapter), in pa-tients with multiple sclerosis.

Mania

Mania is twice as common in patients with multiple sclerosis as in the generalpopulation (Ghaffar and Feinstein 2007). However, no clinical trials havebeen reported for the treatment of mania associated with multiple sclerosis.Mood stabilizers can be used in mania of mild to moderate severity; benzodi-azepines or antipsychotics serve as adjunctive treatment if sedation is requiredor if psychotic symptoms are present (Ameis and Feinstein 2006). If maniadevelops in multiple sclerosis patients receiving corticosteroids, lithium canbe introduced to control the mania rather than discontinuing the steroids(Feinstein 2007). This is well illustrated in the retrospective chart review con-ducted by Falk et al. (1979) to determine the prophylactic effect of lithium inreducing psychosis in multiple sclerosis patients receiving corticotropin.None of the 27 patients receiving lithium developed mania, compared with6 of 44 receiving steroid therapy without lithium.

Psychosis

Psychosis in patients with multiple sclerosis is uncommon, with a prevalencerate of about 1%–3%. Although there are no published trials for the treatmentof psychosis in multiple sclerosis, atypical antipsychotics are preferred becausethey have a lower risk of extrapyramidal symptoms than do typical agents.


Fatigue

Modafinil has been found to be effective for fatigue in an RCT in patientswith multiple sclerosis (Kraft and Bowen 2005).

Parkinson’s Disease

Parkinson’s disease is characterized by motor symptoms, including bradykine-sia, tremor, rigidity, and postural instability. However, neuropsychiatricsymptoms are common and have important clinical consequences on qualityof life, caregiver burden, and course of disease (for a review, see Marsh andBerk 2003).

Cognitive Deficits

Cognitive deficits and dementia are five times more common in patients withParkinson’s disease than in the general population (Hobson and Meara 1999).Cognitive symptoms include psychomotor slowing, impaired verbal andworking memory, and executive dysfunction. Small RCTs have shown done-pezil to improve cognition and memory and to have minimal motor side ef-fects (Leroi et al. 2006). A large RCT of rivastigmine demonstrated moderateimprovements in cognition but increased rates of nausea, vomiting, and wors-ening tremor (Emre et al. 2004). Modafinil and atomoxetine may also be ben-eficial in Parkinson’s disease for treatment of executive dysfunction and othercognitive deficits, such as inattention (Bassett 2005).

Depression

The prevalence of depressive disorders in Parkinson’s disease varies from 7%to 76% (Veazey et al. 2005). Depression in patients with Parkinson’s diseaseis associated with reduced cognitive performance, diminished quality of life,more severe impairment in motor performance, and increased mortality.Clinical trials are limited; in a Cochrane review, Ghazi-Noori et al. (2003)concluded that insufficient data are available on the effectiveness and safetyof antidepressant therapies in patients with Parkinson’s disease. Mild depres-sion in Parkinson’s disease may respond to dopamine agonists, which shouldbe considered first-line therapy. In RCTs, pramipexole was superior to pla-cebo (Corrigan et al. 2000), and to sertraline and placebo (Barone et al.


2006). SSRIs have occasionally been reported to exacerbate motor symptomsin patients with Parkinson’s disease. In an RCT comparing desipramine,citalopram, and placebo in treating the depression of patients with Parkin-son’s disease, a benefit was observed with desipramine as early as 14 days;however, both desipramine and citalopram were superior to placebo at 30days (Devos et al. 2008). Side effects were twice as frequent with desipramineas with citalopram or placebo. In the largest RCT for the treatment of depres-sion in Parkinson’s disease, Menza et al. (2009) found nortriptyline to be su-perior to paroxetine or placebo. Other secondary endpoints, including sleep,anxiety, and social functioning, also improved more with nortriptyline thanwith placebo. Perhaps TCAs are superior in Parkinson’s disease because theiranticholinergic effects are beneficial. Treatment with omega-3 fatty acids infish oil with or without antidepressants improved depression in patients withParkinson’s disease relative to placebo (da Silva et al. 2008). SNRIs and bu-propion can also be considered. Mirtazapine has not been studied.

Psychosis

Psychotic symptoms occur in about one-third of patients with Parkinson’s dis-ease. Visual hallucinations and paranoid delusions are the most common psy-chotic symptoms and occur most often in Parkinson’s disease patients withdementia. Sleep disturbance, rapid eye movement sleep intrusions, and pro-longed dopamine agonist treatment may contribute to visual hallucinations(see “Adverse Psychiatric Effects of Neurological Drugs,” later in this chapter).Treatment of psychosis in Parkinson’s disease is complicated by the potentialfor antipsychotics to exacerbate motor symptoms (Hasnain et al. 2009).

Psychosis in patients with Parkinson’s disease is managed by first reducingdopaminergic agents to the lowest effective dose. If symptoms do not im-prove, adjunctive antipsychotic medication should be considered (see reviewin Zahodne and Fernandez 2008). Clozapine remains the drug of choice fortreatment of psychosis in Parkinson’s disease. A meta-analysis of several RCTsconfirmed the efficacy of low-dose clozapine (6.25–50 mg/day) for psychosiswithout significant worsening of Parkinson’s disease (Frieling et al. 2007).Quetiapine demonstrated equivalency to clozapine for Parkinson’s diseasepsychosis and lack of motor adverse effects in one RCT, but failed to showefficacy in two placebo-controlled trials. Quetiapine is considered less effec-tive than clozapine for Parkinson’s disease psychosis, does not improve tremor,


and may worsen motor symptoms, especially in Parkinson’s disease patientswith dementia. Risperidone has also been noted to improve psychosis in sev-eral open-label studies but is not preferred because of its risk of worseningmotor symptoms (Zahodne and Fernandez 2008). Olanzapine has beenfound to be ineffective and to worsen motor function in two placebo-con-trolled trials and is not recommended (Fernandez et al. 2003). Limited infor-mation is available on the efficacy and side effects of aripiprazole, ziprasidone,and paliperidone for the treatment of psychosis in Parkinson’s disease.

Few RCTs have assessed cholinesterase inhibitors for the treatment of Par-kinson’s disease psychosis in patients with dementia. In two placebo-con-trolled trials, donepezil failed to show significant benefit over placebo(Aarsland et al. 2002; Ravina et al. 2005). Rivastigmine significantly improvedhallucinations compared with placebo in a large RCT (Burn et al. 2006). Nocontrolled trials of galantamine have been reported for this population.

Fatigue

Methylphenidate, in a small RCT, has been shown to improve fatigue in pa-tients with Parkinson’s disease over a 6-week treatment period (Mendonca etal. 2007). An RCT also found modafinil to be effective for fatigue in Parkin-son’s disease (Lou et al. 2007).

Huntington’s Disease

Huntington’s disease is characterized by the triad of movement disorder, de-mentia, and psychiatric disturbances, including depression, mania, obsessive-compulsive disorder, and psychosis. In the absence of controlled trials, psy-chopharmacology in Huntington’s disease is similar to other basal ganglia dis-orders. Patients with basal ganglia disorders are especially vulnerable tosedation, falls, cognitive impairment, and extrapyramidal symptoms (Rosen-blatt 2007).

Depression

Although depression is the most common psychiatric diagnosis in Hunting-ton’s disease, occurring in about 30% of patients (Slaughter et al. 2001), noRCTs have been done to guide treatment. SSRIs are favored because they may


reduce the irritability and anxiety that are commonly seen in patients withHuntington’s disease (De Marchi et al. 2001). TCAs, MAOIs, and mirtaz-apine have also been effective in case reports and small case series (Bonelli andHofmann 2007).

Mania

Approximately 5%–10% of patients with Huntington’s disease becomemanic, with elevated and irritable mood and grandiosity (Rosenblatt 2007).Clinical experience and a literature review suggest that Huntington’s diseasepatients with manic or hypomanic symptoms respond less well to lithium andmay be more susceptible to its toxic side effects (Rosenblatt 2007). Low-dosevalproate or carbamazepine is an alternative treatment. Antipsychotics may beconsidered in patients with psychosis or agitation.

Psychosis

Delusions have been reported in 11% and hallucinations in about 2% of pa-tients with Huntington’s disease (Paulsen et al. 2001). The choice of antipsy-chotics in these patients is determined by the severity of the movementdisorder. High-potency antipsychotics, such as haloperidol, are preferred inpeople with severe movement disorder, whereas atypical antipsychotics maybe best if the movement disorder is not problematic (Chou et al. 2007). Casereports suggest effectiveness for risperidone (Erdemoglu and Boratav 2002),clozapine (Sajatovic et al. 1991), and quetiapine (Seitz and Millson 2004).

Epilepsy

A wide range of chronic and episodic cognitive, mood, and behavioral distur-bances are associated with epilepsy. Psychiatric disturbances in epilepsy can becategorized as ictal, interictal, or postictal (for a review, see LaFrance et al.2008).

Cognitive Deficits

Cognitive disorders are common in epilepsy and are usually managed with ag-gressive seizure control, selection of anticonvulsants with minimal cognitiveside effects (e.g., lamotrigine, levetiracetam), and treatment of comorbid de-


pression (Shulman and Barr 2002). Cholinesterase inhibitors have not beeneffective for cognitive deficits in epilepsy (Hamberger et al. 2007). The use ofmemantine is controversial, with reports suggesting increased risk of seizures(Peltz et al. 2005).

Depression

In patients with uncontrolled seizures, the prevalence of depression is up to10 times that in the general population and up to 5 times that in patients withcontrolled seizures (Harden 2002). Treatment depends on whether the de-pressive symptoms occur ictally, peri-ictally, or interictally. Depression occur-ring during the ictal or peri-ictal period is managed with better seizurecontrol. Antidepressants or electroconvulsive therapy should be consideredfor the occurrence of inter-ictal depressive symptoms. SSRIs are first-lineagents because they have minimal effect on seizure threshold, especially in pa-tients who are well controlled on anticonvulsant drugs (Tucker 2004). Bupro-pion and clomipramine should be used with great caution, if at all, becauseof the risk of lowering seizure threshold (see “Seizures,” later in this chapter).Pharmacokinetic interactions of antidepressant and antiepileptic drugsshould be considered when combining these drugs (see Tables 9–3 and 9–4,later in this chapter; Tucker 2004).

Mania

Although mania is rare in patients with epilepsy, it can occur transiently in upto 10% of patients after epilepsy surgery, particularly those undergoing rightlobectomies (Prueter and Norra 2005). Anticonvulsant mood stabilizers, suchas valproate, carbamazepine, and lamotrigine, should be regarded as first-linedrugs for the treatment of manic episodes in patients with epilepsy (Prueterand Norra 2005). Lithium is a second-line alternative because of its epilepto-genic activity.

Anxiety

Anxiety in epilepsy can occur as an ictal phenomenon, or it can occur duringthe interictal phase as a primary or secondary anxiety disorder or as a comor-bid disorder with depression (Devinsky and Vazquez 1993). To date, noRCTs have been published on anxiety disorders in patients with epilepsy.


SSRIs are first-line agents because of their benign effects on seizure threshold.Benzodiazepines are also useful and provide additive anticonvulsant effects;however, their use must be balanced against risk of addiction and motor andcognitive side effects.

Psychosis

Psychosis in epilepsy may be classified as ictal and postictal psychosis (psycho-ses closely linked to seizures), alternative psychosis (psychosis linked to seizureremission), interictal psychosis (intermittent episodes of psychoses not asso-ciated with seizures), or iatrogenic psychosis (psychosis related to anticonvul-sant drugs). Anticonvulsants are the primary treatment of ictal and postictalpsychosis. The treatment of interictal psychosis includes both anticonvulsantsand antipsychotics. Antipsychotics with a high risk of lowering seizure thresh-old, such as clozapine and low-potency typical agents, should be avoided.

Symptoms and Syndromes Common Across Neurological Disorders

Apathy

Few empirical data are available regarding the treatment of apathy. A Cochranereview of RCTs evaluating interventions for apathy in patients with TBI foundno medication trials (Lane-Brown and Tate 2009). Anecdotal evidence sug-gests the effectiveness for apathy of amantadine, bromocriptine, bupropion,modafinil, methylphenidate, and cholinesterase inhibitors (Galynker et al.1997; Kraus and Maki 1997; Powell et al. 1996; Rodda et al. 2009).

Pathological Laughter and Crying

Patients with a variety of neurological conditions may have episodes of un-controllable crying, laughing, or both, that may be inappropriate and inde-pendent of mood. Terms used to describe pathological laughter and cryinginclude pseudobulbar affect, affective and emotional lability, involuntaryemotional expression disorder, emotional incontinence, and forced crying.SSRIs are recommended as first-line agents (Wortzel et al. 2008). Second-lineagents include TCAs, noradrenergic reuptake inhibitors, dopaminergicagents, and NMDA receptor antagonists. The combination of dextromethor-


phan and quinidine (30 mg of each twice daily) has shown efficacy in RCTs(Panitch et al. 2006).

Sexual Disinhibition

Sexual disinhibition is common in neurological patients with frontal lobe le-sions, particularly in men. Estrogen therapy was effective in a double-blindstudy (Kyomen et al. 1999). Anecdotal evidence suggests using SSRIs, clo-mipramine, carbamazepine, cimetidine, cyproterone, leuprolide, and/or anti-psychotics (Ozkan et al. 2008).

Adverse Neurological Effects of Psychotropic DrugsPsychotropic drugs are well known to produce neurological adverse effects,most notably extrapyramidal symptoms, including tardive dyskinesia, lower-ing of seizure threshold, cognitive impairment and delirium, and behavioraldisinhibition (see Table 9–1). Neuroleptic malignant syndrome and seroto-nin syndrome, which may develop in patients treated with antipsychoticdrugs, are covered in Chapter 2, “Severe Drug Reactions.”

Extrapyramidal Symptoms

Extrapyramidal symptoms most associated with psychotropic agents includeacute dyskinesias, tremor, dystonia, and akathisia. Patients with Parkinson’sdisease, DLB, vascular dementia, and multiple sclerosis are at greatest risk fordeveloping these symptoms. Antipsychotics are the most common cause ofextrapyramidal symptoms, with risk increasing with greater dopamine D2 re-ceptor blockade (as with hyperprolactinemia and tardive dyskinesia). Halo-peridol presents the greatest risk, followed by phenothiazines and atypicalantipsychotics. Among currently available atypical antipsychotics, the hierar-chy of extrapyramidal symptom risk (greater to lesser) is as follows: ziprasi-done > aripiprazole > risperidone = paliperidone (estimated) > olanzapine >quetiapine > clozapine (Gao et al. 2008; Tandon 2002). Extrapyramidalsymptoms have also been reported with antidepressants, most commonlySSRIs (Gill et al. 1997).

Tardive dyskinesia, characterized by repetitive, involuntary, purposelessmovements similar to those found after prolonged levodopa treatment in Par-


Table 9–1. Neurological adverse effects of psychotropic drugs

Medication Neurological adverse effects

Antidepressants

SSRIs or SNRIs Tremor, sedation, apathy

TCAs Cognitive impairment (tertiary> secondary amines), seizure (particularly clomipramine), sedation (tertiary>secondary amines)

MAOIs Sedation

Bupropion Seizure (generally increased risk with doses exceeding 400 mg/day; dose required to produce seizure may be lower in neurological patients)

Amoxapine, maprotiline Lower seizure threshold at therapeutic dosages

Antipsychotics

Atypical and typical agents

Extrapyramidal symptoms and tardive dyskinesia, seizure (particularly clozapine, chlorpromazine, loxapine), cognitive impairment (particularly low-potency typical agents), orthostatic hypotension, neuroleptic malignant syndrome

Mood stabilizers

Carbamazepine Dizziness, drowsiness, incoordination, blurred vision, nystagmus, ataxia

Lithium Seizure, ataxia, delirium, slurred speech, dystonia, tics, tremor; deficits can be acute and chronic and are generally dose and serum concentration dependent

Valproate Somnolence, dizziness, tremor, insomnia

Anticholinergics

Benztropine, trihexyphenidyl

Delirium, visual hallucinations, cognitive impairment

Anxiolytics

Benzodiazepines Withdrawal seizures, delirium, disinhibition, cognitive impairment, sedation, dysarthria

Buspirone Sedation, dizziness

Note. MAOI=monamine oxidase inhibitor; SNRI=serotonin-norepinephrine reuptake inhib-itor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant.


kinson’s disease, is most often associated with abrupt discontinuation of an-tipsychotic medications. It has also been reported with metoclopramide, withphenothiazine antiemetics, and very rarely with SSRIs. Medical complica-tions may include pain and impairment of gait, swallowing, and respiration.Neurologically ill and elderly patients are thought to be at increased risk. Tar-dive dystonia and tardive akathisia may also result from prolonged antipsy-chotic exposure. No cure for tardive dyskinesia has been found, but smallopen-label trials and RCTs suggest that donepezil (Caroff et al. 2001), vita-min E (Lohr and Caligiuri 1996; Zhang et al. 2004b), low-dose clozapine(Spivak et al. 1997), olanzapine (Lucetti et al. 2002), buspirone (Moss et al.1993), and tetrabenazine may be effective.

Seizures

Psychotropics are generally regarded with caution for patients with epilepsy.However, in a retrospective study assessing the impact of psychotropics on sei-zure frequency, Gross et al. (2000) found that seizure frequency decreased in33% of patients, was unchanged in 44%, and increased in only 23%. No sig-nificant difference in average seizure frequency was found between pretreat-ment and treatment periods. The authors concluded that psychotropicmedications can be safely used in epilepsy patients with psychopathology ifintroduced slowly in low to moderate doses. However, certain psychotropics,such as chlorpromazine, clozapine, maprotiline, bupropion, and clomipra-mine, have been associated with increased seizure frequency and should beavoided in patients with epilepsy. Haloperidol and atypical antipsychoticsother than clozapine have a lower risk of causing seizures than do the phe-nothiazine antipsychotics (Guarnieri et al. 2004). The rate of seizures withbupropion is dose related, with the greatest risk (about 0.4%) at 450 mg/dayin non-neurological patients. Patients with epilepsy may have increased risk.Psychostimulants, including dextroamphetamine and methylphenidate, donot appear to increase seizure risk in attention-deficit/hyperactivity disorderpatients with epilepsy and good seizure control (Kanner 2008). However, pa-tients with poor seizure control may be at risk with stimulants (Gonzalez-Heydrich et al. 2007). (For additional information about drug-induced sei-zures, see Chapter 2, “Severe Drug Reactions.”)


Cognitive Impairment and Delirium

The psychotropic drugs most likely to cause or exacerbate cognitive impair-ment and delirium are benzodiazepines, drugs with anticholinergic properties(e.g., benztropine, phenothiazines, tertiary amine TCAs), lithium (especiallyat toxic levels), and topiramate (cognitive impairment). In general, benzodi-azepines and lithium should be used with caution and monitored closely inneurological patients, because each has a low therapeutic index. (See Chapter15, “Surgery and Critical Care,” for discussion of the management of anti-cholinergic delirium.)

Behavioral disinhibition is most often caused by benzodiazepines, partic-ularly in patients with neurological illness, children, and older adults. Behav-ioral disinhibition often co-occurs with cognitive impairment and delirium.

Adverse Psychiatric Effects of Neurological Drugs

Dopamine Agonists

The dopamine agonists (see Table 9–2), including levodopa, amantadine,pramipexole, and ropinirole, have been associated with hallucinations and de-lusions and complex behavior problems in patients with Parkinson’s disease.Patients at greatest risk include those with advanced disease, prolonged treat-ment, cognitive impairment, and dyskinesias.

Complex behavioral problems associated with dopamine receptor stimu-lation in Parkinson’s disease include pathological gambling, hypersexuality,punding (intense fascination with repetitive handling, examining, sorting,and arranging of objects), compulsive shopping, and compulsive medicationuse (Weintraub et al. 2006). Sometimes described as the dopamine dysregu-lation syndrome, these behaviors affect up to 14% of patients with Parkin-son’s disease (Voon and Fox 2007). Management includes dopamine agonistdose reduction and treatment of secondary psychotic, manic, or behavioralsymptoms.

Anticonvulsants

Psychiatric adverse effects, including affective disorder, psychosis, and aggres-sive behavior, were precipitated by the anticonvulsants topiramate in 24%


Table 9–2. Psychiatric adverse effects of neurological drugsMedication Psychiatric adverse effects

Dopamine agonists

Amantadine, levodopa/carbidopa

Psychosis, agitation, insomnia, confusion

Pramipexole, ropinirole Psychosis, agitation, somnolence, confusion

MAO-B inhibitors

Selegiline Dizziness, vivid dreams, agitation, insomnia; risk for hypertensive crisis and serotonin syndrome at doses exceeding 10 mg/day

Rasagiline Dizziness, vivid dreams, anxiety

COMT inhibitors

Entacapone, tolcapone Dyskinesia, sleep disorders, hallucinations, agitation

Anticonvulsants

Gabapentin Sedation

Lamotrigine Euphoria

Levetiracetam Affective disorder, psychosis, aggressive behavior

Topiramate Cognitive impairment, decreased appetite, affective disorder, psychosis, aggressive behavior

Valproate Cognitive impairment, increased appetite

Interferons

Interferon-beta-1a/1b Depression, affective lability, irritability

Immunomodulators

Glatiramer, mitoxantrone, natalizumab

Anxiety, agitation, delirium, depression

Alpha-2 adrenoceptor agonists

Clonidine, guanfacine Depression, anxiety, vivid dreams, restlessness, fatigue

Cholinesterase inhibitors

Donepezil, rivastigmine, galantamine

Insomnia, fatigue, anorexia, vivid dreams

Note. COMT=catechol-O-methyl transferase; MAO-B=monoamine oxidase B.


(Mula et al. 2003a) and levetiracetam in 10%–16% (Mula et al. 2003b) ofpatients with epilepsy. Patients with a personal or family history of psychiatricdisorder were at increased risk for developing a psychiatric adverse effect withtopiramate or levetiracetam.

Interferon-Beta-1a

Although interferon-alpha is commonly associated with depression, the riskof depression from interferon-beta-1a, used for relapsing–remitting multiplesclerosis, is not well established. Interferon-beta-1a is reported to have no de-pressive effect (Zephir et al. 2003) or may even have a benefit on mood anddepression after prolonged treatment (Feinstein et al. 2002). Individuals witha prior history of major depression or psychosis may be at increased risk ofdepression; however, this has not been well established. Psychosis and delir-ium have also been reported (Goëb et al. 2003).

Drug–Drug InteractionsPharmacokinetic and pharmacodynamic interactions between psychiatricand neurological drugs are outlined in Tables 9–3 and 9–4. The pharmaco-kinetic interaction of greatest clinical significance is the induction of cyto-chrome P450 (CYP) 1A2, 2C9, 2C19, and 3A4–mediated metabolism byphenytoin, phenobarbital, carbamazepine, and ethosuximide, resulting in de-creased levels of many psychotropics. Valproate also may alter metabolismthrough hepatotoxicity and complex effects on induction and inhibition ofseveral CYP enzymes. It is prudent to monitor the levels of all coadministeredmedications with the potential for toxicity when prescribing anticonvulsantagents.

Many psychotropics lower seizure threshold (TCAs, bupropion [>450mg/day], high-dose venlafaxine, maprotiline, lithium, low-potency typicalantipsychotics, clozapine) and can erode the therapeutic effects of anticonvul-sants. Amantadine, fosphenytoin, and felbamate may increase QT prolonga-tion when given with other QT-prolonging psychotropic drugs, such asantipsychotics, TCAs, and lithium (for a listing, see Arizona Center for Edu-cation and Research on Therapeutics 2009). Triptans and selegiline (inhibi-tion of monoamine oxidase type A is significant at >10 mg/day) increase therisk of serotonin syndrome when used in patients receiving SSRIs, SNRIs,

292C



Table 9–3. Neurological drug–psychotropic drug interactionsMedication Interaction mechanism Effect on psychotropic drugs and management

Anticonvulsants

Carbamazepine, phenobarbital, phenytoin

Induction of CYP 1A2, 2C9/19, and 3A4, and of UGT

Increased metabolism and decreased levels of clozapine, olanzapine, buspirone, benzodiazepines (except oxazepam, lorazepam, and temazepam), pimozide, trazodone, and zolpidem

Ethosuximide Induction of CYP 3A4 Increased metabolism and decreased levels of buspirone, benzodiazepines (except oxazepam, lorazepam, and temazepam), pimozide, trazodone, and zolpidem

Felbamate, fosphenytoin QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium

Valproate Inhibition of urea cycle Hyperammonemia with topiramate (also a urea cycle inhibitor)

Antiparkinsonian medications

Levodopa Additive psychotogenic effect Erosion of antipsychotic control of psychosis

Amantadine QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium

Additive psychotogenic effect Erosion of antipsychotic control of psychosis

Selegiline, rasagiline MAO-A inhibition at high dose (selegiline>10 mg/day)

Increased risk of serotonin syndrome when combined with SSRIs, SNRIs, mirtazapine, MAOIs, lithium, or TCAs

Central Nervo

us System

Disord

ers293

Pramipexole, ropinirole Additive hypotensive effects Increased risk of hypotensive effects with antipsychotics, TCAs, and MAOIs

Additive psychotogenic effect Erosion of antipsychotic control of psychosis

Cognitive enhancers

Donepezil, galantamine, rivastigmine

Cholinesterase inhibition Exacerbates extrapyramidal symptoms

Triptans Serotonin receptor agonist Serotonin syndrome (FDA black-box warning)

Note. CYP=cytochrome P450; FDA=U.S. Food and Drug Administration; MAO-A=monoamine oxidase A; MAOI=monoamine oxidase inhibitor;SNRI=serotonin–norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant; UGT=uridine5′-diphosphate glucuronosyltransferase.

Table 9–3. Neurological drug–psychotropic drug interactions (continued)Medication Interaction mechanism Effect on psychotropic drugs and management

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Table 9–4. Psychotropic drug–neurological drug interactionsMedication Interaction mechanism Effect on neurological drugs and management

AntidepressantsSSRIs

Fluoxetine, fluvoxamine

Inhibits CYP 1A2, 2C9/2C19, 3A4

Inhibited metabolism and increased levels and toxicities of CYP 1A2 substrates (rasagiline, frovatriptan, zolmitriptan, ropinirole), CYP 2C9 and 2C19 substrates (mephenytoin, phenytoin, tiagabine), and CYP 3A4 substrates (ergotamine, carbamazepine, ethosuximide, phenytoin, phenobarbital, tiagabine, zonisamide).

SNRIs and novel-action agentsBupropion,

venlafaxineReduced seizure threshold Increased risk of seizures and erosion of therapeutic effect of anticonvulsants. Avoid

bupropion at dosages >450 mg/day and high-dose venlafaxine.TCAs Reduced seizure threshold Increased risk of seizures and erosion of therapeutic effect of anticonvulsants. Avoid

clomipramine and maprotiline, especially at high dosages.QT prolongation Additive QT prolongation in combination with amantadine, felbamate, and

fosphenytoin. Consider QT-prolonging effects when selecting psychiatric and neurological medications.

MAOIsMoclobemide,

phenelzine, tranylcypromine

MAO inhibition Inhibition of triptans metabolized by MAO, including sumatriptan, rizatriptan, and zolmitriptan. Avoid combining these triptans with MAOIs. Consider almotriptan, eletriptan, frovatriptan, or naratriptan, which are metabolized by CYP enzymes.

Mood stabilizersValproic acid CYP 2C9 inhibition Increased levels of phenytoin, carbamazepine, phenobarbital, and primidone.

UGT inhibition Reduced metabolism and increased levels of entacapone and tolcapone.Lithium Reduced seizure threshold Increased risk of seizures and erosion of therapeutic effect of anticonvulsants.

Central Nervo

us System

Disord

ers295

QT prolongation Additive QT prolongation in combination with amantadine, felbamate, and fosphenytoin. Consider QT-prolonging effects when selecting psychiatric and neurological medications.

AntipsychoticsAtypical and

typical agentsDopamine receptor

blockadeExtrapyramidal symptoms. Worsening of Parkinson’s disease (except possibly with

low-dose clozapine).Reduced seizure threshold Increased risk of seizures and erosion of therapeutic effect of anticonvulsants. Avoid

clozapine and low-potency typical agents.Paliperidone,

quetiapine, risperidone, thioridazine, ziprasidone

QT prolongation Additive QT prolongation in combination with amantadine, felbamate, and fosphenytoin. Consider QT-prolonging effects when selecting psychiatric and neurological medications.

Clozapine Additive hematological toxicity

Increased risk of bone marrow suppression and agranulocytosis with carbamazepine.

Reduced seizure threshold Increased risk of seizures and erosion of therapeutic effect of anticonvulsants.PsychostimulantsAmphetamine,

atomoxetine (?), methylphenidate

Additive vasoconstriction

Dopamine receptor agonist

Excessive vasoconstriction, hypertension, and “ergotism” with triptans and ergot alkaloids.

Increased risk of psychosis with levodopa, amantadine, pramipexole, ropinirole.

Note. CYP=cytochrome P450; MAO=monoamine oxidase; MAOI=monoamine oxidase inhibitor; SNRI=serotonin-norepinephrine reuptake inhib-itor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant; UGT=uridine 5′-diphosphate glucuronosyltransferase.

Table 9–4. Psychotropic drug–neurological drug interactions (continued)Medication Interaction mechanism Effect on neurological drugs and management


mirtazapine, and TCAs (see Chapter 2, “Severe Drug Reactions”). The risk ofserotonin syndrome with rasagiline and serotonergic antidepressants is notknown. Triptans have a black-box warning of risk of serotonin syndrome incombination with serotonergic antidepressants; however, the frequency andclinical significance of this potential interaction has been questioned (Wenzelet al. 2008). Psychotogenic effects of dopamine agonists, topiramate, andlevetiracetam may erode the therapeutic effects of antipsychotics in patientswith schizophrenia. (For additional information, see Chapter 1, “Pharmaco-kinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions.”)

Key Clinical Points• Establishing a therapeutic relationship with the patient and fam-

ily is important. Patient and family education improves medica-tion compliance and side-effect reporting. Patients withcognitive impairment are at increased risk for noncomplianceand often inaccurately report symptoms and side effects.

• A comprehensive neuropsychiatric evaluation helps to under-stand the nature of the CNS disease, disease stage and timesince injury, and neuropsychiatric disturbances.

• Treatment of psychiatric target symptoms may need to be dis-ease specific, symptom specific, or both. Treatment can some-times be addressed by disease-specific treatments alone (e.g.,dopaminergic agents for mild depression in Parkinson’s disease;antiepileptic drugs for the treatment of ictal or peri-ictal psychi-atric symptoms).

• Psychotropics should be selected based on their pharmacokinet-ics, drug and disease interactions, and neurological side effects.

• The “start low, go slow” approach should be used, but dosagesshould be increased to clinically therapeutic levels. Althoughpolypharmacy should be minimized, augmentation with otheragents may be needed.

• Clinical response, side effects, and drug levels should be as-sessed frequently.

• Patients should be watched for increased susceptibility to neu-rological adverse effects of psychotropics, including extrapyrami-


dal symptoms, delirium, cognitive impairment, behavioraldisinhibition, excessive sedation, neuroleptic malignant syn-drome, and serotonin syndrome.

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10Endocrine and

Metabolic Disorders


Jennifer Kraker, M.D., M.S.

Disorders of the endocrine system are well known for their prominent psy-chiatric manifestations due to their interrelationship with the nervous system.Generally, correction of the underlying endocrine disorder will lead to im-provement in psychiatric symptoms; however, symptoms may persist beyondthe restoration of normal serum hormone levels, in which case psychophar-macological agents are often prescribed.

Three important clinical dimensions are covered in this chapter: 1) pri-mary endocrine disorders and their treatments may cause or exacerbate psy-chiatric symptoms via alterations of serum hormone levels (Table 10–1; seealso Table 10–4, later in this chapter); 2) psychiatric disorders may play a rolein endocrine dysregulation (e.g., depression exacerbates insulin resistance and


impairs glycemic control in diabetes); and 3) psychiatric medications oftencause endocrine side effects (see Table 10–2, later in this chapter).

In general, psychopharmacological treatment in the patient with endo-crine dysfunction must accompany correction of the underlying hormonedisorder. Psychopharmacological agents are generally prescribed when psychi-atric symptoms 1) predate the endocrine disorder, 2) present acute behavioraldysregulation as endocrine treatment is under way, or 3) persist after the en-docrine disorder is treated. No psychopharmacological treatment literatureexists for several endocrine disorders with psychiatric manifestations; the psy-chiatric symptom treatment literature focuses on correction of the hormonaldysfunction. These disorders, Cushing’s disease, Addison’s disease, andgrowth hormone disorders, are not covered explicitly in this chapter, and thereader is referred to standard endocrinology texts.

Diabetes Mellitus

Diabetes has significant associations with psychiatric disorders. Although esti-mates vary, rates of overall mental disorders, particularly anxiety and depres-

Table 10–1. Psychiatric symptoms of endocrine and metabolic disordersEndocrine/metabolic condition Psychiatric symptoms

Acromegaly (overproduction of growth hormone)

Mood lability, personality change

Addison’s disease Apathy, depression, fatigue

Cushing’s disease/syndrome Depression, anxiety, mania, psychosis

Diabetes Depression, anxiety, cognitive dysfunction

Hyperparathyroidism Depression, apathy, psychosis, delirium

Hyperprolactinemia Depression, anxiety, sexual dysfunction

Hyperthyroidism Anxiety, irritability, mania, apathy, depression, psychosis

Hypogonadism Decreased libido, low energy, low mood

Hypothyroidism Depression, psychosis, delirium, “myxedema madness”

Pheochromocytoma Anxiety, panic

Endocrine and Metabolic Disorders 307

sion, are 1.5–2 times higher among people with either Type 1 or Type 2diabetes than in the general population (Das et al. 2007). Patients with schizo-phrenia, independent of antipsychotic medication use, are 2–3 times morelikely than the general population to have Type 2 diabetes (M. Smith et al.2008), and up to 50% of patients with bipolar disorder and 26% of patientswith schizoaffective disorder have Type 2 diabetes (Regenold et al. 2002). Psy-chopharmacological treatments of psychiatric comorbidities may cause diabe-tes (see “Psychotropic-Induced Metabolic Syndrome” later in this chapter).

Differential diagnostic considerations for psychiatric symptoms in dia-betes include prior history of psychiatric disorder; acute mood and cognitiveeffects of hyperglycemia and hypoglycemia; cognitive and behavioral impair-ment resulting from central nervous system (CNS) microvascular disease; andcommon medical comorbidities and their treatments (e.g., cardiovascular, re-nal disease) that cause or exacerbate neuropsychiatric symptoms.

Depression

Depression in diabetes is associated with poor adherence to dietary and med-ication treatment; functional impairment; poor glycemic control; increasedrisk of diabetic complications, such as microvascular and macrovascular dis-ease; increased medical costs; and mortality (Ciechanowski et al. 2000; deGroot et al. 2001). Studies have examined whether treatment of depression isassociated with improved glycemic control, possibly through 1) improvementin adherence to diabetes treatment, 2) reversal of depression-induced physio-logical changes such as hypercortisolism, and/or 3) the potential direct eugly-cemic effects of antidepressant medication. Tricyclic antidepressants (TCAs)may have hyperglycemic effects, especially in the setting of weight gain; hydra-zine monoamine oxidase inhibitors (MAOIs) (tranylcypromine, pargyline)may have severe hypoglycemic effects; and selective serotonin reuptake inhib-itors (SSRIs) have modest hypoglycemic effects (Goodnick et al. 1996).

Several randomized controlled trials (RCTs) of antidepressant treatment ofdepression in patients with diabetes have focused on improvement in depres-sion and the impact of treatment on glycemic control, as measured by glyco-sylated hemoglobin (HbA1c). In a small RCT comparing nortriptyline withplacebo in diabetic patients with poor glycemic control, nortriptyline was sta-tistically superior to placebo in reducing depressive symptoms (Lustman et al.1997). Nortriptyline-treated patients reported more dry mouth. The authors


reported a statistical trend toward worsened glucose regulation in the sampleas a whole; however, this potential hyperglycemic effect was found only amongnondepressed participants. In general, TCAs may be helpful for patients withpainful diabetic peripheral neuropathy; however, the risks of weight gain andexacerbation of autonomic neuropathy (e.g., gastroparesis, postural hypoten-sion) are important considerations. In an RCT comparing fluoxetine with pla-cebo in patients with Type 1 or 2 diabetes with major depression, reduction indepressive symptoms and clinical response were significantly greater in the flu-oxetine-treated group than in the placebo group, with no difference in adverseeffects or glycemic control between groups (Lustman et al. 2000).

Maintenance antidepressant treatment is often necessary for depresseddiabetic patients. In the acute treatment studies cited above, neither of whichexceeded 8 weeks, as few as 4 in 10 diabetic patients with depression remainedwell after 1 year of successful treatment, approximately 15% had chronictreatment-resistant depression, and depression recurrence was associated witha decline in glycemic control (Lustman et al. 2006). In a multisite RCT com-paring sertraline maintenance (after initial open-label response) with placeboin prevention of depression recurrence, sertraline was superior to placebo(hazard ratio for recurrence 0.51, P=0.02) (Lustman et al. 2006). Time to re-currence was 4 times longer in the sertraline group than in the placebo group.Improvements in glycemic control seen during open-label treatment weremaintained in those whose depression remained in remission.

The Pathways Study examined whether enhancing quality of care for de-pression in primary care improved both depression and diabetes outcomes(Katon et al. 2004). Patients with diabetes and major depression and/or dys-thymia were randomly assigned to a stepped case management interventionor usual care. The intervention provided enhanced education and support ofantidepressant medication treatment or problem-solving therapy. After 1year, intervention patients showed greater improvement in adequacy of dos-age of antidepressant medication treatment, less depression severity, a higherrating of patient-rated global improvement, and higher satisfaction with care,but glycemic control did not differ between the two groups.

Anxiety

The association between diabetes and anxiety has been studied less thoroughlythan that between diabetes and depression, even though anxiety symptoms


and disorders may be more prevalent in patients with diabetes. A review of18 studies (N=4,076) found that 27% of individuals with diabetes had ananxiety disorder, and 40% reported subclinical anxiety symptoms (Grigsby etal. 2002). Like depression in patients with diabetes, anxiety is associated withpoor glucose control and an increase in the reporting of symptoms.

A 3-month RCT of alprazolam (maximum 2 mg/day) treatment of gen-eralized anxiety disorder showed a clinically significant reduction in anxietysymptoms and decreased HbA1C levels (Lustman et al. 1995).

Thyroid Disorders

Hypothyroidism

Subclinical to moderate hypothyroidism is often associated with depressivesymptoms. Profound hypothyroidism can produce psychosis (“myxedemamadness”), delirium, and catatonia. A corticosteroid-responsive encephalop-athy has been reported with Hashimoto’s thyroiditis, persistent antithyroidantibodies, and adequate thyroxine (T4) therapy (Fatourechi 2005). Symp-tomatic management with psychotropics may be required in these conditions;however, there is no guidance in the literature.

Some patients with hypothyroidism experience residual symptoms of lowmood, fatigue, and cognitive impairment while on stable T4 monotherapy.Some debate exists over the benefit of supplementing T4 with low doses oftriiodothyronine (T3). Most studies show no additional benefit to combina-tion treatment (Clyde et al. 2003; Wiersinga 2001), with the additional dis-advantage of thyrotoxic side effects (most commonly palpitations andanxiety). However, one crossover study in 33 patients with hypothyroidismgiven T4 monotherapy alternating with supplementation with low-dose (12.5μg/day) T3 showed benefit of the combination on several mood and cognitiveparameters, particularly in patients with thyroid cancer and treatment-induced hypothyroidism (Bunevicius et al. 1999). Little literature is availableon antidepressant treatment of patients with hypothyroidism. One case seriesof psychiatrically hospitalized depressed hypothyroid patients compellinglydocumented poor response to antidepressants and electroconvulsive therapywithout correction of serum T4 (Russ and Ackerman 1989). Treatment ofsubclinical hypothyroidism is controversial; however, T4 treatment to restore


thyroid-stimulating hormone (TSH) to normal levels has been found to im-prove both affective and cognitive symptoms (Baldini et al. 1997; Bono et al.2004).

Rapid cycling and lithium refractoriness has been associated with clinicaland subclinical hypothyroidism in patients with bipolar disorder, underscor-ing the need for thyroid monitoring and treatment (see “Lithium-InducedHypothyroidism,” later in this chapter).

Hyperthyroidism (Graves’ Disease)

Psychiatric symptoms of overt and subclinical hyperthyroidism includeheightened anxiety and mood symptoms and diminished quality of life(Gulseren et al. 2006). Of patients with hyperthyroidism, up to 58% are diag-nosed with anxiety and up to 38% with depressive disorders (Kathol andDelahunt 1986). Prior and current history of mania and hypomania have beenreported; however, their overall incidence is difficult to quantify (Brownlie etal. 2000; Bunevicius et al. 2005). Apathetic hyperthyrodisim, characterized byapathy, somnolence, psychomotor retardation, and cognitive impairment, hasalso been reported, particularly in elderly patients (Wagle et al. 1998). Finally,psychosis and acute encephalopathy can occur, perhaps related to high anti-thyroid antibody concentrations in the CNS (Barker et al. 1996).

Anxiety, affective, and cognitive symptoms usually remit within weeks tomonths after normalization of thyroid function (Kathol and Delahunt 1986).Some studies, however, report residual symptoms that require psychopharma-cological treatment (Fahrenfort et al. 2000).

Beta-blockers, particularly propranolol, are part of standard therapy forhyperthyroidism, targeting adrenergic symptoms of anxiety, tremor, palpita-tions, and tachycardia. High-dose propranolol (and perhaps some other, butnot all, beta-blockers) reduces the transformation of T4 to T3 (Wiersinga andTouber 1977), but this is probably not a major contribution to the drug’s clin-ical benefits. Lithium is an effective adjunct to antithyroid drugs and pro-pranolol in the treatment of hyperthyroid-induced mania (Brownlie et al.2000). Benzodiazepines are not recommended for long-term use, but onestudy documented benefit from the addition of the long-acting benzodiaz-epine bromazepam to antithyroid agents and propranolol for acute hyperthy-roid symptoms (Benvenga 1996). Antipsychotic medications are used for


severe agitation, mania, and psychosis, but no systematic data are available re-garding their use in thyrotoxicosis. Antidepressants for patients with Graves’disease have received little attention and should likely be reserved for persis-tent anxiety and depression after antithyroid treatment with normal serumthyroid levels.

Hyperparathyroidism

Psychiatric symptoms associated with hyperparathyroidism include fatigue,depression, and cognitive impairment; in rare cases, delirium, psychosis, andmania occur (S.W. Brown et al. 2007; Das et al. 2007; Roman and Sosa2007). Some studies of parathyroidectomy for patients with asymptomatichyperparathyroidism documented improvements in health-related quality oflife, depression, and neuropsychological testing (Roman and Sosa 2007; Ro-man et al. 2005; Wilhelm et al. 2004), but a large RCT found no benefit foroperative treatment over observation (Bollerslev et al. 2007). In one study,27% of patients taking antidepressants presurgically were able to discontinueantidepressant treatment, suggesting that a substantial number continued torequire antidepressant treatment after surgery (Wilhelm et al. 2004).

Pheochromocytoma

Pheochromocytoma has been associated with anxiety and panic symptoms;however, development of anxiety disorders per se is rare (Starkman et al.1990). Both TCAs and SSRIs have unmasked silent pheochromocytomas(Korzets et al. 1997; Lefebvre et al. 1995). The presumed mechanism ofTCAs is via inhibition of neuronal uptake of the high circulating levels ofcatecholamines (Korzets et al. 1997). MAOIs would be expected to be evenmore hazardous. The mechanism with SSRIs is less clear (Seelen et al. 1997).

Antidiuretic Hormone

The syndrome of inappropriate antidiuretic hormone (vasopressin) secretionis discussed in Chapter 2, “Severe Drug Reactions.” A discussion of lithium-induced nephrogenic diabetes insipidus appears in “Endocrinological SideEffects of Psychiatric Medications,” later in this chapter.


Reproductive Endocrine System Disorders

Disorders of the female reproductive endocrine system are discussed in Chap-ter 11, “Obstetrics and Gynecology.” Hyperprolactinemia is discussed in “En-docrinological Side Effects of Psychiatric Medications” later in this chapter.

Hypogonadal Disorders

Low serum testosterone, or hypogonadism, in men is associated with agingand many chronic illnesses. Hypogonadism may cause depressed mood, lowenergy, and sexual and cognitive dysfunction. Testosterone replacement inaging men is controversial; however, it has become commonplace in someillnesses, such as human immunodeficiency virus/acquired immunodefi-ciency syndrome (HIV/AIDS) (see Chapter 12, “Infectious Diseases”).

In randomized and open-label extension trials in hypogonadal men,transdermal testosterone and 1% testosterone gel replacement therapy wereassociated with positive effects on fatigue, mood (increased wellness, sociabil-ity, decreased anger, anxiety, irritability), and sexual function, as well as withsignificant increases in sexual activity (Burris et al. 1992; McNicholas et al.2003; Sih et al. 1997; Wang et al. 2004). Two RCTs demonstrated efficacyfor testosterone gel and intramuscular injection augmentation of SSRI inmen with SSRI-refractory major depression (Pope et al. 2003; Seidman et al.2005). In an open-label trial in men with congestive heart failure and hypo-gonadism, depot testosterone (100 mg every other week) resulted in delayedtime to ischemia, improvements in mood, and reductions in total cholesteroland tumor necrosis factor-alpha (Malkin et al. 2004). However, this group ofresearchers observed contrasting results in a subsequent placebo-controlledtrial of testosterone transdermal patch therapy for exercise capacity and heartfailure symptom improvement (Malkin et al. 2006). In the latter study, noimprovement in mood or quality of life was noted, possibly due to lower se-rum levels of testosterone achieved by the transdermal patch compared withdepot injection used in the previous study.

Testosterone replacement therapy improved cognitive function in hypo-gonadal men with impaired verbal fluency (Thilers et al. 2006). In a double-blind RCT, community-dwelling older men receiving 15 mg/day of testoster-one via a scrotal patch showed improved spatial-constructional ability com-


pared with the placebo group (Janowsky et al. 1994). Other studies showedimproved short-term verbal and working memory improvements with testos-terone supplementation (Cherrier et al. 2001; Janowsky et al. 2000).

Psychiatric adverse effects of testosterone therapy are covered in “Psychi-atric Side Effects of Endocrine Treatments,” later in this chapter.

Endocrinological Side Effects of Psychiatric Medications

The endocrinological adverse effects of psychotropic medications, includingantidepressants, antipsychotics, and mood stabilizers, are summarized in Ta-ble 10–2.

Table 10–2. Endocrinological adverse effects of psychotropic drugsMedication Endocrinological adverse effect

Antidepressants

SSRIs or SNRIs Hyperprolactinemia, hypoglycemia (rare), hypothyroidism (rare)

TCAs Hyperglycemia

Tertiary amine TCAs(e.g., imipramine, amitriptyline,

clomipramine)

Hyperprolactinemia

Antipsychotics

Atypical and typical antipsychotics Hyperglycemia, hyperprolactinemia, hypogonadism

Mood stabilizers

Lithium Hypothyroidism, hyperthyroidism, nephrogenic diabetes insipidus

Carbamazepine Hypothyroidism, decreased FSH and LH, hypogonadism

Valproic acid Hypothyroidism, decreased FSH and LH, hyperandrogenism (women)

Note. FSH=follicle-stimulating hormone; LH=luteinizing hormone; SNRIs=serotonin–nor-epinephrine reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclicantidepressants.


Lithium Effects on the Thyroid

Lithium has multifaceted effects on the thyroid axis. Lithium interferes withthyroid uptake of iodine and the iodination of tyrosine, alters thyroglobulinstructure, and inhibits release of T4 (Lazarus 1998). These effects of lithiumcan be used clinically (but rarely are) to enhance the effectiveness of radioac-tive iodine when treating thyrotoxicosis (Bogazzi et al. 1999). Lithium in-creases TSH by decreasing T4 and T3 and by independently evoking anexaggerated TSH response to thyrotropin-releasing hormone. Exaggeratedelevation of TSH is probably the main cause of goiter formation, reported in3%–60% of lithium-treated patients (Lazarus 1998).

Lithium-Induced Hypothyroidism

Lithium-induced hypothyroidism develops in 5%–35% of patients treatedfor bipolar disorder. It presents with varying degrees of severity, from subclin-ical effects to myxedema. Women have three times higher risk than men ofdeveloping lithium-induced hypothyroidism within 2 years of initiating ther-apy (14% for women vs. 4.5% for men) (Johnston and Eagles 1999). Womenwho were 40–59 years of age had the highest risk, with an incidence of 20%.Subclinical hypothyroidism is more prevalent than clinical hypothyroidism inpatients undergoing lithium therapy. In one study of 132 outpatients receiv-ing lithium therapy, 39% had subclinical hypothyroidism versus 3% withclinical hypothyroidism (Deodhar et al. 1999).

There are various risk factors for the development of lithium-inducedhypothyroidism. These include female sex (Ahmadi-Abhari et al. 2003), pre-existing vulnerability to autoimmune thyroiditis (Baethge et al. 2005), first-degree relatives with thyroid anomalies (Kusalic and Engelsmann 1999), in-creased duration of treatment, age older than 50 years (Ozpoyraz et al. 2002),and weight gain of more than 5 kg while receiving treatment (Caykoylu et al.2002).

Screening for thyroid dysfunction via measurement of TSH should occurprior to initiating lithium therapy. TSH should be reassessed 3 months intotreatment. If TSH is normal, follow-up every 6–12 months is suggested whilethe patient is undergoing lithium therapy. A mild increase in TSH and a de-crease in T4 may be seen during the first few months of treatment; these ef-fects are usually self-limited, and T4 replacement is unwarranted (Maarbjerg


et al. 1987). If clinically significant hypothyroidism develops or subclinicaleffects persist after 4 months of lithium treatment, T4 replacement or a switchto an alternative mood stabilizer (e.g., valproate) is recommended (Kleiner etal. 1999).

Lithium-Induced Hyperthyroidism

Cases of hyperthyroidism have occurred with lithium treatment (Brownlie etal. 1976) but less commonly than hypothyroidism and goiter. Because lith-ium is best known for inducing hypothyroidism and has even been used totreat refractory hyperthyroidism, it seems paradoxical that lithium can inducehyperthyroidism (Bogazzi et al. 1999; Lazarus et al. 1974). The prevalence isless well studied, but estimates suggest that approximately 1%–2% of patientstreated with lithium develop hyperthyroidism (Caykoylu et al. 2002). Lith-ium-induced thyrotoxicosis may be missed because it is often transient,asymptomatic, and followed by hypothyroidism (Stowell and Barnhill 2005).

Lithium-induced or exacerbated autoimmune thyroiditis is the likely ex-planation for hyperthyroidism. Also, because lithium is concentrated withinthe thyroid, it is postulated that lithium might directly damage thyroid folli-cular cells, triggering release of thyroglobulin into the circulation and causingthyrotoxicosis (Mizukami et al. 1995).

Although no treatment guidelines are available for lithium-induced thy-rotoxicosis, a switch from lithium to an alternative mood stabilizer is gener-ally necessary. In the interim, sedative-hypnotics, benzodiazepines, beta–blockers, and antipsychotic medications may be employed to treat the spec-trum of activation symptoms.

Lithium and Hyperparathyroidism

Hyperparathyroidism is an underrecognized side effect of long-term lithiumtherapy, and there is some support for routine screening of patients undergo-ing chronic lithium therapy for hypercalcemia (Saunders et al. 2009). Cessa-tion of lithium often does not correct the hyperparathyroidism, necessitatingparathyroidectomy. Although hyperparathyroidism is a risk factor for osteo-porosis, patients taking lithium who have normal calcium and parathyroidhormone levels do not have an increased risk of osteoporosis. One study evenfound that maintenance therapy with lithium carbonate may actually pre-serve or enhance bone mass (Zamani et al. 2009).


Lithium and Nephrogenic Diabetes Insipidus

Lithium impairs antidiuretic hormone–induced water reabsorption in thecortical and medullary collecting tubules of the kidney, resulting in nephro-genic diabetes insipidus (NDI). Lithium-induced NDI occurs in upward of15% of lithium-treated patients, being more prone to occur with higher dos-ages and longer treatment duration. Polydipsia and polyuria are observedclinically. In severe cases, dehydration, renal failure, and lithium toxicity mayoccur due to a combination of water diuresis and lithium-induced natriuresis.Confirmation of NDI requires a water deprivation test, followed by a vaso-pressin challenge. Inability to concentrate urine (greater than twofold increasein urine osmolality following 8-hour water deprivation) is suggestive of dia-betes insipidus. NDI is confirmed by no change in urine osmolality over 1–2hours following subcutaneous administration of 5 U vasopressin. The syn-drome generally remits from days to weeks after discontinuation of lithium.If lithium is continued, ample fluid intake is indicated. The potassium-spar-ing diuretic amiloride may be used to treat lithium-induced NDI. In additionto sparing potassium, amiloride causes less natriuresis, lithium reabsorption,and volume contraction compared with other diuretics, thus reducing therisks for lithium toxicity, dehydration, and renal failure (Boton et al. 1987).

Psychotropic-Induced Metabolic Syndrome

Antipsychotics, both typical and atypical, are associated with metabolic syn-drome (American Diabetes Association et al. 2004) TCAs, valproic acid, andlithium have also been implicated. Metabolic syndrome is defined by five crite-ria: abdominal obesity, triglycerides >150 mg/dl (>1.7 mmol/L), high-densitylipoprotein (HDL) <40 mg/dL (<1.03 mmol/L) for men or <50 mg/dL (<1.28mmol/L) for women, blood pressure >130/85 mm Hg, and fasting glucose>110 mg/dL (>6.0 mmol/L) (Expert Panel 2001). Metabolic syndrome is anindependent risk factor for diabetes (including ketoacidosis) and for cardiovas-cular, cerebrovascular, and peripheral vascular disease (Wilson et al. 2002).

All typical and atypical antipsychotics have a U.S. Food and Drug Admin-istration black-box warning that they may cause metabolic syndrome. The ex-tent to which metabolic syndrome is solely a function of antipsychotictreatment is controversial. Compared with the general population, medica-tion-naïve patients with schizophrenia, bipolar disorder, and schizoaffective


disorder have been found to have impaired glucose tolerance (Cohen et al.2006; Ryan et al. 2003). Overall, the development of metabolic syndrome islikely caused by inherent susceptibility, lifestyle, diet, and medication effects.

Generally, antipsychotic-induced metabolic changes are proportional toweight gain, which has been related to blockade of histamine H2 and 5-hydroxytryptamine (5-HT; serotonin) 2C receptors and to increased levels ofinsulin and leptin (Nasrallah 2003). Prospective data show mean weightincreases during the first year of therapy of 6–12 kg for patients taking cloza-pine, 3–12 kg for olanzapine, 2–4 kg for quetiapine, and 2–3 kg for risperi-done. Aripiprazole and ziprasidone are weight neutral. Elevations in serumtriglycerides and low-density lipoprotein (LDL) cholesterol as well as dimin-ished HDL cholesterol usually occur in parallel, but these changes may existin the absence of weight gain.

Patients taking antipsychotics should be monitored for weight gain,hypertension, glucose intolerance, and lipid derangements. Guidelines for pa-tient monitoring are summarized in Table 10–3.

Treatment of metabolic syndrome begins with dosage adjustment whenthis has been shown beneficial (e.g., olanzapine) or cross-tapering to a moreweight-neutral medication (e.g., aripiprazole, ziprasidone, molindone). Tech-niques including dietary education, exercise, and cognitive-behavioral inter-ventions have been found in RCTs to be effective for either maintaining orlosing weight in patients treated with atypical antipsychotics. Several RCTshave documented modest benefits from the addition of metformin (500–850mg/day in divided doses) to an antipsychotic regimen for reducing or pre-venting weight gain and insulin resistance (Baptista et al. 2007; Klein et al.2006; Wu et al. 2008).

Hyperprolactinemia

Hyperprolactinemia is a relatively common side effect of antipsychotics. Themain physiological action of prolactin is to initiate and maintain lactation.Dopamine D2 receptors of the pituitary lactotrophs, when activated by dopa-mine, suppress prolactin gene expression and lactotroph proliferation. Normalranges of serum prolactin have an upper limit of 10 ng/mL for men and 15 ng/mL for women. Hyperprolactinemia is generally defined as prolactin>20 ng/mL (20 μg/L SI units), and may be physiological or pathogenic.

318C



Table 10–3. Consensus guidelines for monitoring metabolic status in patients taking antipsychotic medicationsMetabolic risk parameter Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years

Personal/family history of DM, CVD X X

Weight (BMI) X X X X X

Waist circumference X X

Blood pressure X X X

Fasting plasma glucose X X X

Fasting lipid profile X X X

Note. BMI=body mass index (weight in kg/[height in m]2); CVD=cardiovascular disease; DM=diabetes mellitis.Source. Reprinted from American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al.: “Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes.” Diabetes Care 27:596–601, 2004. Copyright 2004, American Diabetes Association. Used with permission.


Hyperprolactinemia may cause impotence, menstrual dysregulation, infer-tility, and sexual dysfunction, primarily via inhibition of the pulsatile secretionof gonadotropin-releasing hormone (Bostwick et al. 2009). Symptoms of sex-ual dysfunction for men include loss of libido and erectile and ejaculatory dys-function (Holtmann et al. 2003); for women, symptoms include loss of libidoand anorgasmia (Canuso et al. 2002). Elevated prolactin may also give rise togalactorrhea and gynecomastia (Windgassen et al. 1996). Emerging evidencesuggests long-term sequelae, including loss of bone mineral density, increasingthe risk for osteoporosis (O’Keane and Meaney 2005), breast cancer (Tworogerand Hankinson 2006), and cardiovascular disease (Serri et al. 2006).

Antipsychotics are the most common drug-induced cause of hyperpro-lactinemia, but antidepressants, opioids, antiemetics, and antihypertensivesmay also be causal. An increase in serum prolactin usually occurs within hoursof initiation of antipsychotic medication (Goode et al. 1981). Prolactin levelsare not higher in treatment-naïve psychiatric patients than in healthy controlsubjects (Rao et al. 1994). Although there are reports of drug-induced hyper-prolactinemia with serum concentrations of prolactin exceeding 200 ng/mL,this degree of elevation is rare, and other causes of hyperprolactinemia shouldbe explored. Risk factors for drug-induced hyperprolactinemia include in-creased potency of D2 blockade, female sex, and increased age (Kinon et al.2003). Additionally, an increased risk is identified in those with the cyto-chrome P450 (CYP) 2D6*10 allele (Ozdemir et al. 2007).

Risk for hyperprolactinemia with antipsychotics and antiemetics is pro-portional to potency of D2 receptor blockade. Generally, the phenothiazineand butyrophenone antipsychotics and risperidone carry the greatest risk(Bushe and Shaw 2007). Haloperidol raises the serum prolactin concentrationby an average of 17 ng/mL, whereas risperidone may raise it by 45–80 ng/mL,with larger increases in women than in men (David et al. 2000). The atypicalantipsychotics olanzapine and quetiapine carry modest risk, and ziprasidoneand aripiprazole are low risk (Crawford et al. 1997; Zhong et al. 2006). Anti-emetics, such as prochlorperazine, metoclopramide, and trimethobenzamide,have also been reported to cause hyperprolactinemia and galactorrhea. Sero-tonergic antidepressants, including SSRIs, serotonin–norepinephrine re-uptake inhibitors (SNRIs), trazodone, tertiary amine TCAs, and MAOIs,have also been reported to cause hyperprolactinemia and galactorrhea, likelydue to serotonin-mediated dopamine antagonism (Molitch 2008).


Little emphasis has been placed on monitoring and management of psy-chotropic-induced hyperprolactinemia. Current American Psychiatric Associa-tion guidelines recommend routine monitoring of prolactin serum levels onlyin symptomatic patients (Lehman et al. 2004). However, patients may not beaware of their symptoms or may be reluctant to address them. In light ofemerging evidence of long-term risk for breast cancer, osteoporosis, and cardio-vascular disease, the prudent course is to monitor chronically treated patientsfor symptoms and serological evidence of hyperprolactinemia, perhaps in con-junction with other metabolic parameters, as outlined earlier in this chapter.

Currently, limited data are available to offer insight on an optimal ap-proach to the management of hyperprolactinemia. Treatment strategies in-clude 1) decreasing the dosage of the offending agent, 2) changing medicationto an agent less likely to affect prolactin, 3) using a dopamine agonist such asbromocriptine or a partial agonist such as aripiprazole, and 4) preventinglong-term complications of hyperprolactinemia such as bone deminerali-zation. A recent open-label study (N=27) of either augmentation with orswitching to aripiprazole showed a significant decrease in prolactin and an im-provement in sexual dysfunction (Mir et al. 2008). Treatment with a dopa-mine agonist such as bromocriptine (5–10 mg/day) is controversial due to riskfor exacerbation of psychosis and questionable efficacy (S. Smith 1992). Noreports have been published on the effects of hormone replacement on bonemineral density in patients taking antipsychotics long term, but preliminarydata suggest that active management of bone loss in those with antipsychotic-associated bone disease may halt or even reverse this process (O’Keane 2008).

Psychiatric Side Effects of Endocrine TreatmentsPsychiatric symptoms of endocrine disorders are manifestations of hormonetoxicity or deficiency syndromes described previously in this chapter. How-ever, hormone treatments used for reasons other than mere correction of de-ficiency (e.g., corticosteroids, nonhormonal medications that treat endocrinedisorders) may also cause psychiatric side effects (see Table 10–4).

Oral Hypoglycemic Medications

The psychiatric side effects of oral hypoglycemic medications are secondaryto their hypoglycemic effect. Psychiatric symptoms include most prominently


anxiety, dysphoria, irritability, and confusion. Such effects could be exacer-bated in severely depressed patients with anorexia.

Antithyroid Medications

Carbimazole, methimazole, and propylthiouracil have not been documentedto cause psychiatric side effects.

Corticosteroids

Exogenous corticosteroids (e.g., hydrocortisone, cortisone, prednisone, me-thylprednisolone, dexamethasone) and adrenocorticotropic hormone are wellknown to cause a range of neuropsychiatric side effects (Warrington and

Table 10–4. Psychiatric adverse effects of endocrinological/hormonal treatmentsMedication Psychiatric adverse effect

Steroid hormones

Corticosteroids Mania, anxiety, irritability, psychosis (acute), depression (chronic)

Testosterone and other anabolic/androgenic steroids (especially supraphysiological levels)

Irritability, mania, psychosis

Oral hypoglycemics

Sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides

Anxiety, depression, irritability, cognitive impairment (secondary to hypoglycemia)

Antithyroid medications

Carbimazole, methimazole, propylthiouracil

None reported

Dopamine agonists

Bromocriptine, cabergoline Psychosis, hallucinations

Growth hormone–inhibiting hormones

Somatostatin, octreotide, lanreotide Sleep disruption

Pegvisomant None reported

Growth hormone

Recombinant human growth hormone Insomnia, fatigue


Bostwick 2006). Approximately 13%–62% of patients experience transientmild to moderate symptoms that do not reach severity or duration criteria forpsychiatric disorder (Lewis and Smith 1983). These include activation symp-toms, such as anxiety, insomnia, and irritability, and mood symptoms, suchas dysphoria, euphoria, and lability. More serious corticosteroid-induced psy-chiatric disorders occur in approximately 3%–6% of patients. Althoughmood disorders are most common, about 1 in 6 patients seen psychiatricallyexperiences delirium or psychosis (Boston Collaborative Drug SurveillanceProgram 1972; Wada et al. 2001). Suicidal ideation can occur. High-dose,short-term administration is most often associated with manic spectrum dis-orders, whereas chronic therapy is most often associated with depression (Bol-anos et al. 2004). Impairments in long-term recall of verbal information havebeen reported in optic neuritis and multiple sclerosis patients receiving high-dose glucocorticoids; however, attentional and working memory function re-main intact, and impairments reverse within 5 days of cessation of treatment(Brunner et al. 2005). Although prior psychiatric history, particularly mania,and prior steroid-induced psychiatric disorders are generally considered clin-ical risk factors, these have not been adequately addressed in the literature.

Successful prophylaxis against steroid-induced neuropsychiatric reactionshas been reported for lithium (Falk et al. 1979), valproic acid (Abbas andStyra 1994), lamotrigine (Preda et al. 1999), and chlorpromazine (Bloch etal. 1994). Falk et al. (1979) initiated lithium carbonate (serum levels 0.8–1.2mEq/L) concurrently with adrenocorticotropic hormone in 27 patients withmultiple sclerosis and optic neuritis. None experienced affective or psychoticsymptoms, but 14% of a matched sample of 44 patients had severe mood dis-order with psychosis. The existing evidence is not sufficient to recommendprophylaxis for all patients receiving high-dose corticosteroids; however, pro-phylaxis may be warranted for patients with prior adverse psychiatric reac-tions to steroids.

In a patient with an active corticosteroid-induced mood disorder, tapereddiscontinuation or reduction to minimal effective dosage is recommended,based on status of the underlying illness. Literature on psychopharmacologi-cal treatment of corticosteroid-induced mood and psychotic disorders has fo-cused on TCAs, SSRIs, mood stabilizers, and antipsychotics. In case reportsor series, imipramine, amitriptyline, and doxepin benefited depressive symp-toms (Warrington and Bostwick 2006); however, caution may be warranted


because agitation and psychosis have been reported (Malinow and Dorsch1984). Fluoxetine, sertraline, and venlafaxine have also been reported benefi-cial in case series (Beshay and Pumariega 1998; Ismail and Lyster 2002; Ros2004; Wyszynski and Wyszynski 1993).

For corticosteroid-induced depression and mania, case reports have sup-ported use of antipsychotics, lithium, valproic acid, and carbamazepine (Hallet al. 1979; Kahn et al. 1988; Siegal 1978; Terao et al. 1997). Corticosteroid-treated patients taking lithium should be monitored closely for fluid and elec-trolyte status and lithium levels due to mineralocorticoid effects.

In a systematic review, steroid-induced manic and psychotic symptomsresponded to low-dose typical antipsychotics with cessation of symptoms in83% of patients, 60% of whom responded in less than 1 week and 80% inless than 2 weeks. Olanzapine in dosages of 2.5–15 mg/day has been reportedin a case series (Goldman and Goveas 2002) and an open-label trial (E.S.Brown et al. 2004) to be beneficial for patients with multiple underlying ill-nesses and steroid-induced mixed and manic episodes. Olanzapine and otherantipsychotic exacerbation of weight gain and insulin resistance in conjunc-tion with corticosteroid use should be monitored.

Rapid tapering or discontinuation of corticosteroids can also induce acorticosteroid-withdrawal syndrome. Corticosteroid-withdrawal syndrome ismanifested by headache, fever, myalgias, arthralgias, weakness, anorexia, nau-sea, weight loss, and orthostatic hypotension, and sometimes by depression,anxiety, agitation, or psychosis (Wolkowitz 1989). Symptoms respond to anincrease or resumption of corticosteroid dosage. Adjunctive treatment withantipsychotics, antidepressants, and mood stabilizers can be helpful, depend-ing on the particular psychiatric symptom constellation.

Testosterone

The most common adverse effects of testosterone replacement therapy (TRT)are acne and mild activation symptoms. Chronic administration may result intesticular atrophy and watery ejaculate. Although aggression (“steroid rage”) isa highly publicized effect of androgenic steroid administration, it most oftenoccurs in the context of supraphysiological dosing common among athletes(Pope et al. 1994). Only a small portion of eugonadal and hypogonadal menreceiving TRT develop aggression (O’Connor et al. 2001). Furthermore, in-creased aggressiveness in the depressed, treatment-refractory hypogonadal


male may reflect positive effects on vigor and energy (O’Connor et al. 2002).Rare cases of TRT-induced psychosis have been reported (Weiss et al. 1999).

Although not an adverse psychiatric effect, prostate cancer risk is a theo-retical concern among aging men receiving TRT. A longitudinal study ofTRT in elderly men found that prostate-specific antigen levels remained sta-ble after normalization of testosterone for ≥5 years, and the incidence of pros-tate cancer among men receiving TRT was no greater than in the generalpopulation (Coward et al. 2009). In women, there is concern regarding an-drogenic side effects and elevation of breast and endometrial cancer risk. Ingeneral, these adverse effects have not been supported by the literature and arefound only with sustained supraphysiological levels (Bitzer et al. 2008; Dimi-trakakis et al. 2004).

Growth Hormone (Somatotropin)

Psychiatric adverse effects with growth hormone treatment are infrequent.Pooled data from trials of growth hormone in HIV-associated adipose redis-tribution syndrome indicate higher rates of insomnia and fatigue comparedwith placebo (EMD Serono 2008).

Growth Hormone–Inhibiting Hormones

Both somatostatin and its long-acting analog, octreotide, have been found toreduce total sleep time and rapid eye movement (REM) sleep, particularly inelderly patients (Frieboes et al. 1997; Ziegenbein et al. 2004).

Dopamine Agonists

The dopamine agonists bromocriptine and cabergoline may cause psychosisand hallucinations. Chapter 9, “Central Nervous System Disorders,” coversthis topic. (See especially Table 9–4.)


Potential clinically significant interactions between psychotropic drugs andmedications used for endocrine disorders are listed in Tables 10–5 and 10–6.Clinically significant drug interactions are rarely reported in the literature,and many are speculative in nature (e.g., DeVane and Markowitz 2002). Datapresented are largely derived from information in product monographs.

Endo

crine and

Metab

olic Disord

ers325

Table 10–5. Psychotropic drug–endocrine drug interactionsPsychotropic drug Mechanism of interaction Endocrine drugs/classes affected Clinical effect(s)

AntidepressantsFluvoxamine,

sertralineCYP 2C9 inhibition Glimepiride, glipizide, glyburide,

nateglinide, rosiglitazone, tolbutamideReduced clearance of oral hypoglycemics;

potential enhanced hypoglycemic effectFluoxetine,

fluvoxamine, nefazodone

CYP 3A4 inhibition Nateglinide, pioglitazone, repaglinide Reduced clearance of oral hypoglycemics; potential enhanced hypoglycemic effect

MAOIs Stimulation of insulin release

Corticosteroids Increased steroid levels and adverse effects

TCAs Weight gain, insulin resistance

Insulin and oral hypoglycemics Possibly enhanced hyperglycemic effect

Unknown mechanism Augmentation of vasopressin effects Enhanced antidiuretic effectAll antidepressants Increased receptor

sensitivity to catecholamines

T3, T4 supplementation Increased activation, sympathetic autonomic symptoms

Mood stabilizersLithium Nephrogenic diabetes

insipidus via ADH inhibition in kidney

Corticosteroids, mineralocorticoids, vasopressin

Increased urination, serum osmolality, sodium, thirst

Antithyroid effects Thyroid hormone Undercorrection of hypothyroidismCarbamazepine,

phenobarbital, phenytoin

CYP 2C9 induction Glimepiride, glipizide, glyburide, nateglinide, rosiglitazone, tolbutamide

Possibly reduced levels and effectiveness of oral hypoglycemics

CYP 3A4 induction Nateglinide, pioglitazone, repaglinide Possibly reduced levels and effectiveness of oral hypoglycemics

326C



Induction of Phase 2 metabolism (UGT-sulfation)

T4 Increased hepatic T4 metabolism and decreased effect

Unknown mechanism Augmentation of vasopressin effects Enhanced antidiuretic effectAntipsychoticsTypical and atypical Weight gain, insulin

resistanceAntagonism of insulin and oral

hypoglycemicsPossibly enhanced hyperglycemic effects

Blockade of dopamine D2receptors

Hyperprolactinemia Sexual dysfunction, galactorrhea, gynomastia

Opioids Unknown mechanism Pegvisomant Reduced pegvisomant levels and clinical effect; increase dose with concurrent opioids

Note. ADH=antidiuretic hormone; CYP=cytochrome P450; MAOIs=monoamine oxidase inhibitors; TCAs=tricyclic antidepressants;T3=triiodothyronine; T4=thyroxine; UGT=uridine 5′-diphosphate glucuronosyltransferase.

Table 10–5. Psychotropic drug–endocrine drug interactions (continued)Psychotropic drug Mechanism of interaction Endocrine drugs/classes affected Clinical effect(s)

Endo

crine and

Metab

olic Disord

ers327

Table 10–6. Endocrine drug–psychotropic drug interactions

Endocrine drug Mechanism of interactionPsychotropic drugs/classes affected Clinical effect(s)

Growth hormone

Recombinant human growth hormone

CYP 3A4 induction Anticonvulsants, antidepressants, antipsychotics, benzodiazepines, opioids

Possibly reduced serum psychotropic levels and reduced therapeutic effects

Growth hormone inhibitors

Octreotide General reduction in CYP-mediated metabolism via growth hormone inhibition

All drugs undergoing oxidative metabolism

Possibly increased serum psychotropic levels and increased aftereffects

Note. CYP=cytochrome P450.


Key Clinical Points

• Hormone deficiency and excess states are most likely to be as-sociated with depression, anxiety, and cognitive impairment.

• Mania and hypomania occur predominantly with hyperthyroid-ism and with acute, high-dose corticosteroid therapy.

• Although psychosis is rare, it occurs with severe hypothyroidismand hyperthyroidism, hyperparathyroidism, and acute high-dosecorticosteroid therapy.

• For many endocrinological disorders, correction of the underly-ing hormone deficiency or excess generally improves psychiatricsymptoms.

• Psychiatric symptoms may persist beyond normalization of lab-oratory parameters.

• Successful psychopharmacological treatment generally requiresprior or concurrent correction of the underlying endocrinologicaldisorder.

• Psychotropic-induced endocrinological dysfunction is commonand should be routinely screened via symptom assessment andlaboratory testing. Examples of such dysfunction include lithium-induced hypothyroidism or nephrogenic diabetes insipidus, andantipsychotic-induced metabolic syndrome or hyperprolactine-mia.

• Because clinically significant psychotropic drug–endocrine drugor hormone interactions occur infrequently, these agents cangenerally be combined safely.

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339

11Obstetrics and Gynecology

Margaret Altemus, M.D.

Mallay Occhiogrosso, M.D.

The course of psychiatric illnesses in women is often modulated by repro-ductive events, including the menstrual cycle, pregnancy, lactation, and meno-pause. In addition, physiological changes during pregnancy, the postpartumperiod, and menopause can mimic psychiatric symptoms and should be con-sidered in a differential diagnosis. Several gynecological disorders and treat-ments can also affect psychiatric status. Conversely, psychiatric disorders andpsychopharmacological treatments can impact reproductive functions. Be-cause half of pregnancies are unintended and organ development occurs duringthe first trimester, it is usually too late to avoid teratogenic drug effects beforethe pregnancy is identified. Treatment of any woman of reproductive ageshould include a plan for birth control and consideration of possible drugeffects in the event of pregnancy.



Psychiatric Manifestations of Reproductive Conditions and Disorders

Psychiatric Manifestations of Menstrual Cycle and Fertility Disorders

Premenstrual dysphoric disorder (PMDD), which affects 3%–8% of men-struating women, is diagnosed if distinct mood and physical symptoms ap-pear only during the luteal phase of the menstrual cycle. PMDD must bedistinguished from premenstrual exacerbation of another psychiatric disor-der. Depression, obsessive-compulsive disorder, and bulimia are thought tointensify during the luteal phase, but schizophrenia seems to be exacerbatedin the early follicular phase of the cycle (Bergemann et al. 2007).

Polycystic ovarian syndrome, which affects 5%–10% of women of repro-ductive age, is associated with a three- to fourfold increased risk of depressionand an increased risk of anxiety disorders and binge eating disorder (Hol-linrake et al. 2007; Weiner et al. 2004). In women with comorbid polycysticovarian syndrome and affective illness, hyperandrogenism and insulin resis-tance should be controlled, particularly if the affective illness is treatment re-sistant (Rasgon et al. 2002). It is not known whether depression will resolvewithout psychiatric treatment if hormonal abnormalities are corrected.

Psychiatric Issues Related to Pregnancy

During the postpartum period, women have an increased risk of depression,panic (Sholomskas et al. 1993), and relapse of bipolar disorder (Viguera et al.2000). Postpartum relapse of bipolar disorder is often associated with psycho-sis and occasionally with infanticide or with symptoms of delirium. Thus, itis crucial to assess risk of bipolar illness in pregnant and postpartum depressedwomen, avoiding antidepressant monotherapy and sleep disruption.

Women with antithyroid antibodies (up to 15% of reproductive-agewomen) have a high risk of postpartum thyroiditis, which can precipitate orworsen symptoms of depression and anxiety. Free thyroxine and thyroid-stimulating hormone (TSH) should be checked in women presenting withpostpartum onset or worsening of depression or anxiety. Restless legs syn-drome often occurs during pregnancy and presents as insomnia.

Hyperemesis occurs in up to 2% of pregnant women. No psychiatric riskfactors have been identified, but the condition itself is a severe stressor, causing

Obstetrics and Gynecology 341

insomnia, fatigue, and often anticipatory anxiety. Anecdotal evidence suggeststhat mirtazapine may relieve nausea (Guclu et al. 2005). Benzodiazepines andtricyclic antidepressants (TCAs) have been suggested to target anticipatoryanxiety, but there is no evidence of efficacy.

Psychiatric Manifestations of Menopause

Researchers have reported an increased risk of first-onset depression (approx-imately twofold) (Cohen et al. 2006b; E. Freeman et al. 2006) and recurrentdepression (E. Freeman et al. 2004) during perimenopause, but not aftermenopause (Schmidt et al. 2004). No controlled studies have been done onthe effect of the menopausal transition on bipolar disorder or anxiety disor-ders; however, prevalence of anxiety disorders may increase in women afterage 45 years, suggesting a link to menopause (Wittchen et al. 1994).

Obstetric and Gynecological Manifestations of Psychiatric Disorders

Effects of Psychiatric Disorders on Menstrual Cycle and Fertility

Eating disorders disrupt menstrual cyclicity in proportion to energy deficitsbrought on by dieting and exercise. Major depression and bipolar disordermay contribute to reduced fertility (Williams et al. 2007), and depressionmay reduce success rates of in vitro fertilization (Smeek et al. 2001).

Effects of Psychiatric Disorders on Pregnancy and Fetus

Untreated mental illness can lead to maternal behaviors that can adversely im-pact the fetus, including substance use, insomnia, poor nutrition, poor com-pliance with prenatal care, and ambivalence about the pregnancy. Thesebehaviors may lead to reduced fetal weight gain and shortened gestation,which may have long-term impact on the endocrine systems, cognition, andmental health of offspring (Bergman et al. 2007; Malaspina et al. 2008; Talgeet al. 2007; Wadhwa 2005).

Depression during pregnancy seems to increase the risk of premature birthtwo- to threefold (Li et al. 2009; Wisner et al. 2009) and increases the risk ofpostpartum depression. Posttraumatic stress disorder also has been associatedwith premature birth (Rogal et al. 2007), and anxiety during pregnancy in-creases the risk of behavioral disorders in childhood (O’Connor et al. 2003).Compared with pregnant women without a psychiatric diagnosis, pregnant


women with schizophrenia show increased rates of fetal death (almost two-fold), placental abruption, interventions during labor and delivery, offspringwith congenital anomalies, and neonatal complications (Jablensky et al. 2005;Webb et al. 2005). Eating disorders and dieting during the first trimester havebeen associated with neural tube defects (Carmichael et al. 2003).

Effects of Psychiatric Disorders on Perimenopause

Premorbid anxiety predicts increased risk of vasomotor symptoms during themenopausal transition (E. Freeman et al. 2005; Gold et al. 2006). A historyof depression may predict earlier onset of menopause (Harlow et al. 2003).

Pharmacotherapy of Premenstrual Mood SymptomsPremenstrual Dysphoric Disorder

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrinereuptake inhibitors (SNRIs) are first-line agents for treatment of PMDD, andhave been shown effective when taken either throughout the cycle or only dur-ing the 2 weeks preceding menstruation (Rapkin and Winer 2008). Seroto-nergic antidepressants, including the TCA clomipramine, have been showneffective in several randomized controlled trials (Rapkin 2003). Dosing can berestricted only to symptomatic days to reduce side-effect burden. (Yonkers et al.2006). A novel oral contraceptive containing the progestin drospirenone, Yaz-24, has demonstrated efficacy for treatment of PMDD, but Yasmin, a 21-dayformulation with a lower dose of estradiol, is less effective (Rapkin and Winer2008). Some women experience PMDD while taking other 21-day hormonalcontraceptives (Bancroft and Rennie 1993). Gonadotropin-releasing hormoneagonists, which shut down the gonadal axis, are effective treatments forPMDD, but use is complicated by menopausal side effects. Luteal phase dosingof alprazolam also has been effective in controlled trials (Williams et al. 2007).

Premenstrual Exacerbations of Depression and Anxiety

Despite strong evidence of premenstrual exacerbation of affective illness, lim-ited studies have been done of potential changes in psychotropic drug metab-olism across the menstrual cycle. A common approach to premenstrualexacerbation of affective illness is to increase doses of antidepressants and lith-


ium premenstrually, but as yet only limited evidence of efficacy has beenshown for this approach (Miller et al. 2008).

Pharmacotherapy of Menopause-Related Depression, Anxiety, and Insomnia

Short-term hormone replacement therapy (HRT) can improve subclinical de-grees of depressed mood in perimenopausal women (Zweifel and O’Brien1997) and relieve unipolar major depression in perimenopausal but not post-menopausal women (Cohen et al. 2003; Morrison et al. 2004). Transdermalestradiol has been effective for major and minor depression during perimeno-pause at doses of 50–100 μg/day for 8–12 weeks; response rate was indepen-dent of comorbid hot flashes (Schmidt et al. 2000; Soares et al. 2001).Estrogen augmentation of antidepressant medication also may be effectiveduring perimenopause (Morgan et al. 2005). M. Freeman et al. (2002) re-ported that bipolar women who used HRT had less worsening of mood dur-ing perimenopause.

Vasomotor symptoms are associated with increased risk for depressionand insomnia, although insomnia is also exacerbated in perimenopausalwomen who do not experience hot flashes. Several psychotropic agents, in-cluding venlafaxine (100–150 mg/day) (Archer et al. 2009), paroxetine (10mg/day) (Stearns et al. 2005), and gabapentin (900–2,400 mg/day) (Toulis etal. 2009), can relieve hot flashes, but efficacy is less than that seen with estro-gen treatment. Treatment with the nonbenzodiazepine agents zolpidem andeszopiclone improved sleep, and in one of two studies also produced improve-ment in subclinical depression symptoms and vasomotor symptoms (Dorseyet al. 2004; Soares et al. 2006).

Psychopharmacology in Pregnancy and Breastfeeding

Approach to Pharmacotherapy During Pregnancy and Postpartum Period

Management of any psychiatric disorder during pregnancy and lactation iscomplicated by the need to consider the effects of psychiatric medication on


the fetus and newborn as well as the potential effects of untreated illness onfetal development (see Table 11–1). Pregnant and lactating women should usethe minimal number of medications at the lowest effective dosage. Updatedreviews for reproductive toxicity of specific drugs are available on the Internetthrough the U.S. National Library of Medicine’s (2009) Developmental andReproductive Toxicology (DART) Database and Motherisk (2009).

Recent prospective studies found that 68% of pregnant women who dis-continued antidepressant use because of pregnancy relapsed during the firstor second trimester (Cohen et al. 2006a), and 80% of women who discontin-ued mood stabilizers relapsed during pregnancy (Viguera et al. 2007b).Women with severe disease should continue their mood stabilizer or antide-pressant treatments during the first trimester and throughout pregnancy. Inwomen with mild disease and low relapse risk, the mood stabilizer or antide-pressant may be tapered off entirely or continued until pregnancy is achieved.Use of the lowest effective dose of psychotropics will lessen the adverse effectsof an abrupt taper. Abrupt cessation of mood stabilizers greatly increases therisk of relapse (50% within 2 weeks) compared with a gradual taper (Vigueraet al. 2007b). In women with moderate disease and/or relapse risk who re-spond best to lithium, which has teratogenic risk, an option is to slowly dis-continue lithium for conception and then restart lithium at 12 weeks, afterthe structural development of the fetus’s heart is complete. Monitoring of ma-ternal serum levels and dosage adjustment of medication is advised as preg-nancy progresses and during the early postpartum period, because serumlevels of lithium, TCAs, lamotrigine, and other psychotropics fall with preg-nancy-related increases in volume of distribution, metabolic capacity, and re-nal filtration. These changes reverse in the postpartum period, but timing isvariable, so monitoring is needed to guide dosage adjustments postpartum.

Electroconvulsive therapy is a safe, effective, and generally well-toleratedtreatment option for acute episodes of mania and severe depression duringpregnancy. During pregnancy, electroconvulsive therapy requires some mod-ification of standard techniques (Anderson and Reti 2009).


Teratogenicity. A 1998 review and meta-analysis of fetal exposure to ben-zodiazepines observed that estimates of risk of major malformations, includ-ing oral cleft, varied by study design (Dolovich et al. 1998). Pooled data from


cohort studies, which may include infrequent benzodiazepine users, showedno association between benzodiazepine use and risk of major malformationsor oral cleft. However, retrospective case–control studies, which are prone torecall bias, observed a threefold increased risk of oral cleft (Dolovich et al.1998). More recent large national birth registry studies have not found evi-dence of teratogenic risk when benzodiazepines are used as monotherapy, al-though two studies suggest a twofold increased risk of congenital heart defectsif an SSRI was also administered during pregnancy (Oberlander et al. 2008;Wikner et al. 2007). Several studies suggest an increased, but still very rare,risk of pyloric stenosis or alimentary tract atresia with first-trimester benzodi-azepine exposure (Bonnot et al. 2003; Juric et al. 2009; Wikner et al. 2007).For treatment of insomnia during pregnancy, zolpidem and the over-the-counter antihistamine diphenhydramine are frequently recommended, al-though almost no published studies exist on the safety of these agents(Wikner et al. 2007). One small case series of 39 women receiving gabapentinduring pregnancy did not show evidence of teratogenicity (Montouris 2003).

Restless legs syndrome develops in up to 30% of pregnant women. If irondeficiency is not a factor, treatment options include opioids, carbamazepine,and benzodiazepines (Djokanovic et al. 2008). Dopamine agonists, normallya first-line treatment for restless legs syndrome, should be avoided duringpregnancy because little is known about potential effects on the fetus.

Neonatal symptoms. If benzodiazepines are used late in pregnancy, infantsshould be closely monitored for neonatal adverse effects, including irritability,tremor, withdrawal seizures, floppy baby syndrome, and apnea and other res-piratory difficulties. Patients who wish to discontinue benzodiazepines duringpregnancy should taper gradually to avoid withdrawal effects on mother andfetus. Withdrawal symptoms can be long lasting in newborns. Short half-lifeagents with no active metabolites, such as lorazepam and oxazepam, are lesslikely to accumulate in the fetus.

Postnatal development. Hartz et al. (1975) found no differences in behav-ior at 8 months or IQ at 4 years in children exposed to chlordiazepoxide dur-ing gestation compared with children who were not. However, because littleis known regarding the effects of in utero benzodiazepine exposure on neu-robehavioral development, low doses and time-limited use are recommendedduring pregnancy.

346C



Table 11–1. Effects of psychiatric medications on fetus/infantMedication Pregnancy Neonatal Lactation

Anxiolytics

Benzodiazepines Teratogenic risk low. Sedation and withdrawal symptoms possible.

Little information.Use short-half-life agents (e.g.,

oxazepam).

Antidepressants

SSRIs Two- to threefold increased risk of prematurity.

Teratogenic risk low.Pulmonary hypertension risk

increased three- to sixfold.Placental transfer lowest for sertraline

and paroxetine and highest for citalopram, escitalopram, and fluoxetine.

Neonatal syndrome (irritability, high-pitched cry) for 2–7 days postpartum in up to 50% (more likely with paroxetine).

Transient respiratory difficulty (rare).

Infant generally has low exposure to SSRIs.

Lowest infant blood levels with paroxetine and sertraline.

Fluoxetine produces infant serum levels >10% of maternal in 10% of infants.

SNRIs Venlafaxine: limited data show no teratogenic risk.

Duloxetine: little data.

Neonatal syndrome. Venlafaxine metabolite present in infant serum.

Bupropion No evidence of teratogenicity. Generally undetectable levels in infant serum, but infant seizures have been reported.

TCAs Less data. No evidence of teratogenicity.

Neonatal syndrome with clomipramine.

Low infant serum levels with nortriptyline.

Obstetrics and

Gyn

ecology

347

Electroconvulsive therapy

Case reports of premature labor and placental abruption in 3rd trimester.

Antipsychotics Teratogenic risk low. Limited evidence.Weight gain promotes gestational

diabetes and other birth complications.

Cesarean section more likely.

Extrapyramidal symptoms; may be prolonged.

Large-for-gestational-age infant.Infant sedation.Abnormal muscle tone (transient).

Little evidence; olanzapine and risperidone preferred due to case reports of low infant serum levels.

Mood stabilizers

Lithium Increased risk of heart defect: 2%–8% for any heart defect, 0.1% for Ebstein’s anomaly.

Reports of neonatal hypothyroidism.

Infant serum levels 30%–50% of maternal; monitor for dehydration and thyroid function.

Carbamazepine Increased risk of neural tube defect but less than with valproate.

Infant serum levels 30% of maternal.

Lamotrigine Strong evidence of no increased risk. Infant serum levels 18% of maternal.

Valproic acid 1%–4% risk of neural tube defect.Increased risk of other abnormalities

including abnormal facies and cognitive impairment.

Risk of neonatal hepatic toxicity. Low concentration in breast milk.

Psychostimulants Limited data. No evidence of teratogenicity.

Note. SNRIs=serotonin–norepinephrine reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants.

Table 11–1. Effects of psychiatric medications on fetus/infant (continued)Medication Pregnancy Neonatal Lactation


Antidepressants

Teratogenicity. SSRIs are not associated with an increased rate of stillbirthsor major physical malformations (Wisner et al. 2009). Concerns of increasedrisk of cardiac defects following paroxetine use during pregnancy, whichprompted the U.S. Food and Drug Administration to issue a product warn-ing, have not been confirmed (Einarson et al. 2009). Risk of cardiac malfor-mations may be increased if SSRIs are combined with benzodiazepines(Oberlander et al. 2008; Wikner et al. 2007). An early report of increasedrates of minor physical malformations after fluoxetine exposure (Chambers etal. 1996) was not confirmed by several more recent studies (Wisner et al.2009). Teratogenic effects have not been found for venlafaxine, nefazodone,trazodone, mirtazapine (Einarson et al. 2009), or bupropion (Cole et al.2007). Although less formally studied, TCAs do not seem to be associatedwith birth defects.

In utero development. Several studies have reported a 1.7- to 3.5-fold in-crease in premature births with SSRI use (Chambers et al. 1996; Suri et al.2007; Wisner et al. 2009). Suri et al. (2007) observed increased risk of short-ened gestation, similar to the rate associated with untreated depression (see“Effects of Psychiatric Disorders on Pregnancy and Fetus,” earlier in chapter),with higher doses of SSRIs. This increased rate of premature delivery may berelated to a twofold increase in gestational hypertension and preeclampsiawith SSRI use during the second and third trimesters (Toh et al. 2009). Asmall reduction in birth weight for gestational age (30–100 g) in antidepres-sant-exposed infants has been observed in some but not all studies. An in-creased risk of pulmonary hypertension in offspring exposed to SSRIs duringthe third trimester of pregnancy has been reported in two studies (Chamberset al. 2006; Kallen and Olausson 2008), but two newer studies did not con-firm this finding (Andrade et al. 2009; Wichman et al. 2009). The positivefindings are controversial because of the small number of affected infants ineach study and the use of retrospective data collection in one study and reli-ance on prescription records in the other. Furthermore, the absolute risk re-ported was small: risk was raised in infants born after 34 weeks gestation froma baseline rate of 0.1% to 0.6% in one study and from a baseline rate of0.05% to 0.1% in the other. No associated fatalities were reported. Amongthe TCAs, nortriptyline and desipramine are preferred to minimize risk of


maternal orthostatic hypotension, which could compromise placental perfu-sion.

Neonatal syndromes. A neonatal syndrome has been associated with SSRIexposure in the third trimester. Symptoms can include difficulty feeding,tremor, high-pitched cry, irritability, muscle rigidity or low muscle tone, res-piratory distress, tachypnea, jitteriness, and convulsions. This syndrome,most common with paroxetine and fluoxetine, occurs in approximately 20%of SSRI-exposed infants, but usually lasts only a few days (Moses-Kolko et al.2005; Oberlander et al. 2006; Sanz et al. 2005). A similar neonatal syndromehas been described with in utero clomipramine exposure but not with expo-sure to other TCAs. Prenatal exposure to SSRIs is associated with transientQT prolongation in 10% of neonates (Dubnov-Raz et al. 2008).

Postnatal development. Cognitive function, temperament, and general be-havior were similar in children exposed prenatally to TCAs or fluoxetine andin unexposed comparison children in two studies (Nulman et al. 1997,2002). A recent larger study found small, transient delays in motor develop-ment in infants exposed to antidepressants in the second and third trimester(Pedersen et al. 2010).

Summary. Sertraline is a first-line antidepressant for use during pregnancy,as supported by a large amount of reassuring teratogenicity data for SSRIs(Wisner et al. 2009), evidence of less placental transfer for sertraline thanother SSRIs (Hendrick et al. 2003; Loughhead et al. 2006), lower risk for neo-natal withdrawal syndrome, and benign safety profile during lactation (seelater section “Approach to Psychopharmacotherapy During Breastfeeding”).

Antipsychotics

Teratogenicity. A prospective study based on the Swedish National BirthRegister found no increased rate of birth defects or adverse pregnancy out-comes in 2,260 nonpsychiatrically ill women taking the phenothiazinesdixyrazine or prochlorperazine for nausea and 570 women taking other anti-psychotics (Reis and Kallen 2008); these findings were supported by a secondstudy of phenothiazines administered to healthy women for hyperemesis(Sloane et al. 1977). Data from women using exclusively atypical antipsy-chotic drugs during pregnancy are limited (data are primarily for olanzapine,


clozapine, and risperidone, with less data on birth outcomes for ziprasidone,quetiapine, and aripiprazole), but do not point toward an increased risk of ter-atogenesis (Coppola et al. 2007; Diav-Citrin et al. 2005; Ernst and Goldberg2002; McKenna et al. 2005). A small study suggested that although all atyp-ical antipsychotics examined passed into the placental circulation, quetiapinehad the least and olanzapine the most placental transfer (Newport et al. 2007).

In utero development. Antipsychotic use during pregnancy is associatedwith other adverse birth outcomes. Among 570 women with psychiatric ill-ness taking a variety of antipsychotics, typical and atypical, the risk of gesta-tional diabetes was doubled and the risk of cesarean section was increased by40% (Reis and Kallen 2008). These women exposed to antipsychotics duringpregnancy had an increased rate of premature birth after controlling for smok-ing, body mass index, and maternal age. The effect of atypical antipsychoticson weight gain in pregnancy is not known but is of concern because obesityis associated with an increased rate of multiple birth defects, eclampsia, insulinresistance, and high birth weight (Newham et al. 2008; Waller et al. 2007).

Mood Stabilizers

Teratogenicity. Use of lithium in the pregnant patient has been associatedwith an overall 1.2- to 7.7-fold increase in fetal cardiac defects (Yonkers et al.2004), most of which are correctable and many of which resolve spontane-ously. The risk for the potentially severe Ebstein’s anomaly is increased 20-fold, but is still low (1 in 1,000 infants) (Giles and Bannigan 2006). With fe-tal exposure to lithium in the first trimester, ultrasonography or fetal echocar-diography to assess fetal cardiac development is advised. Use of sustained-release lithium preparations minimizes peak lithium levels, which may beprotective (Yonkers et al. 2004).

Use of antiepileptic agents in pregnancy has been studied mainly in pa-tients with epilepsy. Valproic acid is associated with a significantly increasedrisk of incomplete neural tube closure (1%–4%), cardiac defects, craniofacialabnormalities, and limb defects. Valproate exposure increases the rate of anycongenital malformation to 11%, versus 3.2% in nonexposed infants (Mea-dor et al. 2008). Risk increases with dosage and with combined anticonvul-sant therapy. Carbamazepine is also teratogenic, increasing the risk of neuraltube defects, facial dysmorphism, and fingernail hypoplasia, but the risk of


malformations is much lower than with valproate. The risk of any major mal-formation at birth is 4.6% with carbamazepine, compared with 3.2% in un-exposed infants (Meador et al. 2008). Overall, lamotrigine registry data todate indicate no increased risk of congenital malformations. An increased riskof oral clefts is reported from one registry (10-fold to 0.7%) (Holmes et al.2008) but not confirmed by data from other registries (Holmes et al. 2008)or a case control study (Dolk et al. 2008). Topiramate was not associated withany structural abnormalities in a small prospective study of 52 women (Or-noy et al. 2008). Another agent with more limited, but positive efficacy andsafety data is verapamil (Wisner et al. 2002). Insufficient data are available toassess oxcarbazepine’s teratogenicity.

Folate supplementation decreases the incidence of neural tube defects incarbamazepine-exposed pregnancies (Hernandez-Diaz et al. 2001) but not invalproate-exposed pregnancies (Wyszynski et al. 2005).

In utero development. Valproic acid exposure is associated with fetalgrowth restriction. Preliminary evidence suggests that topiramate reducesbirth weight but does not increase the risk of prematurity (Ornoy et al. 2008).

Neonatal syndromes. Lithium completely equilibrates across the placenta.Significantly lower Apgar scores, longer hospital stays, and higher rates of cen-tral nervous system (CNS) and neuromuscular complications were observedin infants with higher lithium concentrations (>0.64 mEq/L) at delivery.Withholding lithium therapy for 24–48 hours before delivery reduces mater-nal lithium levels by more than one-third (Newport et al. 2005). Symptomsof neonatal lithium toxicity include flaccidity, lethargy, and poor reflexes. Forthe mother, intravenous fluids are indicated at delivery to counterbalance ma-ternal blood volume contraction during delivery. Following delivery, theprepregnancy dosage should be resumed, with close monitoring for dosageadjustments as maternal fluid volume contracts.

Postnatal development. A 5-year follow-up of 60 children exposed to lith-ium in utero did not find evidence of neurobehavioral toxicity (Schou 1976).In utero valproic acid exposure has been clearly linked to a dose-dependentcognitive impairment, with IQ at 3 years reduced by 9 points and 6 pointscompared with children exposed to lamotrigine and carbamazepine, respec-tively (Meador et al. 2009).


Summary. Because of the significant risks to the fetus of valproic acid ex-posure, a switch to lithium, lamotrigine, carbamazepine, or an antipsychoticshould be considered.

Psychostimulants

Insufficient data are available to evaluate the teratogenic effects of the thera-peutic use of amphetamine, methylphenidate, modafinil, or atomoxetine dur-ing pregnancy. Two cohort studies of amphetamine administration for weightcontrol during pregnancy did not show an increase in the rate of malforma-tions. Animal studies, however, suggest the neurodevelopmental toxicity ofamphetamine exposure; stimulant medications should be avoided duringpregnancy, and behavioral and organizational therapeutic approaches shouldbe emphasized (U.S. Department of Health and Human Services 2005).

Approach to Psychopharmacotherapy During Breastfeeding

Concern about the exposure of breastfeeding infants to maternal medicationsleads women and their physicians to avoid medications, at times unnecessar-ily, and to avoid lactation. The clinician should put breastfeeding in context,giving the mother permission to forgo lactation if she requires a medicationthat poses a risk to the infant, or if the demands of breastfeeding are impedingher recovery. Infant exposure to medication can be reduced by replacingbreast milk with formula at some feedings. Long-term outcome data frommedication exposure during lactation are not available, but the long-termrisks of maternal depression on infants and older siblings are substantial andwell documented (Pilowsky et al. 2008).

Although the quantitative data on infant exposure to drugs throughbreast milk are limited, the exposure is, with some exceptions, orders of mag-nitude less than exposure during pregnancy. In general, milk concentrationsof medications and active metabolites are in equilibrium with maternal serumconcentrations. Infant exposure is also determined by maturation of theinfant’s metabolic systems, gut–blood barrier, and blood–brain barrier. Forexample, lamotrigine levels are relatively high in infant serum because the glu-curonidation metabolic pathway is inefficient in infants. For medicationstaken infrequently on an as-needed basis, half-life is an important consider-ation. Maternal serum and milk concentrations will be reduced by 75% after


2 half-lives. Therapeutic drug level monitoring in infants is of limited clinicaluse because serum levels associated with toxicity have not been established forinfants.

Online resources, including the U.S. National Library of Medicine’s(2009) Drugs and Lactation Database (LactMed), can provide more detailed,up-to-date information for specific drugs.


Limited information is available on the safety of benzodiazepines and thenewer nonbenzodiazepine sleep agents in lactating women, and no long-termexposure data are available. However, case reports of exposure to clonazepamsuggest low infant serum levels (Birnbaum et al. 1999). Exposed infantsshould be monitored for sedation and withdrawal. If sleep aids are necessaryfor mothers, agents with short half-lives (e.g., zolpidem and oxazepam) arepreferred. Nortriptyline, which has minimal serum levels in breastfed infants,also can be used to promote sleep in lactating women.

Antidepressants

Paroxetine, sertraline, citalopram, mirtazapine, and nortriptyline have mini-mal or undetectable circulating levels in breastfed infants. A few medications,including venlafaxine, fluoxetine, and doxepin, frequently produce infant se-rum levels of parent drug plus active metabolites that are greater than 10% ofmaternal serum levels, although these higher levels have not been linked toadverse outcomes (Weissman et al. 2004). One study found that infants ex-posed to fluoxetine during pregnancy and lactation had less weight gain afterbirth (Chambers et al. 1996). Although infant levels of bupropion and itsactive metabolite are reportedly low (Baab et al. 2002; Briggs et al. 1993),authors of two case reports described seizures in infants exposed to bupropion(Chaudron and Schoenecker 2004; “Bupropion” 2005).

Antipsychotics

Little research has focused on infants exposed to antipsychotic medicationsthrough breastfeeding. Based on case reports of infant serum levels, the Lact-Med database (U.S. National Library of Medicine 2009) notes that olanza-pine and risperidone have the best, although limited, evidence of low orundetectable infant serum levels and lack of adverse effects in the infant.


Mood Stabilizers

Lithium levels in breastfed infants average 25% of maternal levels, raising con-cerns of lithium toxicity should the infant become dehydrated or febrile(Viguera et al. 2007a). Signs of lithium toxicity in an infant are lethargy, poorfeeding, and hypotonia. Monitoring of lithium levels, blood urea nitrogen, cre-atinine, and TSH is indicated in exposed infants at 6-week intervals after the inutero contribution has been cleared. Use of infant blood sampling equipmentcontaining lithium heparin may produce spuriously high lithium levels.

Studies suggest very limited diffusion of valproic acid into breast milk, al-though one case of thrombocytopenia and anemia, which resolved after ces-sation of breastfeeding, has been reported (Stahl et al. 1997). Liver function,platelets, and valproic acid levels should be monitored in exposed infants.

Carbamazepine is present in infant plasma at concentrations averaging31% of maternal levels, and a few reports describe adverse events, including he-patic toxicity and poor feeding, in breast-fed infants (U.S. National Library ofMedicine 2009). Use of carbamazepine while breastfeeding should be ap-proached with caution, and infant serum levels, liver function, and completeblood count should be monitored.

Infant serum levels of lamotrigine have been found to be 18%–33% ofmaternal concentrations. No adverse effects, other than a case of mild throm-bocytopenia, have been reported in infants (Newport et al. 2008). Completeblood count and liver function should be monitored.

Psychostimulants

Amphetamine or methylphenidate can suppress prolactin release and thusmay inhibit lactation. Few data are available to evaluate infant exposure tomethylphenidate or other stimulants through breast milk. No data have beenpublished to guide use of modafinil or atomoxetine during lactation.

Adverse Obstetric and Gynecological Reactions to Psychotropic DrugsHyperprolactinemia

Hyperprolactinemia is a relatively common side effect of psychotropic drugs.A full discussion of this topic is provided in Chapter 10, “Endocrine and Met-abolic Disorders.”


Polycystic Ovarian Syndrome

Women receiving valproate have a 10% risk of developing polycystic ovariansyndrome, which often corrects on medication discontinuation (Joffe 2007).For premenopausal women starting to take valproate, menstrual cycle pat-tern, hirsutism, acne, and weight should be assessed at baseline and moni-tored closely, particularly during the first year of treatment, to detect devel-opment of polycystic ovarian syndrome.

Effects of Psychotropic Drugs on Sexual Function

SSRIs and SNRIs produce sexual side effects in 30%–70% of users. Womenexperience impairments in libido, genital sensitivity, and the ability to expe-rience orgasm. The biological mechanism responsible for these side effects isnot clear, but recent data suggest use of the phosphodiesterase type 5 inhibitorsildenafil on an as-needed basis to enhance ability to reach orgasm and sexualsatisfaction (Nurnberg et al. 2008). Antipsychotics, TCAs, and monoamineoxidase inhibitors (MAOIs) also can impair sexual function. No pharmaco-logical antidotes for these agents have been identified in controlled studies.

Psychiatric Adverse Effects of Obstetric and Gynecological Agents and Procedures

As discussed in the following subsections, a variety of obstetric and gyneco-logical medications and procedures have negative psychiatric effects. Table11–2 lists the psychiatric adverse effects of the medications.

Hormonal Contraceptives

Little systematic study has been done of the effects of hormonal contracep-tives on mood, but estimates suggest that 10%–21% of patients experienceadverse mood symptoms (Segebladh et al. 2009). A history of mood disordersor premenstrual mood symptoms has been linked to increased mood labilityand depressive symptoms during oral contraceptive use (Kurshan and Epper-son 2006; Segebladh et al. 2009). Hormonal contraceptives lower free tes-tosterone levels and may thereby reduce libido (Greco et al. 2007). Progestin-only contraceptives, recommended for lactating women because estrogen can


reduce milk supply, have been reported to cause psychiatric adverse effects,more commonly with subdermal and injectable than with oral formulations.

Infertility Treatment

Often during the course of artificial insemination, intrauterine insemination,and in vitro fertilization, medications are administered to stimulate ovarianfollicle development, producing supraphysiological levels of circulating estro-gen. Almost no systematic study has been done of the effects of ovarian stim-ulation on psychiatric disorders. In a retrospective survey, 40%–60% ofwomen treated with clomiphene or gonadotropins reported mood swings andirritability (Choi et al. 2005). In addition, there are case reports of manic andpsychotic reactions to clomiphene and gonadotropins, often in women withpreexisting mood disorders (Choi et al. 2005; Grimm and Hubrich 2007;Persaud and Lam 1998). Gonadotropin-releasing hormone agonists, oftenused to stop endogenous cycling for in vitro fertilization protocols, also cancause depression (Warnock et al. 2000). In light of these reports, womenprone to mood destabilization who are undergoing ovarian stimulation mayconsider remaining on antidepressant medication or a mood stabilizer at leastuntil pregnancy is achieved.

Table 11–2. Psychiatric adverse effects of obstetrics and gynecology drugsMedication Psychiatric adverse effect(s)

Hormonal contraceptives Increased mood lability and depressive symptoms

Beta-adrenergic agonists (systemic)

Terbutaline Anxiety

Galactogogues

Metoclopramide Anxiety, depression, and extrapyramidal symptoms

Gonadotropins Mood lability and irritability

Estrogen receptor modulators

Clomiphene Mood lability and irritability

Gonadotropin-releasing hormone agonists

Buserelin, goserelin, histrelin, leuprolide, nafarelin

Depression


Tocolytics

Beta-adrenergic agonists prescribed to halt premature labor, such as terbuta-line, can be anxiogenic (Hastwell et al. 1978).

Galactogogues

Agents commonly used to increase breast milk production include the herbalsupplement fenugreek and the dopamine antagonists metoclopramide anddomperidone, both of which enhance lactation by increasing prolactin re-lease. Domperidone (not available in the United States) has very limited CNSaccess and is without psychoactive effects. Metoclopramide acts centrally andperipherally and may cause clinically significant anxiety and depression andextrapyramidal symptoms (Anfinson 2002; Kluge et al. 2007).

Surgical or Medication-Induced Menopause

Ovariectomy or medical precipitation of menopause during treatment of en-dometriosis, fibroids, or breast cancer increases risk for hot flashes, depres-sion, anxiety, and sexual dysfunction compared with natural menopause andits more gradual drop in hormone levels (Aziz et al. 2005). Surgical meno-pause increases lifelong risk for anxiety, depression (Rocca et al. 2008), anddementia (Rocca et al. 2007), likely due to a longer lifetime exposure to re-duced hormone levels. Estrogen replacement therapy and the estrogen agonisttibolone improve anxiety in surgically menopausal women (Baksu et al.2005). Menopausal phenomenology and treatment were also discussed earlierin this chapter.

Hormone Replacement Therapy

Estrogen and progesterone are often administered at menopause for a rangeof physical symptoms, including hot flashes, osteoporosis, and vaginal dry-ness. A proportion of healthy women have adverse mood reactions to HRT,particularly the progestin components, and premorbid anxiety is a risk factorfor adverse mood reactions to combined HRT (Bjorn et al. 2006). Micron-ized progesterone, used in place of progestins, is speculated to have less ad-verse effects on mood. Cessation of HRT may also adversely affect mood insome women, but this possibility has not been well studied. The risk of de-mentia in women with surgical menopause may be attenuated by HRT initi-


ated prior to age 50 (Rocca et al. 2007). These findings are in contrast to theNational Institutes of Health–sponsored Women’s Health Initiative (WHI)study, which found that women initiating hormone therapy 10–15 years aftermenopause had increased risk for dementia (Shumaker et al. 2003). Althoughthe WHI study also found increased risk of breast cancer, heart disease,stroke, and pulmonary embolism with HRT, no studies have reported if med-ical risks increase in women who initiate HRT at onset of menopause.

Testosterone supplementation can improve sexual desire in menopausalwomen. However, because available formulations have much higher doses formen, low-dose preparations must be specially compounded for women (seealso Chapter 10, “Endocrine and Metabolic Disorders”).


A number of complex pharmacokinetic and pharmacodynamic interactionscan occur between psychotropic drugs and obstetrics and gynecology drugs(see Tables 11–3 and 11–4). See Chapter 1, “Pharmacokinetics, Pharmaco-dynamics, and Principles of Drug–Drug Interactions,” for a comprehensivediscussion.


A number of psychotropics, including carbamazepine, phenytoin, oxcarbaz-epine, armodafinil, modafinil, and St. John’s wort, induce cytochrome P450(CYP) 3A4, the principal enzyme involved in sex steroid metabolism. This in-creased metabolism may reduce the effect of oral contraceptives and the vag-inal ring (Thorneycroft et al. 2006). A survey and case series suggest anincrease in contraceptive failure in the presence of anticonvulsant medications(Krauss et al. 1996). Estrogen, in turn, increases glucuronidation reactionsthrough induction of uridine 5′-diphosphate glucuronosyltransferase. Forpsychotropic drugs primarily eliminated through conjugation (lamotrigine,oxazepam, lorazepam, temazepam, desvenlafaxine, and olanzapine), increasedclearance and reduced therapeutic effects have been observed. Estrogen-con-taining hormonal contraceptives reduce serum levels of lamotrigine by ap-proximately 50%. Lamotrigine dosage adjustments are also required with theonset or cessation of HRT (Harden et al. 2006). By increasing estrogen, treat-

Obstetrics and

Gyn

ecology

359Table 11–3. Obstetrics/gynecology drug–psychotropic drug interactions

Medication Interaction mechanism Effect(s) on psychotropic drugs and management

Beta-adrenergic agonists (systemic)Terbutaline

Additive hypertensive effect Increased risk of hypertension with MAOIs. Avoid concurrent use.

Estrogen-containing preparations

Induction of UGT Increased clearance and reduced therapeutic effect of drugs primarily eliminated through conjugation (e.g., desvenlafaxine, lamotrigine, lorazepam, olanzapine, oxazepam, temazepam). Estrogen in hormonal contraceptives reduces lamotrigine levels by 50%.

Domperidone, terbutaline QT prolongation Increased QT prolongation in combination with other QT-prolonging drugs such as TCAs, typical antipsychotics, lithium, pimozide, iloperidone, paliperidone, quetiapine, risperidone, and ziprasidone.

Domperidone Peripheral dopamine receptor antagonism

Increased hyperprolactinemia and galactorrhea with antipsychotics.

Metoclopramide Peripheral and central dopamine receptor antagonism

Increased EPS with antipsychotics, SNRIs, and SSRIs.Increased hyperprolactinemia and galactorrhea with antipsychotics.

Tamoxifen Inhibits CYP 2C9 Reduced phenytoin metabolism with increased toxicity.

Note. CYP=cytochrome P450; EPS=extrapyramidal symptoms; MAOIs=monoamine oxidase inhibitors; SNRIs=serotonin-norepinephrine reuptakeinhibitors; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants; UGT=uridine 5′-diphosphate glucuronosyltransferase.


ments that stimulate ovulation may also enhance glucuronidation (Reimerset al. 2005; Thorneycroft et al. 2006).


Several drugs used in obstetrics and gynecology, including terbutaline anddomperidone, prolong QT interval (Arizona Center for Education and Re-search on Therapeutics 2009). These agents should be used with caution inthe presence of other drugs that have QT-prolonging effects, such as TCAs,typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, que-tiapine, ziprasidone, and lithium (Kane et al. 2008; van Noord et al. 2009).Systemic beta-adrenergic agonist tocolytics, such as terbutaline, may precipi-tate a hypertensive crisis in combination with MAOIs. Metoclopramide mayincrease extrapyramidal symptoms when co-administered with antipsychot-ics, SSRIs, or SNRIs.

Table 11–4. Psychotropic drug–obstetrics/gynecology drug interactions

MedicationInteraction mechanism

Effect(s) on obstetrics/gynecology drug and management

Carbamazepine, oxcarbazepine, phenytoin

Armodafinil, modafinilSt. John’s wort

Induction of CYP 3A4

Increased metabolism of sex steroids. Reduced effect of oral contraceptives and vaginal ring. Surveys suggest increased risk of contraceptive failure.

Atomoxetine, bupropion, duloxetine, fluoxetine, moclobemide, paroxetine

Inhibition of CYP 2D6

Reduced bioactivation of prodrug tamoxifen. Decreased therapeutic effect.

Atypical antipsychotics: iloperidone, paliperidone, quetiapine, risperidone, ziprasidone

LithiumPimozideTCAsTypical antipsychotics

QT prolongation Increased QT prolongation in combination with other QT-prolonging drugs such as terbutaline and domperidone.

Note. CYP=cytochrome P450; TCAs=tricyclic antidepressants.


Key Clinical Points

Menstruating Women• All medications must be selected assuming the possibility of

pregnancy.• To distinguish PMDD from premenstrual exacerbation of an-

other psychiatric disorder, PMDD should be diagnosed with twocycles of prospective ratings and a diagnostic interview prior toinitiating treatment.

• SSRIs and the oral contraceptive Yaz-24 are effective treatmentsfor PMDD.

Pregnant Women• Untreated psychiatric illness carries a risk to mother and fetus.• Monotherapy with agents that have short half-lives is preferred.• The clinician should maximize use of alternative therapies to

pharmacotherapy, including psychotherapy and sleep hygiene.• Valproate should be avoided if possible due to teratogenic and

neurodevelopmental effects.

Lactating Women• Generally, infant exposure to psychotropic drugs through breast

milk is substantially lower than levels of exposure in utero. Lith-ium, carbamazepine, and lamotrigine are exceptions.

• Among antidepressants, sertraline and paroxetine have themost data supportive of safety during lactation.

Perimenopausal Women• Risk of first-onset depression and relapse of depression is in-

creased during perimenopause, but not after menopause.• Short-term hormone replacement therapy can relieve depres-

sion during perimenopause, but not after menopause.• Vasomotor symptoms respond to venlafaxine, paroxetine, and

gabapentin in some women, but response rates are much lowerthan with estradiol treatment.


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12Infectious Diseases




Psychiatric symptoms are part of many systemic and central nervous system(CNS) infections. Even limited infections may cause neuropsychiatric symp-toms in vulnerable patients, such as those who are elderly or who have preexistingbrain disease. In this chapter, we discuss bacterial, viral, and parasitic infectionswith prominent neuropsychiatric involvement, with a focus on human immu-nodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS).(Hepatitis C is covered in Chapter 4, “Gastrointestinal Disorders.”) Neuropsy-chiatric side effects of commonly used antibiotics, as well as drug–disease anddrug–drug interactions, are reviewed (see also Chapter 1, “Pharmacokinetics,Pharmacodynamics, and Principles of Drug–Drug Interactions”).


Bacterial Infections

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections

Pediatric autoimmune neuropsychiatric disorders associated with streptococ-cal infections (PANDAS) refers to a subset of obsessive-compulsive and ticdisorders that appear to have been triggered by an infection with group Abeta-hemolytic streptococci (GABHS). PANDAS is defined by onset ofsymptoms during early childhood; an episodic course characterized by abruptonset of symptoms with frequent relapses and remissions; associated neuro-logical signs, especially tics; and temporal association with GABHS infections(most commonly pharyngitis). Children with uncomplicated strep infectionstreated with antibiotics appear to have no increased risk for PANDAS (Perrinet al. 2004).

Although PANDAS is conceptualized as an autoimmune disorder, antibi-otics active against GABHS may be beneficial in reducing current symptoms(Snider et al. 2005). In children with recurrent streptococcal infections, anti-biotic prophylaxis to prevent neuropsychiatric exacerbations has yieldedmixed results. Whereas one double-blind, placebo-controlled trial found nobenefit of penicillin over placebo in preventing PANDAS exacerbations(Garvey et al. 1999), another trial found that either penicillin or azithromycinwas able to lower rates of recurrent streptococcal infections and to decreasePANDAS symptom exacerbations (Snider et al. 2005). Improvements inPANDAS symptoms have also been demonstrated in patients following useof plasma exchange and intravenous immunoglobulin. In one study, severityof obsessive-compulsive disorder symptoms diminished by 45%–58% fol-lowing treatment with either plasma exchange or intravenous immunoglobu-lin (Perlmutter et al. 1999). However, immunomodulatory therapies have notbeen recommended as a routine treatment for PANDAS.

Neuroborreliosis

Lyme disease is caused by the spirochete Borrelia burgdorferi. If untreated, pa-tients may develop chronic neuroborreliosis, including a mild sensory radic-ulopathy, difficulty with concentration and memory, fatigue, daytimehypersomnolence, irritability, and depression. These chronic symptoms are

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not distinctive but are almost always preceded by the classic early symptomsof Lyme disease. The differential diagnosis of neuroborreliosis in a patientpresenting with poorly explained fatigue, depression, and/or impaired cogni-tion includes fibromyalgia, chronic fatigue syndrome, other infections, so-matoform disorders, depression, autoimmune diseases, and multiple sclerosis.

Neither serological testing nor antibiotic treatment is cost effective in pa-tients who have a low probability of having the disease (i.e., nonspecificsymptoms, low-incidence region). Multiple controlled trials have found nobenefit of extended intravenous or oral antibiotics in patients with well-docu-mented, previously treated Lyme disease who had persistent pain, neurocog-nitive symptoms, dysesthesia, or fatigue (Kaplan et al. 2003; Klempner et al.2001; Krupp et al. 2003; Oksi et al. 2007). The only exception is a very small(N=37) placebo-controlled trial of 10 weeks of intravenous ceftriaxone in pa-tients with at least 3 weeks of prior intravenous antibiotics; moderate gener-alized cognitive improvement was seen at week 12 but was not sustained toweek 24 (Fallon et al. 2008). The consensus of experts is that chronic antibi-otic therapy is not indicated for persistent neuropsychiatric symptoms in pa-tients previously adequately treated for Lyme disease (Feder et al. 2007).

Neurosyphilis

Neurosyphilis is now the predominant form of tertiary syphilis and most fre-quently presents in immunocompromised patients. Symptoms include cog-nitive dysfunction including dementia, changes in personality, psychosis, andseizures. Intravenous penicillin G is the recommended treatment for all formsof neurosyphilis (Jay 2006). In some patients with dementia due to neuro-syphilis, the infection appears to have “burned out,” and they show no clinicalresponse to penicillin G. Multiple case reports but no controlled trials haveaddressed treatment of psychiatric symptoms associated with neurosyphilis. Arecent review recommended treatment of psychosis in neurosyphilis patientsusing the typical antipsychotic haloperidol or the atypical agents quetiapineor risperidone (Sanchez and Zisselman 2007). An anticonvulsant such as di-valproex sodium was also recommended for agitation and mood stabilization.Case reports have supported atypical antipsychotics, such as olanzapine andquetiapine, in treatment of neurosyphilis-associated psychosis (Taycan et al.2006; Turan et al. 2007).


Tuberculosis in the Central Nervous System

Tuberculosis of the brain, spinal cord, or meninges (CNS TB) is caused pri-marily by Mycobacterium tuberculosis and most often occurs in immuno-compromised patients. CNS TB may manifest with meningitis, cerebritis,tuberculomas, and abscesses. Seizures are common, and psychiatric symptomsinclude delirium, delusions, hallucinations, and affective lability. Corticoster-oids used to reduce inflammation and edema may exacerbate these symptoms(see Chapter 10, “Endocrine and Metabolic Disorders”). Antitubercularagents have been reported to cause multiple psychiatric adverse effects (see Ta-ble 12–1) and may be associated with significant interactions with psychotro-pic drugs (see Table 12–2). Literature on psychopharmacological treatment ofCNS TB is scant. Anticonvulsants are used for seizures and may treat affectiveinstability, whereas antipsychotics may be used for psychotic symptoms, withcaution exercised due to the risk of developing extrapyramidal side effects andlowering of the seizure threshold (Woodruff and Gleason 2002).

Viral Infections

HIV/AIDS

Substantial research data demonstrate the safety and efficacy of psychophar-macological treatments in patients with HIV/AIDS. Knowledge about differ-ential diagnosis, neuropsychiatric adverse effects of antiretrovirals, and drug–drug interactions are particularly important in the psychopharmacologicalmanagement of these patients.


The differential diagnosis of psychiatric symptoms in HIV/AIDS patients isextensive. HIV-infected patients have a higher prevalence of psychiatric dis-orders than the general population, with mood and anxiety disorders, sub-stance abuse, and cognitive disorders predominating (Bing et al. 2001;Ferrando 2000). Delirium, dementia, and manic spectrum disorders are com-monplace in the medically hospitalized patient with HIV/AIDS (Ferrandoand Lyketsos 2006).

Even though 60%–70% of patients with HIV have a history of psychiat-ric disorder prior to contracting HIV illness (Williams et al. 1991) and HIV


Table 12–1. Psychiatric adverse effects of antibiotic therapyMedication Neuropsychiatric adverse effect(s)

Antibacterials

Aminoglycosides Delirium, psychosis

Antitubercular agents

Cycloserine Agitated depression, psychosis, confusion

Ethambutol Confusion

Ethionamide (thiocarbamides) Depression, psychosis, sedation

Isoniazid (hydrazides) Insomnia, cognitive dysfunction, hallucinations, delusions, obsessive-compulsive symptoms, depression, agitation, anxiety, mania

Rifampin Drowsiness, cognitive dysfunction, delusions, hallucinations, dizziness

Beta-lactam agents

Cephalosporins Euphoria, delusions, depersonalization, visual illusions

Imipenem Encephalopathy

Lactam antibiotics Confusion, paranoia, hallucinations, mania

Penicillins Anxiety, illusions and hallucinations, depersonalization, agitation, insomnia, delirium, mania (amoxicillin)

Fluoroquinolones

Ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin

Class effects: psychosis, insomnia, delirium, mania

Macrolides

Clarithromycin, erythromycin Nightmares, confusion, anxiety, mood lability, psychosis, mania

Metronidazole Agitated depression, insomnia, confusion, panic, delusions, hallucinations, mania, disulfiram-like reaction

Quinolones Class effects: restlessness, hallucinations, delusions, irritability, delirium, anxiety, insomnia, depression

Sulfonamides

Trimethoprim/sulfamethoxazole, dapsone

Class effects: depression, mania, restlessness, irritability, panic, hallucinations, delusions, delirium, confusion, anorexia

Tetracyclines Class effects: memory disturbance


AntiviralsNucleoside reverse transcription

inhibitors

Abacavir Depression, suicidal ideation, psychosis, insomnia, fatigue

Didanosine Nervousness, agitation, mania, insomnia, dizziness, lethargy

Emtricitabine Depression, abnormal dreams, insomnia, dizziness

Interferon-alpha-2a Depression, suicidal ideation, anxiety, mania, psychosis, sleep disturbance, fatigue, delirium, cognitive dysfunction

Lamivudine Depression, insomnia, dizziness

Zidovudine Anxiety, agitation, restlessness, insomnia, mild confusion, mania

Non-nucleoside reverse transcription inhibitors

Delavirdine Anxiety, agitation, amnesia, confusion, dizziness

Efavirenz Anxiety, insomnia, depression, suicidal ideation, psychosis, vivid dreams/nightmares, cognitive dysfunction, dizziness

Nevirapine Vivid dreams/nightmares

Protease inhibitors

Atazanavir Depression, insomnia

Fosamprenavir Depression

Indinavir Anxiety, agitation, insomnia

Lopinavir/ritonavir Insomnia

Nelfinavir Depression, anxiety, insomnia

Ritonavir Anxiety, agitation, insomnia, confusion, amnesia, emotional lability, euphoria, hallucinations, decreased libido

Saquinavir Anxiety, agitation, irritability, depression, excessive dreaming, hallucinations, euphoria, confusion, amnesia

Tipranavir Depression

Table 12–1. Psychiatric adverse effects of antibiotic therapy (continued)Medication Neuropsychiatric adverse effect(s)


diagnosis or disease exacerbation may trigger relapse, it is essential to considerpotential medical etiologies. HIV-associated neuropsychiatric disorders canhave multiple cognitive as well as behavioral symptoms, including apathy,depression, sleep disturbances, mania, and psychosis (Ferrando 2000). CNSopportunistic infections (including cryptococcal meningitis, toxoplasmosis,progressive multifocal leukoencephalopathy) and cancers can also presentwith a wide range of behavioral symptoms, as a result of focal or generalizedneuropathological processes. Substance intoxication and withdrawal states arealso common, and preexisting psychopathology may be exacerbated by ongo-ing substance use (Batki et al. 1996). The high rate of polysubstance abusecomplicates the assessment of behavioral symptoms and presents the chal-lenge of treating mixed withdrawal states.

Antiretroviral and other medications used in the context of HIV havebeen associated with neuropsychiatric side effects (see Table 12–1). Most ofthese effects are infrequent, and causal relationships are often difficult to

Antiherpetics

Acyclovir, valacyclovir Visual hallucinations, depersonalization, mood lability, delusions, insomnia, lethargy, agitation, delirium

Other antivirals

Amantadine Insomnia, anxiety, irritability, nightmares, depression, confusion, psychosis

Foscarnet Irritability, hallucinations

Ganciclovir Nightmares, hallucinations, agitation

Antifungals

Amphotericin B Delirium, lethargy

Ketoconazole Somnolence, dizziness, asthenia, hallucinations

Pentamidine Confusion, anxiety, mood lability, hallucinations

Antihelmintics

Thiabendazole Hallucinations

Source. Compiled in part from Abouesh et al. 2002; “Drugs That May Cause Psychiatric Symp-toms” 2002; Sternbach and State 1997; Warnke et al. 2007;Witkowski et al. 2007.

Table 12–1. Psychiatric adverse effects of antibiotic therapy (continued)Medication Neuropsychiatric adverse effect(s)

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Table 12–2. Antibiotic drug–psychotropic drug interactionsMedication Mechanism of interaction Effects on psychotropic drug levels Potential clinical effect(s)

Antibacterials

Antitubercular agents

Isoniazid Inhibition of MAOI-A Increased potential for serotonin syndrome with SSRIs, SNRIs

Hypertensive crisis possible with TCAs, meperidine, tyramine-containing foods, OTC sympathomimetics, stimulants

Serotonin syndrome

Hypertensive crisis

Inhibition of CYP 2C19 and 3A4

Phenytoin levels increased Increased phenytoin effects and adverse effects

Carbamazepine levels increased Increased carbamazepine adverse effects

Benzodiazepine serum levels increased, except for oxazepam, lorazepam, and temazepam

May increase benzodiazepine effects

Rifampin, rifabutin (to a lesser degree)

Induction of CYP 3A4 Risperidone levels reducedSertraline levels reducedBenzodiazepine (especially midazolam and

triazolam) serum levels reduced, except for oxazepam, lorazepam, and temazepam

Reduced risperidone effectSertraline withdrawal symptomsMay reduce benzodiazepine effects

Phenytoin levels reduced Reduced phenytoin effects

Methadone levels reduced Reduced methadone effects and opioid withdrawal

Clozapine levels reduced Reduced clozapine therapeutic effects

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Morphine and codeine levels reduced Reduced analgesic effect

Zolpidem levels reduced (AUC reduced 73%)

Reduced hypnotic effect

Clarithromycin, erythromycin, telithromycin, troleandomycin

Inhibition of CYP 3A4 Benzodiazepine serum levels may increase, except for oxazepam, lorazepam, and temazepam

Buspirone levels increase (AUC increased sixfold)

May increase benzodiazepine levels and effects (sedation, confusion, respiratory depression)

May increase psychomotor impairment and buspirone adverse effects


Pimozide levels increased Increased pimozide effects, including hypotension, arrhythmias

Ciprofloxacin, norfloxacin

Inhibition of CYP 1A2 and 3A4



Methadone levels increased Increased methadone effects (sedation, respiratory depression)

Clozapine levels increased Increased clozapine effects

Olanzapine levels increased Increased olanzapine effects

Enoxacin Inhibition of CYP 1A2 Clozapine levels increased Increased clozapine effects

Olanzapine levels increased Increased olanzapine effects

Table 12–2. Antibiotic drug–psychotropic drug interactions (continued)Medication Mechanism of interaction Effects on psychotropic drug levels Potential clinical effect(s)

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Linezolid Inhibition of MAOI-A Increased potential for serotonin syndrome with SSRIs, SNRIs

Serotonin syndrome

Hypertensive crisis possible with TCAs, meperidine, tyramine-containing foods, OTC sympathomimetics, stimulants

Hypertensive crisis

Antivirals

Delavirdine Inhibition of CYP 3A4 and 2C9



Efavirenz Induction of CYP 2B6 Bupropion levels reduced (AUC reduced 55%)

Reduced bupropion effects

Induction of CYP 3A4 Phenytoin levels reducedCarbamazepine levels reduced (AUC

reduced 26%)

Reduced phenytoin effectsReduced carbamazepine efficacy

Buprenorphine levels reduced (AUC reduced 49%)

Possible reduced buprenorphine effects

Methadone levels reduced 30%–60% Reduced methadone effects and opioid withdrawal

Nevirapine Induction of CYP 3A4 Carbamazepine levels reducedMethadone levels reduced 30%–60%

Reduced carbamazepine efficacyReduced methadone effects and opioid

withdrawal


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General protease inhibitor interactions

Most protease inhibitors inhibit CYP 2D6 and 3A4

Exceptions include darunavir, fosamprenavir, and ritonavir, which induce CYP 2D6 and inhibit CYP 3A4; and tipranavir, which in itself is a CYP 3A4 inducer (see below)


Pimozide levels increased

Clozapine levels increased

Methadone levels reduced 16%–53%

Increased benzodiazepine levels and effects (sedation, confusion, respiratory depression)

Increased pimozide effects, including hypotension, arrhythmias

Increased clozapine effects and adverse effects

Reduced methadone effects and opioid withdrawal

Amprenavir Inhibition of CYP 3A4 Carbamazepine levels increased Increased carbamazepine adverse effects

Darunavir Induction of CYP 2D6 Paroxetine levels reduced (AUC reduced 39%)

Sertraline levels reduced (AUC reduced 49%)

Reduced paroxetine effects

Reduced sertraline effects

Inhibition of CYP 3A4 Trazodone levels increased (AUC increased 240%)

Increased trazodone adverse effects (nausea, dizziness, hypotension, syncope)

Fosamprenavir Induction of CYP 2D6 Paroxetine levels reduced (AUC reduced 39%)

Reduced paroxetine effect

Indinavir Inhibition of CYP 3A4 Trazodone levels increased Increased trazodone adverse effects (nausea, dizziness, hypotension, syncope)



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Lopinavir Inhibition of CYP 3A4 Trazodone levels increased (AUC increased 240%)


Possible induction of CYP 2C9

Phenytoin levels reduced Reduced phenytoin effects

Possible induction of UGT-mediated glucuronidation by lopinavir + ritonavir

Lamotrigine levels reduced (AUC reduced 50%)

Reduced lamotrigine effects

Nelfinavir Inhibition of CYP 2D6 and 3A4


Ritonavir Inhibition of CYP 2D6 initially, followed by induction of CYP 2D6 within a few days

Initial increase followed by long-term decrease in levels for sertraline, desipramine, amitriptyline, and other CYP 2D6 substrates

Reduced drug effects

Inhibition of CYP 3A4 Trazodone levels increased (AUC increased 240%)



Induction of CYP 1A2 Olanzapine levels reduced (AUC reduced 53%)

Reduced olanzapine effects

Clozapine levels reduced Reduced clozapine effects

Induction of CYP 2B6 Bupropion levels reduced Reduced bupropion effects


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Tipranavir Alone, tipranavir is an inducer of CYP 3A4; however, the combination with ritonavir is a CYP 3A4 inhibitor

Tipranavir alone: reduced bupropion (AUC reduced 46%) and carbamazepine levels

Tipranavir and ritonavir combination: increased bupropion and carbamazepine (AUC increased 24%) levels

Increased or reduced bupropion and carbamazepine effects and adverse effects

Fluconazole Inhibition of CYP 2C19 Amitriptyline and nortriptyline levels increased

Increased adverse effects (behavioral changes and toxicity)

Phenytoin levels increased Increased phenytoin effects and adverse effects

Triazolam and midazolam serum levels increased

Increased triazolam and midazolam levels and effects, including adverse effects (sedation, confusion, respiratory depression)

Itraconazole Inhibition of CYP 3A4 Benzodiazepine serum levels increased, except for oxazepam, lorazepam, and temazepam


Buspirone levels increased (by 13-fold) May increase psychomotor impairment and buspirone adverse effects

Ketoconazole Inhibition of CYP 3A4 Benzodiazepine serum levels increased, except for oxazepam, lorazepam, and temazepam


Buspirone levels possibly increased May increase psychomotor impairment and buspirone adverse effects


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Miconazole, sulfamethoxazole

Inhibition of CYP 2C9 Phenytoin levels increased Increased phenytoin effects and adverse effects

Note. AUC=area under the curve; CYP=cytochrome P450; MAOI-A=monoamine oxidase inhibitor type A; OTC=over the counter;SNRIs=serotonin–norepinephrine reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants; UGT=uridine5′-diphosphate glucuronosyltransferase.Source. Compiled in part from Bruce et al. 2006; Cozza et al. 2003; Desta et al. 2001; Finch et al. 2002; Flockhart et al. 2000; Kharasch et al. 2008; Kuper and D’Aprile 2000; Ma et al. 2005; Mahatthanatrakul et al. 2007; Venkatakrishnan et al. 2000; Warnke et al. 2007;Witkowski et al. 2007; Yew 2002.



establish. Clinical concern resulted from early reports of sudden-onset de-pression and suicidal ideation associated with interferon-alpha-2a (see Chap-ter 4, “Gastrointestinal Disorders”) and neuropsychiatric adverse effects ofefavirenz in more than 50% of patients (Staszewski et al. 1999). However, theonly prospective study of efavirenz’s neuropsychiatric side effects found thatonly vivid dreams and vestibular dysfunction symptoms were significantlymore frequent in patients treated with efavirenz than in patients treated witha triple-nucleoside regimen (Clifford 2003). The side effects generally re-solved within the first 4 weeks of treatment and caused few treatment discon-tinuations (<5%).

HIV/AIDS patients often experience endocrinopathies that may producepsychiatric symptoms. These include clinical and subclinical hypothyroidism(16% of patients) (Beltran et al. 2003; Chen et al. 2005), hypogonadism(50% of males) (Mylonakis et al. 2001; Rabkin et al. 1999b), and adrenal in-sufficiency (50% of patients) (Marik et al. 2002; Mayo et al. 2002). These en-docrinopathies can be associated with fatigue, low mood, low libido, and lossof lean body mass. Graves’ disease (autoimmune thyroiditis), when it occursin the setting of immune reconstitution (Chen et al. 2005), presents with anx-iety, irritability, insomnia, weight loss, mania, and agitation.

Treatment of Psychiatric Symptoms in Patients With HIV/AIDS

Depression. Conventional antidepressants. Multiple open-label and dou-ble-blind, placebo-controlled clinical trials of antidepressant treatment of de-pression in patients with HIV have been conducted. Two early randomizedcontrolled trials (RCTs) demonstrated the efficacy of imipramine for depres-sion in patients with HIV (Manning et al. 1990; Rabkin et al. 1994a). How-ever, in the imipramine-treated groups, anticholinergic, antihistaminic, andantiadrenergic side effects were common and contributed to significant attri-tion. Response rates and adverse effects did not vary as a function of CD4+lymphocyte count.

Early open-label trials (Ferrando et al. 1997, 1999a; Rabkin et al. 1994a,1994b, 1994c) and more recent RCTs of selective serotonin reuptake inhibi-tors (SSRIs) alone or compared with tricyclic antidepressants (TCAs) andgroup therapy for patients with HIV have demonstrated efficacy of SSRIswith few adverse effects, supporting use of SSRIs as first-line treatment for de-pression in patients with HIV (Batki et al. 1993; Elliott et al. 1998; Rabkin


et al. 1999a; Schwartz and McDaniel 1999; Zisook et al. 1998). Women andinjection drug users have been underrepresented in these studies, however.

Results from one study suggest that combining psychotherapy with med-ication may be the optimal approach to treating depression in patients withHIV (Markowitz et al. 1998). In a comparison of four treatment approaches,both interpersonal psychotherapy with imipramine and supportive therapywith imipramine were superior to supportive therapy alone or cognitive-behavioral therapy in ameliorating depressive symptoms and improving thepatient’s Karnofsky Performance Scale score (a measure of physical function).

Mirtazapine, nefazodone, venlafaxine, and sustained-release bupropionhave been studied in small open-label trials in patients with major depressionand HIV infection (Currier et al. 2003; Elliot and Roy-Byrne 2000; Elliot etal. 1999). All of the medications were associated with favorable response rates(<60%–70%) and few adverse effects. One nefazodone-treated patient dis-continued treatment due to a clinically significant interaction with ritonavir.

Psychostimulants. Psychostimulants have demonstrated efficacy in the treat-ment of depressed mood, fatigue, and cognitive impairment in both open-label(Holmes et al. 1989; Wagner et al. 1997) and placebo-controlled studies in pa-tients with HIV (Breitbart et al. 2001; Wagner and Rabkin 2000). For patientsin both RCTs, overstimulation was more common with psychostimulants thanwith placebo. Also, concern over abuse liability may limit the use of psycho-stimulants, particularly in substance abusers with early HIV infection.

Nonconventional agents with antidepressant efficacy. Testosterone deficiencywith clinical symptoms of hypogonadism (depressed mood, fatigue, diminishedlibido, decreased appetite, and loss of lean body mass) is present in up to 50%of men with symptomatic HIV or AIDS (Rabkin et al. 1999b). Deficiency ofadrenal androgens, particularly dehydroepiandrosterone (DHEA), is also com-mon in both men and women with HIV (Ferrando et al. 1999b). These abnor-malities have led to clinical interest in administering anabolic androgenicsteroids, most commonly testosterone, to patients with HIV infection.

Open-label trials and RCTs have demonstrated efficacy of weekly to bi-weekly testosterone decanoate injections for HIV-infected men with lowserum testosterone and low libido, low energy, and subclinical depressivesymptoms (Rabkin et al. 2000). In these studies, fewer than 5% of patientsdropped out of treatment due to adverse effects (irritability, tension, reduced


energy, bossiness, hair loss, and acne). Extreme irritability and assaultiveness(“roid rage”) did not occur at replacement dosages (usually 400 mg), unlikethe supraphysiological dosing used illicitly for anabolic effects. Long-term ad-verse effects include testicular atrophy, decreased volume of ejaculate, andwatery ejaculate. No studies have reported serious hepatotoxicity or prostatecancer associated with chronic treatment.

Testosterone replacement preparations include esterified oral (unde-canoate capsules, available in Canada only) and intramuscular depot testos-terone (propionate, enanthate, and cypionate), skin patches, and testosteronegel. Intramuscular depot preparations are the least expensive and most stud-ied. Patch and gel formulations may produce less variability in serum testos-terone levels and, therefore, in target symptoms.

DHEA, an adrenal androgen, has mild androgenic and anabolic effectsand is a precursor to testosterone. It has been studied in an RCT, and efficacywas demonstrated for doses of 100–400 mg/day in HIV patients with dys-thymia or subsyndromal depression (Rabkin et al. 2006). Other steroid hor-mones, including nandrolone and oxandrolone, are widely used but have notbeen studied for their mood effects in patients with HIV.

St. John’s wort is not recommended for use by HIV patients because it is acytochrome P450 (CYP) 3A4 inducer and may reduce levels of protease inhib-itors. S-adenosyl methionine demonstrated mood improvement in an open-label trial in HIV-infected patients with major depression (Jones et al. 2002).

Anxiety. Anxiety is present in 11%–25% of patients with HIV, is often co-morbid with depression, and is associated with fatigue and physical functionallimitations (M.C. Sewell et al. 2000). The most common manifestations areposttraumatic stress disorder, social phobia, agoraphobia, generalized anxietydisorder, and panic disorder.

SSRIs are first-line agents for the treatment of chronic anxiety disorders;however, there are no published trials in patients with HIV. Buspirone hasbeen shown to be effective for treating anxiety symptoms in asymptomaticgay men and intravenous drug users with HIV and is well tolerated, with alow risk for drug interactions (Batki 1990; Hirsch et al. 1990). Benzodiaz-epines should be used with caution due to their risk for drug interactions (seeTable 12–2), excessive sedation, cognitive impairment, and abuse liability.Lorazepam has the advantage of having no active metabolites and nonoxida-


tive metabolism, but disadvantages include a shorter half-life and more fre-quent dosing. Benzodiazepines should be avoided in HIV/AIDS patientswith cognitive impairment and delirium (Breitbart et al. 1996). Nonaddictivealternatives to benzodiazepines for rapid anxiety relief include the antihista-mines diphenhydramine and hydroxyzine, sedating TCAs, and trazodone.Excessive sedation and anticholinergic-induced cognitive impairment shouldbe monitored.

Mania. Manic symptoms in patients with HIV may be found in conjunc-tion with primary bipolar illness or with HIV infection of the brain (HIV-associated mania) (Lyketsos et al. 1997). HIV-associated mania is a secondaryaffective illness associated with HIV infection of the brain and, compared withprimary bipolar mania, is less associated with a personal or family history ofmood disorder and may include more irritability, less hypertalkativeness, andmore cognitive impairment. Given that HIV-associated mania is directly re-lated to HIV brain infection, antiretroviral agents that penetrate cerebrospinalfluid may offer some protection from incident mania (Mijch et al. 1999). De-spite some reports of manic or hypomanic symptoms being associated withantiretroviral medications (Kieburtz et al. 1991), since the advent of highly ac-tive antiretroviral therapy HIV-associated mania appears to be declining inincidence, consistent with the reduction in HIV-associated dementia.

Practice guidelines recommend lithium, valproic acid, or carbamazepineas standard therapy for bipolar mania (American Psychiatric Association2002). However, there are concerns regarding their use in patients with HIVinfection, especially those with later-stage illness. Lithium has a low therapeu-tic index and a risk for neurotoxicity. Valproate is associated with hepatotox-icity (Cozza et al. 2000) and has been found to stimulate HIV-1 replicationin vitro (Jennings and Romanelli 1999). Carbamazepine may cause blooddyscrasias and may lower serum levels of protease inhibitors. Their use is fur-ther complicated by the requirement for serum drug level monitoring.

Relatively little research has been published on the psychopharmacologi-cal treatment of HIV-associated mania. A case report of lithium for HIV-associated mania in an AIDS patient showed control of symptoms at a dosageof 1,200 mg/day; however, significant neurotoxicity (cognitive slowing, finetremor) occurred, leading to discontinuation (Tanquary 1993). One studyshowed that valproic acid, up to 1,750 mg/day, led to significant improve-


ment in acute manic symptoms, with few adverse effects, at serum levels of50–110 μg/L (Halman et al. 1993; RachBeisel and Weintraub 1997). Therehave been reports that valproic acid increases HIV replication in vitro in adose-dependent manner (Jennings and Romanelli 1999) and that it both in-creases cytomegalovirus replication and reduces the effectiveness of antiviraldrugs used to treat cytomegalovirus (Michaelis et al. 2008). The clinical rele-vance of these findings remains controversial and, to date, no reports havebeen published of valproic acid causing elevations in viral load in vivo.

The anticonvulsant lamotrigine, which has been approved by the U.S.Food and Drug Administration for maintenance therapy in bipolar illness,may be useful for treating mania in patients with HIV. A study of lamotriginetreatment for peripheral neuropathy in patients with HIV suggests its safety;however, careful upward dose titration is required due to risk of severe hyper-sensitivity (Simpson et al. 2003). Gabapentin, an anticonvulsant commonlyused to treat HIV-associated peripheral neuropathy, has not demonstratedmood-stabilizing properties in controlled trials (Evins 2003).

Atypical antipsychotics may improve HIV-associated mania. Risperidonetreatment significantly decreased patients’ Young Mania Rating Scale scoresin a case report of four patients with HIV-related manic psychosis (Singh andCatalan 1994).

A case report of clonazepam treatment of HIV-associated manic symp-toms described rapid clinical response, reduction of concurrent antipsychoticdosage, and few adverse effects (Budman and Vandersall 1990). However,given the cognitive impairment associated with HIV mania, as well as comor-bid substance abuse, benzodiazepines should be used only for acute stabiliza-tion.

Psychosis. New-onset psychosis in patients with HIV, which has a preva-lence ranging from 0.5% to 15% (McDaniel 2000), is most often seen in neu-rocognitive disorders, such as delirium, HIV-associated dementia, or HIV-associated minor cognitive motor disorder. One study comparing new-onsetpsychotic to nonpsychotic HIV patients with similar demographic and illnessprofiles showed a trend toward greater global neuropsychological impair-ment, prior history of substance abuse, and higher mortality in the psychosisgroup (D.D. Sewell et al. 1994a). Psychosis presumed secondary to antiret-roviral medications has been reported (Foster et al. 2003); however, as with


HIV-associated mania, antiretrovirals are much more likely to be protectivein this regard (de Rohchi et al. 2000).

Antipsychotic treatment is complicated by HIV-infected patients’ sus-ceptibility to drug-related extrapyramidal symptoms (EPS) as a result of HIV-induced damage to the basal ganglia. Movement disorders (acute dystonia,parkinsonism, ataxia) can be seen in advanced HIV disease in the absence ofantipsychotic exposure. General recommendations include avoidance ofhigh-potency typical antipsychotics (e.g., haloperidol) and depot antipsy-chotics, and brief treatment when possible.

Studies of treatment of psychosis in patients with HIV are rare and havegenerally focused on psychosis occurring in encephalopathic, schizophrenic,and manic patients. The typical antipsychotics haloperidol and thioridazinewere effective in treating positive psychotic symptoms associated with HIVand schizophrenia. Haloperidol, but not thioridazine, was associated with ahigh incidence of extrapyramidal side effects (Mauri et al. 1997; D.D. Sewellet al. 1994b). Similarly, molindone was beneficial for HIV-associated psycho-sis and agitation, with minimal extrapyramidal side effects (Fernandez andLevy 1993).

Clozapine was found to be effective and generally safe in treating HIV-associated psychosis (including negative symptoms) in patients with priordrug-induced parkinsonism (Dettling et al. 1998; Lera and Zirulnik 1999).However, clozapine must be used with caution in HIV-infected patients dueto the risk of agranulocytosis, and it is contraindicated with ritonavir. Risperi-done improved HIV-related psychotic and manic symptoms and was associ-ated with mild sedation and sialorrhea but few extrapyramidal side effects(Singh et al. 1997; Zilikis et al. 1998). Olanzapine treatment of a patient withAIDS and psychosis who developed EPS with risperidone and other antipsy-chotics is described in a case report; however, this patient experienced akathi-sia, requiring propranolol (Meyer et al. 1998). Lorazepam was reported to beuseful in the treatment of AIDS-associated psychosis with catatonia (Scam-vougeras and Rosebush 1992).

Delirium. Delirium is diagnosed in 11%–29% of hospitalized patients withHIV and AIDS, is generally multifactorial in etiology, and is often superim-posed on HIV-associated neurocognitive disorders (Ferrando et al. 1998). Ina study of delirium in AIDS, patients had an average of 12.6 medical compli-


cations, with the most common being hematological (anemia, leukopenia,thrombocytopenia) and infectious diseases (e.g., septicemia, systemic fungalinfections, Pneumocystis carinii pneumonia, tuberculosis, disseminated viralinfections) (Breitbart et al. 1996).

Pharmacological treatment of delirium in HIV is generally with atypicalantipsychotics because of concern for extrapyramidal side effects. However,the only double-blind clinical trial of delirium treatment in AIDS comparedlow-dose haloperidol, chlorpromazine, and lorazepam (Breitbart et al. 1996).There were three important findings in that study: 1) haloperidol and chlor-promazine were equally effective; 2) lorazepam worsened delirium symptoms,including oversedation, disinhibition, ataxia, and increased confusion; and3) antipsychotic adverse effects were limited and included mild EPS. Benzo-diazepines should be reserved for delirium secondary to the withdrawal ofalcohol or another CNS-depressant agent, or for severe agitation that fails torespond to antipsychotics.

Sleep disorders. Sleep disorders, primarily insomnia, are prevalent in theHIV-infected population. In a survey study of 115 HIV clinic patients, 73%endorsed insomnia (Wiegand et al. 1991). Poor sleep quality in HIV-infectedpatients accompanies higher levels of depressive, anxiety, and physical symp-toms; daytime sleepiness; and cognitive and functional impairment (Nokesand Kendrew 2001; Rubinstein and Selwyn 1998). High efavirenz serum lev-els have been associated with the development of insomnia (Núñez et al.2001) and with transient vivid dreams and insomnia during the early stagesof treatment (Clifford 2003).

Psychopharmacological treatment of insomnia should utilize a hierarchi-cal approach based on safety, abuse liability, and chronicity of symptoms, sim-ilar to that of anxiety disorders. Generally, benzodiazepines are indicated forshort-term use only and should be avoided in patients with substance abusehistories. The nonbenzodiazepine sedative-hypnotics eszopiclone, zopiclone(available in Canada), and zolpidem are preferred for long-term use. In gen-eral, they have less abuse potential; however, patients with substance use his-tories should be monitored because abuse of these drugs has been reported(Brunelle et al. 2005; Hajak et al. 2003; Jaffe et al. 2004). Other agents, suchas sedating antidepressants, atypical antipsychotics, and anticonvulsants, maybe used with comorbid psychiatric symptoms.


Viral Infections Other Than HIV

Viruses can produce psychiatric symptoms by primary CNS involvement,through secondary effects of immune activation, or indirectly from systemiceffects. One serious sequela of several viral infections is acute disseminated en-cephalomyelitis, which can present with encephalopathy, acute psychosis, sei-zures, and other CNS dysfunction.

Systemic Viral Infections

Patients who have chronic viral infections (e.g., Epstein-Barr virus and cyto-megalovirus) may report overwhelming fatigue, malaise, depression, low-grade fever, lymphadenopathy, and other nonspecific symptoms. Althoughviral infections may resemble chronic fatigue syndrome, only a small fractionof chronic fatigue symptoms are attributable to specific viral infection, andthe differential diagnosis should also include depression and other commoncauses of fatigue. Epstein-Barr virus infection is most common in adolescentsand young adults. Cytomegalovirus should be considered when acute depres-sion or cognitive dysfunction appears in immunocompromised patients (e.g.,during the first few months after transplantation). Although controlled trialsare lacking, both antidepressants and stimulants have been reported as bene-ficial in patients with depressive symptoms and fatigue following recoveryfrom acute viral infection or accompanying chronic viral infection.

Herpes Encephalitis

Herpes simplex virus type 1 causes herpes simplex encephalitis (HSE), whichis the most common source of acute viral encephalitis in the United States andis the most common identified cause of viral encephalitis simulating a pri-mary psychiatric disorder (Arciniegas and Anderson 2004; Caroff et al. 2001;Chaudhuri and Kennedy 2002). HSE can cause personality change, dyspha-sia, seizures, olfactory hallucinations, autonomic dysfunction, ataxia, delir-ium, psychosis, and focal neurological symptoms. One possible sequela isKlüver-Bucy syndrome, which includes oral touching compulsions, hypersex-uality, amnesia, placidity, agnosia, and hyperphagia. Early antiviral treatmentmay ameliorate some of these symptoms; however, especially in the youngand elderly, cognitive impairment secondary to HSE may lead to postenceph-alitic dementia.


HSE is treated with intravenous acyclovir. Recovery is related to the speedof treatment, with increased morbidity and mortality associated with delaysin treatment. Acyclovir may cause neuropsychiatric adverse effects, includinglethargy, agitation, delirium, and hallucinations (see Table 12–1) (Rashiq etal. 1993). These effects may be difficult to distinguish from HSE itself, butare generally self-limited and dose dependent. Patients who are elderly, whohave renal impairment, or who are taking other neurotoxic medications are atheightened risk for neuropsychiatric effects of acyclovir. Although there areno well-defined treatments for the associated cognitive and neuropsychiatricsymptoms of HSE, case reports describe success with anticonvulsants, such ascarbamazepine (Vallini and Burns 1987), especially in patients with comor-bid seizure; atypical antipsychotics (Guaiana and Markova 2006); SSRIs(Mendhekar and Duggal 2005); stimulants; clonidine (Begum et al. 2006);and cholinesterase inhibitors (Catsman-Berrevoets et al. 1986).

Parasitic Infections: NeurocysticercosisNeurocysticercosis, caused by the tapeworm Taenia solium acquired from un-dercooked pork, is the most common parasitic disease of the CNS, particu-larly in Asia, Latin America, and Africa. It is now appearing more frequentlyin the southwestern United States. Neurocysticercosis is the major etiologyfor acquired epilepsy in affected areas, and patients are often left with chronicneurocognitive and psychiatric problems, including psychosis, depression,and dementia (Del Brutto 2005; Signore and Lahmeyer 1988). Neurocys-ticercosis is treated with antihelmintic agents, such as praziquantel and al-bendazole, which are relatively free of neuropsychiatric side effects and drug–drug interactions (Nash et al. 2006). Other agents given with these drugs in-clude systemic corticosteroids (see Chapter 10, “Endocrine and MetabolicDisorders”) to treat pericystic inflammation and encephalitis, as well as anti-convulsants to treat seizures. Antipsychotics may be used to treat psychoticsymptoms, but patients may be susceptible to extrapyramidal side effects, in-cluding tardive dyskinesia (Bills and Symon 1992).

Adverse Psychiatric Effects of AntibioticsAntimicrobials can cause a multitude of psychiatric symptoms. Althoughmany of these adverse effects are rare, clinical suspicion is warranted with new-


onset or exacerbation of preexisting psychiatric symptoms when these drugsare initiated. The best documented psychiatric side effects of selected antibioticdrugs are listed in Table 12–1 (Abouesh et al. 2002; “Drugs That May CausePsychiatric Symptoms” 2002; Sternbach and State 1997; Warnke et al. 2007;Witkowski et al. 2007). Delirium and psychosis have been particularly associ-ated with quinolones (e.g., ciprofloxacin), procaine penicillin, antimalarial andother antiparasitic drugs, and the antituberculous drug cycloserine. The mostcommon adverse effect causing discontinuation of interferon is depression.Depression, anxiety, and insomnia are the most frequently reported neuropsy-chiatric adverse effects of antiretroviral medications for HIV infection.

Drug–Drug InteractionsAcute infection results in the downregulation of multiple CYP enzymes aswell as of uridine 5′-diphosphate glucuronosyltransferase (UGT) activity, po-tentially resulting in impaired drug metabolism and excretion and elevatedtoxicity (Morgan et al. 2008; Renton 2005). This effect appears to be me-diated by proinflammatory cytokines, including interferon, interleukin-1,tumor necrosis factor, and interleukin-6. Inhibition of CYP 1A2 and 3A4 ap-pears to have the most potential clinical significance in humans. For example,elevated levels of clozapine, a CYP 1A2 substrate, have been reported in thesetting of acute bacterial pneumonia (Raaska et al. 2002) and urinary tract in-fection (Jecel et al. 2005) in the absence of other causal factors. The clinicalsignificance of this phenomenon for the metabolism of other psychotropicdrugs is not known; however, in the setting of acute infection, careful dosagetitration and serum level monitoring (when available) are prudent.

A number of pharmacokinetic drug interactions may occur between anti-biotics and psychotropic drugs. Selected well-established interactions aredescribed in Table 12–2. Drug interactions are discussed in more detail inChapter 1, “Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions.” Many antibacterials, including macrolides and fluoroqui-nolones, conazole antifungals, and antiretrovirals, are potent inhibitors of oneor more CYP isozymes, whereas the antitubercular agent rifampin and severalnon-nucleoside reverse transcription inhibitors and protease inhibitors in-duce multiple CYP enzymes. Isoniazid and linezolid are irreversible inhibitorsof monoamine oxidase type A (MAO-A).


Erythromycin (and similar macrolide antibiotics, such as clarithromycin)and ketoconazole (and similar antifungals) may cause QT interval prolonga-tion and ventricular arrhythmias when given to a patient taking other QT-prolonging drugs, including TCAs and many antipsychotics.

Multiple case reports have described serotonin syndrome associated withcoadministration of linezolid, indicated for the treatment of methicillin-resis-tant Staphylococcus aureus, and SSRIs and serotonin–norepinephrine reuptakeinhibitors (SNRIs), with an incidence of 1.8%–3% in retrospective studies(Lorenz et al. 2008; Taylor et al. 2006). Linezolid is an irreversible MAO-Ainhibitor. Patients receiving an SSRI or SNRI and linezolid should be closelymonitored for serotonin syndrome. Coadministration of linezolid with director indirect sympathomimetic drugs (e.g., psychostimulants, meperidine) mayprecipitate hypertensive crisis.

Use of the anticonvulsants carbamazepine, phenytoin, and phenobarbital isof concern in HIV infection. In addition to possible anticonvulsant toxicitycaused by protease inhibitor–mediated inhibition of anticonvulsant metabolism,these anticonvulsants also induce protease inhibitor metabolism, which reducesprotease inhibitor serum levels and leads to virological failure (Bartt 1998).

Potentially dangerous cardiovascular side effects have occurred due to in-creased levels of sildenafil, commonly used for sexual dysfunction, followingconcurrent administration of ritonavir, saquinavir, and indinavir (Merry et al.1999; Muirhead et al. 2000). Illicit drugs may have dangerous clinical interac-tions with protease inhibitors. Fatalities have been reported with concurrentuse of 3,4-methylenedioxymethamphetamine (MDMA; commonly called“ecstasy”), methamphetamine, and ritonavir (Hales et al. 2000; Mirken 1997).

Key Clinical Points• Systemic and CNS infectious diseases may cause psychiatric and

cognitive symptoms that persist despite antibiotic treatment andrequire psychopharmacological intervention.

• Acute infection may inhibit metabolism of psychotropic drugs,warranting caution with initial dosage and subsequent titration.

• There is significant potential for interaction between psychotro-pic drugs and antibiotics. Clinicians should query for potential in-teractions prior to combining these agents.


• Substantial evidence supports the efficacy of SSRIs and somenovel agents for the treatment of depression in HIV/AIDS. How-ever, the psychopharmacology literature is limited for other psy-chiatric disorders within the context of infectious diseases.

• Patients with HIV/AIDS and other infections with CNS involve-ment are susceptible to extrapyramidal side effects of antipsy-chotic drugs.

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405

13Dermatological Disorders

Madhulika A. Gupta, M.D., F.R.C.P.C.


Psychiatric and psychosocial comorbidity is present among 25%–30% ofdermatology patients (Gupta and Gupta 1996), and effective management ofthe dermatological condition involves management of the associated psychi-atric factors. The skin is both a source and a target of immunomodulatorymediators of psychological stress response (Arck et al. 2006). Acute psycho-logical stress adversely affects skin barrier function recovery and may exacerbatebarrier-mediated dermatoses such as psoriasis and atopic dermatitis (Choi etal. 2005).

Psychodermatological disorders are generally classified into two majorcategories (Gupta and Gupta 1996; Medansky and Handler 1981): 1) derma-tological symptoms of psychiatric disorders and 2) psychiatric symptoms ofdermatological disorders. The second category has been further subdividedinto a) disorders that have a primary dermatopathological basis but may be


influenced in part by psychological factors (e.g., psoriasis, atopic dermatitis,urticaria and angioedema, alopecia areata, acne, and possibly lichen planus,vitiligo, viral warts, and rosacea); b) disorders that represent an accentuatedphysiological response (e.g., hyperhidrosis and blushing); and c) disordersthat result in an emotional reaction primarily as a result of cosmetic disfigure-ment and/or the social stigma associated with the disease. These subcategoriesare not mutually exclusive.

The focus in this chapter is on psychopharmacological treatment of psy-chiatric comorbidity, including adverse dermatological reactions to psycho-tropic drugs, adverse psychiatric effects of dermatological drugs, and drug–drug interactions, but a comprehensive biopsychosocial approach includespsychological therapies as well (e.g., behavior therapy, psychoeducation,hypnosis, group therapy) (Gupta and Gupta 2001b). Currently, no orallyadministered psychotropic agents are approved by the U.S. Food and DrugAdministration (FDA) for the treatment of a primary dermatological disor-der; 5% topical doxepin cream is FDA approved for short-term management(up to 8 days) of moderate pruritus in adults with conditions such as atopicdermatitis.


Dermatological Manifestations of Psychiatric Disorders

Cutaneous Symptoms of Psychiatric Disorders

Cutaneous delusions include delusions of disfigurement, parasitosis, andbromhidrosis (belief that a foul odor is being emitted from the skin or ori-fices) and may occur in any of the psychotic disorders. Tactile hallucinationsare particularly frequent in delirium, drug intoxication, and drug withdrawal.

Flushing of the skin and profuse perspiration may be the presenting fea-tures of panic attacks. Dramatic unexplained cutaneous sensory symptomsmay represent a conversion reaction or a posttraumatic flashback. Excessivecomplaints about imagined or slight “flaws” of the skin suggest body dysmor-phic disorder but also occur in obsessive-compulsive disorder (OCD) and inanorexia nervosa.

Neurotic excoriations (self-inflicted skin lesions produced by repetitivescratching or picking), onychophagia (nail biting), and onychotillomania

Dermatological Disorders 407

(nail picking or peeling) occur in anxiety states and especially in OCD. Indermatitis artefacta, cutaneous lesions are self-inflicted, but the patient deniesdoing so, suggesting an underlying personality, dissociative, or factitious dis-order. Picking serves as a means of regulating intense emotional states. Tricho-tillomania (hair pulling) occurs alone as an impulse control disorder but alsooccurs in OCD and other anxiety states, as well as in dissociative states.

Cutaneous and Mucosal Sensory Syndromes

Idiopathic localized cutaneous dysesthesias are common, often affecting thescalp, genitals (e.g., vulvodynia), mouth (burning mouth syndrome, glosso-dynia), or other body part. Comorbid psychopathology is common in suchsyndromes. Pruritus (itching) is the most common and distressing symptomof dermatological disease, but also may be a manifestation of an underlyingmedical disorder.

Psychiatric Manifestations of Dermatological Disorders

General Psychopathological Effects of Dermatological Diseases

Stress due to having a dermatological disease frequently exacerbates dermato-logical disorders and is emotionally traumatic, especially when stigmatizingvisible body regions are involved. Interference of nighttime sleep in patientswith pruritic dermatoses aggravates mood and anxiety disorders. Dermato-logical disorders such as atopic dermatitis, acne, psoriasis, other disfiguringskin conditions, and severe pruritus have been associated with a high preva-lence of suicidal ideation (Gupta et al. 2005). In some instances, the degreeof suicidality may be severe and out of proportion to the clinical severity ofthe skin disorder.

Psychopathology in Specific Dermatological Diseases

Atopic dermatitis or eczema. Anxiety and depression are frequent conse-quences of atopic dermatitis, but they also aggravate it. Suicidal ideation hasbeen reported at rates ranging from 2% in U.S. patients with mild to moder-ate atopic dermatitis (Gupta and Gupta 1998) to 20% of Japanese patientswith severe atopic dermatitis (Kimata 2006). Sleep disruption in children asa result of pruritus can stress the entire family, exacerbate the atopic dermatitisas a result of the itch–scratch cycle, and affect cognitive functioning.


Psoriasis. Psoriasis is associated with a variety of psychological difficulties,including poor self-esteem, sexual dysfunction, anxiety, depression, and sui-cidal ideation in 2.5%–10% of patients (Gottlieb et al. 2008; Gupta andGupta 1998; Levenson 2008a; Picardi et al. 2006). Severity of depression in-creases with increasing psoriasis severity. Inpatients with severe psoriasis arealmost 2.5 times more likely than the general population to be receiving psy-chotropic medications (Gerdes et al. 2008).

Urticaria and angioedema. Stress can precipitate acute urticaria (hives) andperpetuate chronic urticaria (Gupta 2009). Urticarial reactions can occur as aconditioned response to a previously neutral stimulus, including a psychoso-cial stressor (Gupta 2009). The frequency of psychiatric comorbidity is wellestablished, with about half of patients with chronic urticaria having an AxisI disorder, especially OCD and major depression (Staubach et al. 2006; Uguzet al. 2008). The role of chronic posttraumatic stress disorder tends to be un-derrecognized as a factor in idiopathic urticaria (Gupta 2009). Depressionand insomnia resulting from pruritus aggravate chronic urticaria (Yang et al.2005; Yosipovitch et al. 2002).

Alopecia areata. Patients with alopecia areata can have high rates (23%–93%) of psychiatric comorbidity, primarily depression and anxiety (Guptaand Gupta 1996). No clear correlation exists between severity of psychiatricsymptoms and severity of alopecia (hair loss), but cosmetic disfigurement canbe a significant source of psychological distress.

Acne. Severe acne is associated with increased depression, anxiety, poor self-image, and poor self-esteem. Body image pathologies such as eating disordersand body dysmorphic disorder are commonly encountered in patients whoare excessively preoccupied by clinically mild acne. In addition, frequentbingeing in eating disorders is associated with flareups of acne. Psychiatric co-morbidity is often the most disabling feature of acne and is one of the consid-erations in deciding whether to institute dermatological therapies. Psychiatricmorbidity in acne, including the 5%–7% prevalence rate of suicidal ideation(Gupta and Gupta 1998; Picardi et al. 2006), is not consistently related to theclinical severity of the skin condition.


Pharmacotherapy of Specific DisordersDermatological Manifestations of Psychiatric Disorders

Delusions of Parasitosis

The biggest challenge in the pharmacotherapy of delusions of parasitosis isconvincing patients to take a psychiatric drug, because they do not view them-selves as having a psychiatric disorder. An extensive dermatological literatureexists on the use of pimozide, starting at 1 mg/day and increasing dosage every5–7 days by 1 mg to a maximum of 4 mg/day (Lee 2008); this is not an FDA-approved indication for pimozide, and no clinical trials have demonstrated su-periority of pimozide over other antipsychotics. Sudden unexpected deathshave been reported with pimozide, the possible mechanism being ventriculararrhythmias caused by QTc prolongation. Additive effects on QTc prolonga-tion should be anticipated if pimozide is administered with phenothiazines ortricyclic antidepressants (TCAs), which also prolong the QT interval, or withcytochrome P450 (CYP) 3A4 inhibitors (e.g., fluoxetine), with azole antifun-gals (e.g., ketoconazole), or with some macrolide antibiotics (see Table 13–1),as a result of elevated levels of pimozide, which is a CYP 3A4 substrate. Ac-cording to FDA guidelines, use of pimozide with some selective serotonin re-uptake inhibitors (SSRIs) may increase risk of QTc prolongation. Case reportsindicate that other typical and atypical antipsychotics, including olanzapine(Meehan et al. 2006) and risperidone (De León et al. 1997), have been effec-tive for delusional parasitosis. Furthermore, antipsychotics with antihista-minic and sedative properties may be helpful in ameliorating anxiety andpruritus. SSRIs have sometimes been helpful in patients whose parasite sensa-tions have been more obsessional than delusional. In some patients, delusionsof parasitosis may be a feature of delirium or early dementia.

Cutaneous and Mucosal Dysesthesias

The cutaneous dysesthesias represent a heterogeneous group of disorders, usu-ally treated with the same agents used for the treatment of neuropathic pain,such as low doses of a TCA (e.g., amitriptyline 25–50 mg at bedtime). Forburning mouth syndrome, no definitive treatment has been established, indi-cating the heterogeneity of the comorbid psychopathology (Zakrzewska et al.2005). For glossodynia (a term sometimes used synonymously with burning

410C



Table 13–1. Some dermatological drug–psychotherapeutic drug pharmacokinetic interactions

MedicationInteraction mechanism Effect(s) on psychotropic drug levels Management

Azole antifungals (oral formulations only) (itraconazole, ketoconazole)

Inhibition of CYP 3A4

Benzodiazepine serum levels for agents undergoing hepatic oxidative metabolism, such as alprazolam and triazolam, may increase.

Consider alternative benzodiazepines, such as oxazepam, which is metabolized by glucuronidation.

Macrolide antibiotics (clarithromycin, erythromycin)

Inhibition of CYP 3A4

Buspirone levels increased.Carbamazepine levels increased.

Consider alternative anxiolytics.Use alternate anticonvulsants.

Cyclosporine Substrate and inhibition of CYP 3A4

Doxepin, amitriptyline, and imipramine levels increased.

Pimozide levels increased, with risk of arrhythmias.

Decrease dosage or use alternative antidepressants.

Do not coadminister pimozide with these agents.

Note: Several atypical antipsychotics (e.g., clozapine, quetiapine, ziprasidone, aripiprazole) are also CYP 3A4 substrates; if used with CYP 3A4 inhibitor, their dosage may need to be decreased.

Derm

atological D

isord

ers411

Terbinafine Inhibition of CYP 2D6

Antidepressant serum level may increase for CYP 2D6 substrates, including TCAs, paroxetine, venlafaxine, and atomoxetine.

Consider alternative agents such as citalopram or sertraline.

Atomoxetine dosage usually needs to be reduced.

Antipsychotic serum levels may increase for CYP 2D6 substrates, including phenothiazines (risking arrhythmias), haloperidol, risperidone, olanzapine, clozapine, and aripiprazole.

Decrease dosage or consider alternatives such as paliperidone or quetiapine.

Antihistamines (chlorpheniramine, diphenhydramine, hydroxyzine)

Substrate of CYP 2D6

Potential for QTc prolongation at higher dosages if taken with CYP 2D6 inhibitors (e.g., the SSRIs paroxetine, fluoxetine, sertraline).

Lower dosage of antihistamine or use alternative antidepressant (e.g., venlafaxine)


Table 13–1. Some dermatological drug–psychotherapeutic drug pharmacokinetic interactions (continued)

MedicationInteraction mechanism Effect(s) on psychotropic drug levels Management


mouth syndrome), a few case reports have described benefits from an anticon-vulsant (Meiss et al. 2002; Siniscalchi et al. 2007). The treatment literaturefor vulvodynia is similar, with no controlled clinical trials. Treatment guide-lines for vulvodynia based on expert consensus include TCAs, such as amitrip-tyline, nortriptyline, and desipramine, starting at 10–25 mg at bedtime,which may be increased to 100–150 mg depending on the response; other an-tidepressants, including venlafaxine and SSRIs; and some anticonvulsants(Haefner et al. 2005). Scalp dysesthesia and other idiopathic pruritic condi-tions may respond to antihistaminic TCAs, such as amitriptyline and doxepin(Hoss and Segal 1998).

Self-Induced Dermatoses

For cutaneous excoriation (skin picking), several small trials suggest the effi-cacy of SSRIs, including clomipramine 50–100 mg/day (Gupta et al. 1986),fluoxetine up to 80 mg/day (Gupta and Gupta 1993; Simeon et al. 1997), ser-traline up to 200 mg/day (Kalivas et al. 1996), and fluvoxamine up to 300mg/day (Arnold et al. 1999), with little correlation with the presence of or im-provement in psychiatric comorbidity. Also, case reports have supported theefficacy of doxepin 30–75 mg/day (Harris et al. 1987), olanzapine 2.5–5 mg/day (Gupta and Gupta 2000), and naltrexone 50 mg at bedtime (Smith andPittelkow 1989).

For patients with trichotillomania, a 10-week controlled trial found clo-mipramine (100–250 mg/day) to be more effective than desipramine (150–200 mg/day) (Swedo et al. 1989). However, subsequent studies have failed todemonstrate durable benefits of serotonergic drugs, including placebo-con-trolled trials using fluoxetine 20–80 mg/day (Christenson et al. 1991; Streich-enwein and Thornby 1995) and an open trial of fluvoxamine up to 300 mg/day (Stanley et al. 1997). An open-label, flexible-dose trial of venlafaxine upto 375 mg/day reported improvement over a 12-week period; however, likeother antidepressants, venlafaxine was not effective in maintaining sustainedimprovement of trichotillomania (Ninan 2000; Ninan et al. 1998).

In patients whose self-induced dermatoses represent an attempt to regu-late intense emotional states, there may also be a role for low dosages of moodstabilizers, such as lithium carbonate 300 mg/day and divalproex sodium 500mg/day (M.A. Gupta, “Successful Treatment of Self-Induced DermatosesWith Mood Stabilizers” (manuscript in preparation), 2009). The mood sta-


bilizers aid in the regulation of emotions and decrease dissociation, which arefactors in the perpetuation of the self-injurious behaviors.

Psychiatric Manifestations of Dermatological Disorders

Atopic Dermatitis or Eczema

An important goal in the pharmacotherapy of atopic dermatitis is the inter-ruption of the itch-scratch cycle and optimization of nighttime sleep (Leven-son 2008a). Topical doxepin (5% cream) is effective in the treatment ofpruritus in atopic dermatitis (Drake and Millikan 1995), and is FDA ap-proved for short-term (up to 8 days) treatment of moderate pruritus in adultswith atopic dermatitis, but not in children because of the greater risk of sys-temic side effects such as drowsiness. Low-dose oral doxepin (e.g., starting at10 mg at bedtime and titrated based on efficacy and side effects) is helpful inadults because of its antihistaminic sedative properties (Kelsay 2006). Sedat-ing antidepressants may be beneficial in part through promoting sleep. Fur-thermore, the strongly antihistaminic antidepressants doxepin, trimipramine,and amitriptyline may also be effective because of their strong anticholinergicproperties, as the eccrine sweat glands in atopic dermatitis have been foundto be hypersensitive to acetylcholine. Reports have also suggested some ben-efits from bupropion (Modell et al. 2002), mirtazapine (Hundley and Yosi-povitch 2004; Mahtani et al. 2005), and trimipramine (Savin et al. 1979). Noguidelines have been established for the treatment of sleep disturbance inatopic dermatitis (Kelsay 2006). In a small short–term, double-blind, pla-cebo-controlled crossover trial, the benzodiazepine nitrazepam did not signif-icantly reduce nocturnal scratching (Ebata et al. 1998). For anxiety in atopicdermatitis, an antihistaminic TCA such as doxepin starting at 10 mg/day isrecommended over benzodiazepines, because benzodiazepine withdrawalmay further exacerbate pruritus.

Psoriasis

Improvement in the clinical severity of psoriasis is associated with an improve-ment in psychiatric comorbidity. Several studies (e.g., Bassukas et al. 2008;Tyring et al. 2006) have reported a significant improvement in psychiatriccomorbidity in psoriasis patients treated with the biological response modifi-ers. Meditation, relaxation training, and cognitive-behavioral stress manage-ment are some psychological therapies that have been reported to be effective


for patients with psoriasis (Levenson 2008b). Obesity, moderately heavy alco-hol use, and tobacco smoking should be addressed because they have been as-sociated with poor response to dermatological therapies (Gottlieb et al. 2008).The association between psoriasis and metabolic syndrome (Gottlieb et al.2008) has important implications in the choice of psychopharmacologicalagents. Treatment of depressive symptoms may reduce pruritus and insomniain patients with psoriasis. In a placebo-controlled trial, the reversiblemonoamine oxidase inhibitor (MAOI) moclobemide (currently not availablein the Unites States) reduced psoriasis severity and anxiety (Alpsoy et al. 1998).In a small open-label trial, bupropion induced improvement in psoriasis, withreturn to baseline levels after its discontinuation (Modell et al. 2002), andparoxetine was reported to be effective in two patients with both depressionand psoriasis (Blay 2006). Overall, the evidence base is limited, and antide-pressants sometimes cause or aggravate psoriasis (Warnock and Morris 2002a).

Urticaria

In interpreting the chronic idiopathic urticaria treatment literature, one mustfirst recognize the very high rate of response to placebo (Rudzki et al. 1970).A low dose of a sedating antihistaminic antidepressant, such as doxepin, ishelpful for the management of pruritus in chronic idiopathic urticaria, espe-cially because pruritus interferes with sleep (Yosipovitch et al. 2002). Doxepinmay provide more than symptomatic relief, reducing the urticarial reactionitself (Goldsobel et al. 1986; Greene et al. 1985; Rao et al. 1988). Potent his-taminic H1 plus H2 blockers, such as doxepin, trimipramine, and amitrip-tyline, are more effective than H1 antihistamines alone for urticaria (Levenson2008b). There are also case reports of the benefits of mirtazapine (Bigata et al.2005) and SSRIs (Gupta and Gupta 1995). A mood stabilizer may be usedwhen urticaria is a feature of the physiological effect of severe emotional dys-regulation in posttraumatic stress disorder (Gupta 2009).

Alopecia Areata

The literature on the use of psychotropic agents in treating alopecia areata isinconclusive and further confounded by the fact that patients may experiencespontaneous remission of their alopecia in the absence of any treatments (Lev-enson 2008b). Very small double-blind, placebo-controlled trials have foundbenefit from imipramine (Perini et al. 1994) and paroxetine (Cipriani et al.2001), as well as from citalopram in a case series (Ruiz-Doblado et al. 1999).


Acne

The focus of psychiatric drug treatment for patients with acne should be onany underlying psychiatric disorder. Isotretinoin, which is often used to treatacne, may cause serious psychiatric adverse effects (discussed below), in addi-tion to other side effects, including teratogenicity. In some case studies, hor-monal contraceptives have failed in patients who self-medicated theirdepression with St. John’s wort (Hall et al. 2003). St. John’s wort is a CYP 3A4inducer that increases the metabolism of some hormonal contraceptives anddecreases their efficacy; therefore, the acne patient taking isotretinoin andhormonal contraceptives should be advised of this. Case reports attest to thebenefits of a wide variety of psychiatric and psychological treatments for acne,including paroxetine (Moussavian 2001) and olanzapine (Gupta and Gupta2001a), but no controlled clinical trials have been reported.

Adverse Cutaneous Drug Reactions to Psychotropic AgentsAdverse cutaneous drug reactions (ACDRs) (Litt 2004; Warnock and Morris2002a, 2002b, 2003) can be divided into common (usually relatively benign)ACDRs, rare life-threatening ACDRs, and precipitation or aggravation of aprimary dermatological disorder. ACDRs are reported to affect 2%–3% ofhospitalized patients, and 2% of these cutaneous reactions are severe and lifethreatening. Approximately 2%–5% of patients receiving psychotropic med-ications will develop adverse cutaneous reactions, which remain the mostcommon allergic reaction to these agents (Kimyai-Asadi et al. 1999).

Mild ACDRs

Common ACDRs include pruritus, exanthematous rashes, urticaria with orwithout angioedema, fixed drug eruptions, photosensitivity reactions, drug-induced pigmentation, and alopecia. Pruritus is the most common ACDR,encountered with all antipsychotics, antidepressants, and mood stabilizers,and is usually secondary to other ACDRs.

Exanthematous rashes (morbilliform or maculopapular eruptions) can oc-cur with all antipsychotics, antidepressants, and mood stabilizers. The rashusually occurs within the first 3–14 days of starting the drug and may subsidewithout discontinuation of the causative agent. In some cases, the rash, espe-


cially if presenting with painful lesions, may represent the early stages of oneof the more severe and life-threatening ACDRs, such as Stevens-Johnson syn-drome.

Urticaria, with or without angioedema, is the second most commonACDR after pruritus, and occurs within minutes to a few hours but some-times as late as several days after starting the drug, and can lead to laryngealangioedema and anaphylaxis. Urticaria can occur with all antipsychotics, an-tidepressants, and anticonvulsants.

Fixed drug eruptions can theoretically occur with any drug. They charac-teristically present as sharply demarcated, solitary, or occasionally multiplelesions that occur within a few to 24 hours after ingestion of the drug, andresolve within several weeks of drug discontinuation.

Photosensitivity reactions are the result of an interaction of the drug withultraviolet radiation and are limited to body regions exposed to light. Such re-actions can be caused by any of the antipsychotics but are much more fre-quently associated with chlorpromazine (3% incidence). Photosensitivity alsooccurs with antidepressants, including the TCAs and SSRIs; some mood sta-bilizers, including carbamazepine, valproic acid, topiramate, gabapentin, andoxcarbazepine; and some sedatives and hypnotics, including amobarbital,phenobarbital, pentobarbital, alprazolam, estazolam, chlordiazepoxide, es-zopiclone, zaleplon (up to 10%), and zolpidem. Patients should be advisedregarding the use of sunscreen and minimization of sun exposure in those in-stances in which the medication has to be continued. Photosensitivity causedby psychotropic drugs may interfere with psoralen + ultraviolet A and ultra-violet B light therapy for psoriasis and other pruritic dermatoses.

Drug-induced pigmentation, which may involve the skin and eyes (retina,lens, and cornea), has been reported after long-term (>6 months), high-dose(>500 mg/day) use of low-potency typical antipsychotics, especially chlorpro-mazine and thioridazine. The cutaneous discoloration in some instances issecondary to dermal granules containing melanin bound to the drug or its me-tabolites; the discoloration can take months to years to completely resolve afterdiscontinuation of the drug. Pigmentary changes have been associated withsome antidepressants, including various TCAs, all SSRIs, and venlafaxine(hypopigmentation), and with some anticonvulsants, including lamotrigine(also associated with leukoderma), carbamazepine, topiramate, gabapentin,and valproic acid (also associated with changes in hair color and texture).


Alopecia, which typically presents as diffuse, nonscarring, localized or gen-eralized hair loss from the scalp, is usually reversible after discontinuation ofthe offending drug. Hair loss may occur rapidly or a few months after thedrug has been started, with recovery generally 2–5 months after drug dis-continuation. Alopecia has been frequently reported with lithium (>5%) andvalproic acid (>5%), and less frequently with the other mood stabilizers.Alopecia has also been associated with most antidepressants, including allSSRIs, bupropion, venlafaxine, and duloxetine, and with several antipsychot-ics, including olanzapine, risperidone, ziprasidone, loxapine, and haloperidol.

Severe ACDRs

Severe and life-threatening skin reactions are most frequently associated withanticonvulsants, and include erythema multiforme (EM), Stevens-Johnsonsyndrome (SJS), toxic epidermal necrolysis (TEN or Lyell’s syndrome), drughypersensitivity syndrome or drug rash (or reaction) with eosinophilia andsystemic symptoms (DRESS), exfoliative dermatitis, and vasculitis (Litt2004; Warnock and Morris 2002a, 2002b, 2003). EM, SJS, and TEN lie ona continuum of increasing severity. About 16% of cases with SJS or TEN havebeen associated with short-term use of anticonvulsant drugs, with greatestrisk for development of TEN within the first 8 weeks of initiating therapy.Use of multiple anticonvulsants and higher doses increases the risk. Treat-ment of severe reactions should include immediate discontinuation of thedrug and an emergency dermatology consultation. Patients typically requirefluid and nutritional support, as well as infection and pain control, whichmay involve management in an intensive care or burn unit.

Erythema multiforme occurs within days of starting the drug and maypresent as a polymorphous eruption, with pathognomonic “target lesions” typ-ically involving the extremities and palmoplantar surfaces. Progression of EMto more serious SJS and TEN should always be considered a possibility. Al-though EM is most commonly associated with carbamazepine, valproic acid,lamotrigine, gabapentin, and oxcarbazepine, it has also (albeit rarely) been as-sociated with antipsychotics (e.g., clozapine, risperidone) and antidepressants(e.g., fluoxetine, paroxetine, bupropion), and occasionally with sedative-hyp-notics (including barbiturates, some benzodiazepines, and eszopiclone).

Stevens-Johnson syndrome usually occurs within the first few weeks afterdrug exposure and presents with flu-like symptoms, followed by mucocuta-


neous lesions and a mortality rate as high as 5% due to loss of the cutaneousbarrier and sepsis. Bullous lesions can involve mucosal surfaces, including theeyes, mouth, and genital tract. SJS is most frequently associated with the sameanticonvulsants as EM.

Toxic epidermal necrolysis is considered to be an extreme variant of SJS, re-sulting in epidermal detachment in more than 30% of patients, occurringwithin the first 2 months of treatment, with a mortality rate as high as 45%due to sepsis. In 80% of TEN cases, a strong association is made with specificmedications (vs. a 50% association with specific medications in SJS), most of-ten anticonvulsants (Litt 2004; Warnock and Morris 2002a, 2002b, 2003).Use of more than one anticonvulsant increases the risk of SJS/TEN. For lamo-trigine (Physicians’ Desk Reference 2009), the risk of a serious rash may be in-creased by coadministration with divalproex sodium, exceeding the initialrecommended dosage, or exceeding the recommended dosage escalation. Be-nign rashes also occur with lamotrigine, and it is not possible to reliably predictwhich rash will prove to be serious or life-threatening. Therefore, lamotrigineshould be discontinued at the first sign of a rash, unless the rash is clearly be-nign or not drug related (Physicians’ Desk Reference 2009).

Drug hypersensitivity syndrome, or DRESS, characteristically occurs 1–8weeks after starting drug treatment, and presents as a drug eruption with fe-ver, eosinophilia, lymphadenopathy, and multiple organ involvement (in-cluding liver, kidney, lungs, and brain). Treatment involves immediatediscontinuation of the suspected drug. Antihistamines and systemic corticos-teroids may be required. The mortality rate is 10% if symptoms are unrecog-nized or untreated. The rash can range from a simple exanthem to TEN, andis almost exclusively associated with anticonvulsants.

Exfoliative dermatitis presents as a widespread rash characterized bydesquamation, pruritic erythema, fever, and lymphadenopathy within thefirst few weeks of drug therapy, with a good prognosis if the causative agentis withdrawn immediately. It has been reported with antipsychotics, mostTCAs and other antidepressants, mood stabilizers, lithium, sedatives, andhypnotics.

Drug hypersensitivity vasculitis is characterized by inflammation and ne-crosis of the walls of blood vessels within a few weeks of starting a drug. Le-sions (e.g., palpable purpura) are primarily localized on the lower third of thelegs and ankles. It has been associated with clozapine, maprotiline, trazodone,


carbamazepine, lithium, phenobarbital, pentobarbital, diazepam, and chlor-diazepoxide.

Exacerbation of Dermatological Disorders by Psychotropic Medications

Psychotropic drugs may precipitate or exacerbate a number of primary der-matological disorders (Litt 2004; Warnock and Morris 2002a, 2002b, 2003),including acne, psoriasis, seborrheic dermatitis, hyperhidrosis, and porphyria.Acne has been associated with most TCAs, all SSRIs, and other antidepres-sants such as venlafaxine, duloxetine, and bupropion; lithium carbonate andoccasionally other anticonvulsant mood stabilizers including topiramate,lamotrigine, gabapentin, and oxcarbazepine; and antipsychotics such as que-tiapine and haloperidol.

Lithium is well known to precipitate or exacerbate psoriasis (Gupta andGupta 1996). Lithium-induced psoriasis can occur within a few months butusually occurs within the first few years of treatment. Lithium has an inhibi-tory effect on intracellular cyclic adenosine monophosphate and the phos-phoinositides. Inositol supplements have been shown to have a significantbeneficial effect on psoriasis in patients taking lithium (Allan et al. 2004).Beta-blockers such as propranolol, which are often used to treat lithium-induced tremors, have also been associated with psoriasis, but a recent popu-lation-based study does not support this (Brauchli et al. 2008). Psoriasis pre-cipitated or exacerbated by lithium is typically resistant to conventionalantipsoriatic treatments, and usually there is no family history of psoriasis.When psoriasis becomes intractable, lithium must be discontinued, and re-mission usually follows within a few months. Anticonvulsants, atypical anti-psychotics, and SSRIs have been less commonly reported to precipitate oraggravate psoriasis.

Seborrheic dermatitis typically occurs in regions where the sebaceousglands are most active, such as the scalp, face, chest, and genitalia. Seborrheicdermatitis is very common in patients taking phenothiazines for a long term,and also has been reported with other antipsychotics, including olanzapine,quetiapine, and loxapine. Seborrheic eruptions have also been reported withlithium and anticonvulsants.

Hyperhidrosis, often manifested as night sweats, is common with SSRIs,serotonin-norepinephrine reuptake inhibitors, bupropion, and MAOIs.


Sweating is mediated by the sympathetic cholinergic innervation of the ec-crine sweat glands; however, the more anticholinergic TCAs have also causedhyperhidrosis, and therefore switching to a more anticholinergic antidepres-sant is not necessarily helpful. The mechanism underlying the antidepressant-mediated hyperhidrosis is believed to be centrally mediated but is unclear.Hyperhidrosis has also been reported with antipsychotics (e.g., olanzapine,quetiapine, pimozide) and mood stabilizers (e.g., carbamazepine, topiramate[1% of patients], lamotrigine [2%], gabapentin, oxcarbazepine [3%]) (Litt2004; Warnock and Morris 2002a, 2002b, 2003).

Porphyria may be exacerbated by certain drugs, such as carbamazepine,valproic acid, and many sedative-hypnotics (especially barbiturates and othersedative-hypnotics excluding benzodiazepines), resulting in acute dermato-logical, neuropsychiatric, and abdominal pain symptoms. Chlorpromazine,although photosensitizing, is considered to be safe and actually was approvedby the FDA for use in acute intermittent porphyria.

Adverse Psychiatric Effects of Dermatological Agents

Corticosteroids

Psychiatric side effects of systemic glucocorticoid therapy are reviewed in de-tail in Chapter 7, “Respiratory Disorders,” and Chapter 10, “Endocrine andMetabolic Disorders.” Topical corticosteroids may also cause psychiatric ad-verse effects, especially in patients with extensive lesions who are using high-potency topical steroids (Hughes et al. 1983).

Retinoids

Isotretinoin, generally used to treat severe acne, has been associated with de-pression, psychosis, and suicide. The general consensus is that the relation-ship between psychiatric side effects and isotretinoin is unclear, with littlesupport from controlled trial data (Marqueling and Zane 2005; Strahan andRaimer 2006). However, in some individual cases, the relationship betweendepression and isotretinoin use was confirmed by rechallenge with isotreti-noin (Scheinman et al. 1990). Overall, improvement in acne from use of iso-tretinoin is associated with an improvement in depression scores. Patients


who develop depression with isotretinoin may have previously used the drugwith no adverse psychiatric effects (Scheinman et al. 1990).

The current guidelines for prescribing isotretinoin (trade name Accutane)(Physicians’ Desk Reference 2009) include the following warning:

Accutane may cause depression, psychosis and, rarely, suicidal ideation, sui-cide attempts, suicide, and aggressive and/or violent behaviors. No mecha-nism of action has been established for these events.. . .Therefore prior toinitiation of Accutane therapy, patients and family members should be askedabout any history of psychiatric disorder, and at each visit during therapy pa-tients should be assessed for symptoms of depression, mood disturbance, psy-chosis, or aggression to determine if further evaluation may be necessary.(pp. 2607–2614)

The guidelines further indicate that if patients develop psychiatric symptoms,they should promptly stop the isotretinoin and contact the prescriber. Dis-continuation of isotretinoin does not always lead to remission of the psychi-atric symptoms. The determination as to whether a patient should continuetaking isotretinoin after having experienced a psychiatric reaction should bebased on the risk–benefit ratio for that particular patient. In addition, femalepatients should be cautioned not to self-medicate with St. John’s wort. Be-cause this agent is an inducer of hepatic microsomal enzymes that metabolizesome hormonal contraceptives (required during isotretinoin therapy), its usecan lead to a reduction in the levels of the hormonal contraceptive and re-duced contraceptive efficacy. Other retinoids such as etretinate and acitretinhave also been reported to cause depression and suicidal thoughts (Arican etal. 2006; Henderson and Highet 1989).

Antihistamines

Sedating first-generation H1 histamine-receptor antagonists such as diphen-hydramine and hydroxyzine readily cross the blood–brain barrier and haveantianxiety and sedative effects. Diphenhydramine overdose may present as atoxic psychosis with bizarre behavior and hallucinations (Jones et al. 1986).Their anticholinergic effects may cause subtle cognitive impairment and, inoverdose, an anticholinergic delirium. The H2 histamine-receptor antagonistscimetidine, ranitidine, and famotidine have been associated with mania (vonEinsiedel et al. 2002), depression, and delirium (Catalano et al. 1996).


Antimicrobial Agents

Antimicrobials can cause a variety of psychiatric symptoms. These medica-tions are discussed in Chapter 12, “Infectious Diseases.”

Biological Response Modifiers

Several studies have reported significant improvement in comorbid psychiat-ric symptoms in psoriasis patients treated with biological response modifiers(or “biologics”), such as adalimubab, alefacept, efalizumab, etanercept, and in-fliximab (e.g., Bassukas et al. 2008; Tyring et al. 2006). The marked improve-ment has been attributed in part to a possible direct antidepressant effect ofthe biologics, which is attributed to a decrease in proinflammatory cytokines,such as tumor necrosis factor–alpha (O’Brien et al. 2004).

Other Agents

Finasteride, used for alopecia, has been associated with higher depressionscores (Altomare and Capella 2002; Rahimi-Ardabili et al. 2006). Cyclospor-ine, an immunosuppressant used in organ transplantation, has been associatedwith organic mental disorders, with symptoms—including mood disorders,anxiety disorders, hallucinations and delusions, cognitive difficulties, and de-lirium—usually observed within 2 weeks of beginning treatment (Craven1991). Cyclosporine is covered in Chapter 16, “Organ Transplantation.” Dap-sone, used for a variety of dermatological conditions, has been associated withmania (Carmichael and Paul 1989) in several reports.


Most pharmacokinetic interactions (Litt 2004) between dermatological andpsychotropic drugs result from inhibition of CYP-mediated drug metabo-lism, mainly the CYP 2D6 and 3A4 isoenzymes. Key interactions are listed inTable 13–1 (see also Chapter 1, “Pharmacokinetics, Pharmacodynamics, andPrinciples of Drug–Drug Interactions,” for a comprehensive drug interactionlisting; Chapter 12, “Infectious Diseases,” for antimicrobials; and Chapter10, “Endocrine and Metabolic Disorders,” for corticosteroids).

Many drugs used in dermatological conditions are inhibitors of CYP3A4, including azole antifungals (e.g., itraconazole, ketoconazole), some


macrolides (erythromycin and clarithromycin), and cyclosporine, which isalso a CYP 3A4 substrate. Use of these drugs can dramatically increase bloodlevels of psychotropic drugs that are CYP 3A4 substrates, including anticon-vulsants such as carbamazepine; antidepressants such as doxepin, amitrip-tyline, and imipramine; benzodiazepines such as alprazolam, triazolam, anddiazepam, and the antipsychotic pimozide. Elevated levels of pimozide can re-sult in prolongation of the QTc interval and cardiac arrhythmias. The clinicalimportance of this interaction is exemplified by the fact that the antihista-mines terfenadine and astemizole, both CYP 3A4 substrates, have been with-drawn from the market because of potentially fatal interactions with CYP3A4 inhibitors resulting in life-threatening ventricular arrhythmias.

The antifungal agent terbinafine is a CYP 2D6 inhibitor and can result indrug toxicity, such as serious cardiac arrhythmias, when administered in con-junction with CYP 2D6 substrates, such as the TCAs and the phenothiazineantipsychotics. Alternatively, elevated levels of the antihistamines chlorphenir-amine, diphenhydramine, and hydoxyzine, all of which are CYP 2D6 sub-strates, may occur when these drugs are used in conjunction with psychiatricagents that are CYP 2D6 inhibitors (e.g., SSRI antidepressants) (Table 13–1).

In addition, significant adverse effects may occur as a result of elevatedlevels of CYP 3A4 substrates such as cyclosporine and corticosteroids whenthey are coadministered with psychotropic agents that are CYP 3A4 inhibi-tors, such as fluoxetine, fluvoxamine, and nefazodone.

Cyclosporine is both substrate and inhibitor of CYP 3A4, resulting inmany potential drug–drug interactions. Carbamazepine and other CYP 3A4inducers lower cyclosporine and pimozide blood levels and may decrease theirtherapeutic effect.

Key Clinical Points

• Standard psychopharmacological agents may be used to treatpsychiatric comorbidity in dermatological disorders, with ade-quate clinical monitoring.

• Pruritus and sleep difficulties contribute to dermatological andpsychiatric morbidity, including increased suicide risk. Effectivemanagement of sleep difficulties and pruritus is important in thechoice of a psychopharmacological agent.


• The strongly antihistaminic TCA doxepin is effective for pruritusand sleep difficulties in the pruritic dermatoses.

• Disease-related stress should be addressed in the treatmentplan because it can increase psychiatric morbidity and contrib-ute toward stress-related exacerbations of certain disorders(e.g., atopic dermatitis and psoriasis).

• The high prevalence of suicidal ideation in dermatology patientsis not always associated with more clinically severe skin disease(e.g., in the adolescent patient with acne). Covert body dysmor-phic disorder can increase suicide risk and treatment resistance.

• Severe and life-threatening dermatological reactions such asStevens-Johnson syndrome, toxic epidermal necrolysis, and thedrug hypersensitivity syndrome are most frequently associatedwith the mood-stabilizer anticonvulsants, with greatest risk ofdevelopment within the first 2 months of therapy.

• Most important dermatology–psychiatry drug interactions in-volve the use of CYP 3A4 inhibitors (e.g., azole antifungals, mac-rolide antibiotics) with CYP 3A4 substrates such as pimozide,resulting in increased blood levels of pimozide and increasedrisk of cardiac side effects.

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Warnock JK, Morris DW: Adverse cutaneous reactions to antipsychotics. Am J ClinDermatol 3:629–636, 2002b

Warnock JK, Morris DW: Adverse cutaneous reactions to mood stabilizers. Am J ClinDermatol 4:21–30, 2003

Yang HY, Sun CC, Wu YC, et al: Stress, insomnia, and chronic idiopathic urticaria: acase-control study. J Formos Med Assoc 104:254–263, 2005

Yosipovitch G, Ansari N, Goon A, et al: Clinical characteristics of pruritus in chronicidiopathic urticaria. Br J Dermatol 147:32–36, 2002

Zakrzewska JM, Forssell H, Glenny AM: Interventions for the treatment of burningmouth syndrome. Cochrane Database Syst Rev (1):CD002779, 2005

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14Rheumatological Disorders



Neuropsychiatric disorders are common in patients with rheumatologicaldisorders. Based on standardized research interviews, nearly one-fifth of pa-tients with rheumatoid arthritis are estimated to have a psychiatric disorder,most often a depressive disorder (Levenson et al. 2010). Depressed patientswith rheumatoid arthritis are more likely to report pain, are less likely to complywith medications, and have poorer quality of life than other patients withrheumatoid arthritis. Research on depression in osteoarthritis has revealed sim-ilar findings, with high rates of depression associated with increased pain andpoorer quality of life. Studies of systemic lupus erythematosus found that30%–50% of the patients have depression, 13%–24% have anxiety, 3%–4%have mania or mixed episodes, and up to 5% have psychosis (Levenson et al.2010). The differential diagnosis of psychiatric disorders in patients with rheu-matological disorders includes primary psychiatric disorders, secondary syn-


dromes (e.g., psychosis due to central nervous system [CNS] lupus), and sideeffects of rheumatological medications.

Treatment of Psychiatric DisordersFor the most part, treatment of depression, anxiety, mania, psychosis, delir-ium, and pain in patients with rheumatological disorders is similar to theirtreatment in patients with other medical diseases, following the principlescovered in other chapters in this book. Few clinical trials have been done spe-cifically in patients with rheumatological disorders. One study observed thatsertraline had robust effects on depression outcomes in a group of depressedrheumatoid arthritis patients, compared with a group of patients who wereclinically followed but received no antidepressants (Parker et al. 2003). Simi-larly, sertraline 100 mg/day was effective with very few side effects (<4% ofpatients treated) in depressed rheumatoid arthritis patients treated openly forup to 15 months (Slaughter et al. 2002). In an open-label trial, dothiepin, asedating tertiary amine tricyclic antidepressant (TCA) similar to doxepin, wasfound to be effective and well tolerated for depression and anxiety in rheuma-toid arthritis patients with major depression (Dhavale et al. 2005). With re-spect to the potential limitations of TCA treatment in depressed rheumatoidarthritis patients, in a large randomized controlled trial (RCT) comparingparoxetine 20–40 mg/day with amitriptyline 75–150 mg/day, the two drugswere equally efficacious for depression and pain reports; however, paroxetinewas better tolerated, with significantly fewer anticholinergic side effects (Birdand Broggini 2000). There is some suggestion from basic science that activa-tion of serotonin receptors has potent anti-inflammatory effects (Yu et al.2008), although the clinical implication of these findings for the treatment ofdepression in patients with rheumatoid arthritis is not known.

Despite the wide prevalence of depression in patients with osteoarthritis,few intervention studies have examined the efficacy of antidepressants inosteoarthritis. Those that have been performed suggest that antidepressantsare beneficial in the treatment of depression in patients with osteoarthritisand that improvement in depression is associated with reduced pain and dis-ability (Lin et al. 2003).

Although current evidence indicates that all antidepressants have roughlyequal efficacy in the treatment of depression, they differ in their analgesic

Rheumatological Disorders 433

efficacy, tolerability, and potential drug interactions. TCAs have long beenrecognized to have analgesic benefits, even at low dose (e.g., amitriptyline 25mg) and independent of the presence of depression (see also Chapter 17,“Pain Management”). In higher doses, the tolerability and safety of TCAs arepoor. Selective serotonin reuptake inhibitors (SSRIs) have comparable antide-pressant efficacy but less analgesic efficacy. Serotonin–norepinephrine re-uptake inhibitors (SNRIs) possess more analgesic potential than SSRIs.Nearly all RCTs demonstrating analgesic efficacy of antidepressants in rheu-matological disorders have been of TCAs (e.g., Ash et al. 1999; Grace et al.1985). More recently, duloxetine (60–120 mg/day) has been shown to be ef-ficacious in a large RCT for knee pain in osteoarthritis patients, with addi-tional improvements in mental health and vitality measures (Chappell et al.2009). Drug interactions may occur, although this is generally not a problemwith first- and second-line treatments for rheumatoid arthritis.

Psychopharmacological treatment of neuropsychiatric symptoms (partic-ularly psychosis and mania) in patients with lupus cerebritis is a challenge,with no guidance from randomized trials (Tincani et al. 1996). High-dosecorticosteroids are considered first-line treatment to suppress CNS inflamma-tion; however, they may exacerbate neuropsychiatric symptoms. Thus, anti-psychotics are frequently used for symptomatic treatment concurrent withcorticosteroids. Clinically, agents with high potency at dopamine D2 recep-tors appear generally the most effective, especially in severe cases. Patientswith lupus cerebritis must be monitored closely for extrapyramidal symptomsand seizures. Anticonvulsant mood stabilizers are often used for prophylaxisor treatment of seizures, as well as for their mood-stabilizing properties. Ben-zodiazepines should be used with caution due to risk of confusion and behav-ioral disinhibition.

Psychiatric Side Effects of Rheumatological MedicationsThe differential diagnosis of psychiatric disorders in patients with rheumato-logical disorders includes side effects of rheumatological medications. Table14–1 lists the reported psychiatric side effects of rheumatological medica-tions. Corticosteroid-induced psychiatric symptoms are reviewed in Chapter10, “Endocrine and Metabolic Disorders.”


Rheumatological Side Effects of Psychotropic Medications: Psychotropic Drug–Induced Lupus

Patients who are receiving antipsychotic drugs, particularly chlorpromazine,may have positive antinuclear and antiphospholipid antibodies, but most donot develop signs of an autoantibody-associated disease. Compared with other(nonpsychiatric) drugs known to cause a symptomatic lupus-like syndrome,chlorpromazine and carbamazepine carry low risk, and several other psycho-tropics (valproic acid, other anticonvulsants, phenelzine, and lithium) carryvery low risk. There are isolated reports of lupus with sertraline and bupropion

Table 14–1. Psychiatric side effects of medications used in treating rheumatological disordersMedication Psychiatric side effect(s)

Azathioprine Delirium

Corticosteroids Mood lability, euphoria, irritability, anxiety, insomnia, mania, depression, psychosis, delirium, cognitive disturbance

Cyclophosphamide Delirium (at high doses) (rare)

Cyclosporine Anxiety, delirium, visual hallucinations

Gold None reported

Hydroxychloroquine Confusion, psychosis, mania, depression, nightmares, anxiety, aggression, delirium

Immunoglobulin (intravenous) Delirium, agitation

Leflunomide Anxiety

LJP394a None reported

Methotrexate Delirium (at high doses) (rare)

Mycophenolate mofetil Anxiety, depression, sedation (all rare)

NSAID (high dose) Depression, anxiety, paranoia, hallucinations, concentration, hostility, confusion, delirium

Penicillamine None reported

Sulfasalazine Insomnia, depression, hallucinations

Tacrolimus Anxiety, delirium, insomnia, restlessness

Note. NSAID=nonsteroidal anti-inflammatory drug.aB-cell tolerogen–anti-anti-double-stranded deoxyribonucleic acid (DNA) antibodies.


(Cassis and Callen 2005; Hussain and Zakaria 2008). CNS involvement isusually absent in drug-induced lupus. Laboratory findings may include mildcytopenia, elevated erythrocyte sedimentation rate, and elevated antinuclearantibody titers. Antihistone antibodies are positive in up to 95% of patientsbut are not pathognomonic of drug-induced lupus. After discontinuation ofthe drug, symptoms and antibody titers decline usually over a period of weeks;however, the recovery can take more than a year (Vedove et al. 2009).

Drug–Drug InteractionsRelatively few important drug interactions occur between rheumatologicaland psychopharmacological agents. These are summarized in Table 14–2,with the exception of most chemotherapeutic agents (discussed in Chapter 8,“Oncology”) and corticosteroids (discussed in Chapter 10, “Endocrine andMetabolic Disorders”). The most important possible interactions involve po-tential for increased gastrointestinal bleeding when nonsteroidal anti-inflam-matory drugs are combined with serotonergic agents, particularly SSRIs,SNRIs, and tertiary amine TCAs. The potential for synergistic myelosuppres-sive effects exists with the combination of immunosuppressive agents (sul-fasalazine, azathioprine, chemotherapeutic agents) and psychotropics withthis effect (e.g., clozapine, carbamazepine, valproate, mirtazapine). Gold,penicillamine, and leflunomide are relatively free of interactions.

Key Clinical Points• Depression is highly prevalent among patients with rheumato-

logical disorders.• Randomized controlled trials have shown antidepressants to be

effective for the treatment of depression in patients with rheu-matoid arthritis.

• TCAs and SNRIs possess more analgesic potential than do SSRIs.• Psychiatric drugs are uncommon causes of drug-induced lupus,

with chlorpromazine and carbamazepine most common amongthose that do.

• Among the drugs used to treat rheumatological disorders, corti-costeroids are the most likely to cause psychiatric side effects.


ReferencesAsh G, Dickens CM, Creed FH, et al: The effects of dothiepin on subjects with rheu-

matoid arthritis and depression. Rheumatology (Oxford) 38:959–967, 1999Bird H, Broggini M: Paroxetine versus amitriptyline for treatment of depression asso-

ciated with rheumatoid arthritis: a randomized, double blind, parallel group study.J Rheumatol 27:2791–2797, 2000

Cassis TB, Callen JP: Bupropion-induced subacute cutaneous lupus erythematosus.Australas J Dermatol 46:266–269, 2005

Table 14–2. Rheumatology drug–psychotropic drug interactions

Medication Interaction mechanismEffect on psychotropic drugs and management

Azathioprine Synergistic myelosuppression

Potential increased risk for blood dyscrasias with some psychotropics (e.g., clozapine, carbamazepine, valproate, mirtazapine)

NSAIDs Additive anticoagulant effect

Increased risk of bleeding with SSRIs

Sulfasalazine Additive nausea Increased nausea with some psychotropics (e.g., SSRIs, SNRIs, cholinesterase inhibitors, anticonvulsants, lithium)

Synergistic myelosuppression

Potential increased risk for blood dyscrasias with some psychotropics (e.g., clozapine, carbamazepine, valproate, mirtazapine)

Tacrolimus QT prolongation Increased risk of cardiac arrhythmias with other QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium

Note. NSAIDs=nonsteroidal anti-inflammatory drugs; SNRIs=serotonin–norepinephrine re-uptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants.Drug interactions between chemotherapeutic agents used in rheumatology (e.g., cyclophospha-mide, methotrexate, cyclosporine, tacrolimus) and psychotropic drugs are covered in Chapter 8,“Oncology.”


Chappell AS, Ossanna MJ, Liu-Seifert H, et al: Duloxetine, a centrally acting analgesic,in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized,placebo-controlled trial. Pain 146:253–260, 2009

Dhavale HS, Gawande S, Bhagat V, et al: Evaluation of efficacy and tolerability ofdothiepin hydrochloride in the management of major depression in patients suf-fering from rheumatoid arthritis. J Indian Med Assoc 103:291–294, 2005

Grace EM, Bellamy N, Kassam Y, et al: Controlled, double-blind, randomized trial ofamitriptyline in relieving articular pain and tenderness in patients with rheuma-toid arthritis. Curr Med Res Opin 9:426–429, 1985

Hussain HM, Zakaria M: Drug-induced lupus secondary to sertraline. Aust N Z JPsychiatry 42:1074–1075, 2008

Levenson JL, Dickens C, Irwin MR: Rheumatology, in The American Psychiatric Pub-lishing Textbook of Psychosomatic Medicine: Psychiatric Care of the MedicallyIll, 2nd Edition. Edited by Levenson JL. Arlington, VA, American PsychiatricPublishing, 2010 (in press)

Lin EH, Katon W, Von Korff M, et al: Effect of improving depression care on painand functional outcomes among older adults with arthritis: a randomized con-trolled trial. JAMA 290:2428–2429, 2003

Parker JC, Smarr KL, Slaughter JR, et al: Management of depression in rheumatoidarthritis: a combined pharmacologic and cognitive-behavioral approach. ArthritisRheum 49:766–777, 2003

Slaughter JR, Parker JC, Martens MP, et al: Clinical outcomes following a trial of sertralinein rheumatoid arthritis. Psychosomatics 43:36–41, 2002

Tincani A, Brey R, Balestrieri G, et al: International survey on the management ofpatients with SLE, II: the results of a questionnaire regarding neuropsychiatricmanifestations. Clin Exp Rheumatol 14 (suppl 16):S23–S29, 1996

Vedove CD, Del Giglio M, Schena D, et al: Drug-induced lupus erythematosus. ArchDermatol Res 301:99–105, 2009

Yu B, Becnel J, Zerfaoui M, et al.: Serotonin 5-hydroxytryptamine(2A) receptor acti-vation suppresses tumor necrosis factor-alpha–induced inflammation with ex-traordinary potency. J Pharmacol Exp Ther 327:316–323, 2008

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15Surgery and Critical Care




The psychopharmacological treatment of patients in the critical care settingand perioperative period can be particularly challenging due to severe andmultiorgan system disease, rapid shifts in clinical status, and the introductionof multiple medications such as anesthetics, analgesics, and antibiotics thatmay interact with psychotropic drugs. In this chapter, we address the preven-tion and treatment of delirium; management of psychotropic drugs in theperioperative period; psychopharmacological treatment of presurgical anxietyand acute and posttraumatic stress syndromes that are often seen in the wakeof traumatic incidents, such as orthopedic trauma and burns; and drug–druginteractions that may be encountered in the critical care setting. The reader isreferred to relevant chapters in this volume that address psychopharmacolog-ical treatment within specific organ system disease states.


Delirium

Delirium, characterized by disturbance in consciousness, attention andarousal, and cognition, is highly frequent in hospitalized patients who aremedically ill. It causes lasting distress to patients and families, and is an inde-pendent predictor of morbidity and mortality, particularly when persisting athospital discharge (Inouye and Young 2006; McAvay et al. 2006). Upon ad-mission to the general hospital, 14%–24% of patients have delirium, andduring hospital admission, 6%–56% develop delirium, including as many as87% of patients in intensive care units (ICUs) (Inouye and Young 2006).Clinically, delirium has three subtypes: hypoactive, hyperactive, and mixed.The hypoactive form is often mistaken for depression, whereas the hyperac-tive form is associated with agitation, hallucinations, and delusions. Althoughmanagement of behavioral disturbances of delirium accounts for approxi-mately one-third of psychiatric consultation requests (Schellhorn et al. 2009),it remains underdiagnosed and undertreated.

The most common predisposing causes of delirium include age, centralnervous system (CNS) and systemic disease, anticholinergic medications, andintoxication and withdrawal states from alcohol and pharmacological andtoxic substances. The optimal management of delirium entails early assess-ment of patients at risk, identification and treatment of underlying causes(e.g., infection, dehydration, metabolic derangements), environmental inter-ventions (i.e., optimizing level of stimulation, familiarizing with surround-ings, frequent orientation), and psychopharmacology. It is important toreview medications that may cause or exacerbate delirium, including benzo-diazepines and other sedative-hypnotics, anticholinergics, antihistaminics,opioid analgesics, and corticosteroids.

In a randomized controlled trial (RCT) of a multimodal consultationintervention to reduce delirium in elderly patients with hip fractures, only19% required low-dose haloperidol to control agitation (Marcantonio et al.2001). This finding underscores the importance of nonpharmacological in-terventions to prevent and control delirium.

Psychopharmacological interventions for the treatment of delirium areaimed at correcting disturbances in one or more neurotransmitter systems(i.e., cholinergic, dopaminergic, noradrenergic, and serotonergic). Correctionof sleep-wake cycle disturbance that is characteristic of delirium is targeted via

Surgery and Critical Care 441

anti–alpha-1 adrenergic, antihistaminic, and gamma-aminobutyric acid(GABA) agonist properties. Psychopharmacology clinical trials in the pub-lished literature are aimed at the prevention of delirium in patients (mostlyelderly) undergoing orthopedic, gastrointestinal, and cardiovascular surgeriesand treatment of delirium once diagnosed. Medications studied in RCTs in-clude haloperidol, olanzapine, risperidone, chlorpromazine, lorazepam, mi-dazolam, propofol, donepezil, and dexmedetomidine. Quetiapine andaripiprazole have been studied only in open-label trials. The treatment ofanticholinergic delirium requires specific psychopharmacological interven-tion and is covered separately later in this section. Delirium from alcoholwithdrawal is covered in Chapter 18, “Substance Use Disorders.”

Delirium Prevention Trials

A trial comparing haloperidol 5 mg/day given intravenously at 9 P.M. fromthe first to the fifth postoperative day after gastrointestinal surgery versus asimilar volume of saline solution found a reduced incidence of delirium withhaloperidol (10.5%) compared with saline (32.5%, P<0.05). The severityand duration of delirium, once developed, were also lower in the haloperidolgroup. One patient developed uncomplicated transient tachycardia while tak-ing haloperidol, but no other adverse events were noted (Kaneko et al. 1999).

In an RCT comparing haloperidol with placebo in preventing delirium inelderly patients with hip fractures, haloperidol 0.5 mg or placebo was admin-istered orally three times daily for 1–3 days before hip replacement surgery andcontinued for 3 days postoperatively (Kalisvaart et al. 2005). The incidence ofdelirium did not differ between the haloperidol and placebo groups (15.1 vs.16.5%, respectively). However, significant differences were seen between pa-tients given haloperidol and those given placebo; those taking haloperidol hadreduced severity of delirium (mean 4 points lower on the Delirium RatingScale [DRS-98], P<0.001), reduced duration of delirium (mean 6.4 dayslower, P< 0.001), and reduced length of hospital stay (mean 5.5 days lower,P<0.001). Importantly, no drug-related side effects, including extrapyramidalsymptoms (EPS), were encountered. The low overall incidence of deliriumwas likely attributable, at least in part, to proactive assessment and follow-up,as observed by Marcantonio et al. (2001), with the effect of haloperidol beingto reduce severity and duration of delirium once developed.


Two small RCTs comparing donepezil—5 mg/day for 14 days preopera-tively and 14 days postoperatively in one study (Liptzin et al. 2005) and4 days preoperatively in the other (Sampson et al. 2007)—with placebo failedto yield significant differences between groups in the incidence of deliriumafter joint replacement surgery.

Olanzapine 5 mg given orally preoperatively and immediately postopera-tively was compared with placebo in a large RCT aimed at reducing the inci-dence of delirium in high-risk patients having joint replacement surgery(Larsen et al. 2007). The incidence of delirium was 15% in the olanzapinegroup compared with 41% in the placebo group (P<0.001). In addition, theolanzapine-treated group had lower Delirium Rating Scale–Revised–98(DRS-R-98) scores during the first 5 postoperative days, required lower dos-ages of narcotics, and were more likely to be discharged to home (vs. a reha-bilitation facility) compared with the placebo group.

Dexmedetomidine, an intravenously administered alpha-2 receptor ago-nist that decreases norepinephrine release centrally, was compared with mida-zolam and propofol in an open-label randomized trial for the prevention ofdelirium in patients undergoing valve replacement surgery (Maldonado et al.2009). Patients were randomly assigned to one of the three agents for imme-diate postoperative sedation: dexmedetomidine (loading dose: 0.4 μg/kg, fol-lowed by a maintenance drip of 0.2–0.7 μg/kg/hour), propofol (25–50 μg/kg/minute drip), or midazolam (0.5–2 mg/hour drip). The patients were as-sessed twice daily postoperatively for onset of delirium, and rescue dosages ofhaloperidol and lorazepam were allowed for agitation. Using intention-to-treat analysis, the incidence of delirium in the dexmedetomidine group was10%, compared with 44% in both the midazolam and propofol groups.There were no statistical differences in haloperidol or lorazepam usage or inlength of ICU stay; however, dexmedetomidine patients received significantlylower amounts of opioid analgesia compared with midazolam-treated pa-tients. Similar reductions in the incidence of agitated delirium have been doc-umented in RCTs comparing either perioperative dexmedetomidine infusion(0.2 μg/kg/hour) (Shukry et al. 2005) or 1 μg/kg once after induction ofanesthesia (Isik et al. 2006) with placebo in pediatric surgery patients receiv-ing sevoflurane anesthesia.

On the theory that correction of sleep–wake cycle disturbance would helpto prevent postoperative delirium in elderly patients who underwent resection


of either gastric or colon cancer, Aizawa et al. (2002) conducted a randomizedtrial of intramuscular diazepam nightly plus continuous intravenous infusionof flunitrazepam and meperidine (pethidine) administered over 8 hours forthe first 3 nights postoperatively compared with usual care. The incidence ofdelirium was significantly lower in the intervention group (5%) than in theusual care group (35%). Morning lethargy was seen more frequently in theintervention group; however, there were no other adverse events.

In summary, although data are limited, in patients undergoing joint, gas-trointestinal, and valve replacement surgeries, dexmedetomidine and olanza-pine have been shown to reduce the incidence of delirium, and haloperidolhas been shown to reduce the severity and duration of delirium, whereasdonepezil has shown no benefit in small RCTs. Adverse events, particularlyEPS with antipsychotics, have been minimal in prevention trials; however,excessive sedation may be problematic with benzodiazepines. Regardless ofpsychopharmacological strategy, proactive consultation and intervention is apowerful prophylactic intervention for delirium.

Delirium Treatment Studies

Haloperidol, chlorpromazine, and lorazepam (mean dosages 1.4 mg, 36 mg,and 4.6 mg orally per day, respectively) were compared in an RCT for thetreatment of delirium in patients with acquired immunodeficiency syndrome(AIDS) (Breitbart et al. 1996). Haloperidol and chlorpromazine were equallyeffective for both hyperactive and hypoactive variants, but lorazepam was in-effective and even worsened delirium in some patients, necessitating discon-tinuation of that treatment arm. Notably, these patients had mild to moderateand not severe delirium symptoms, thus necessitating low dosages of medica-tion, and the incidence of EPS was low.

In a small randomized, single-blind delirium treatment trial comparinghaloperidol (mean dosage 1.7 mg/day) with risperidone (mean dosage 1 mg/day) in ICU and oncology patients, no statistical differences were found in de-gree of improvement at 3 or 7 days, dropouts, or adverse events (Han and Kim2004). An apparent difference in overall clinical response rate at 7 days (75%for haloperidol, 42% for risperidone) was not statistically significant due tosmall sample size.

Hu et al. (2004) compared olanzapine (mean dosage 4.52 mg/day), halo-peridol by injection (mean dosage 7.08 mg/day), and placebo in the treat-


ment of delirium in a heterogeneous group of hospitalized patients. All threegroups had significant decreases in Delirium Rating Scale (DRS) scores byday 7 of treatment (olanzapine, 72.2%; haloperidol, 70.4%; placebo,29.7%), with improvement in olanzapine and haloperidol patients signifi-cantly greater than improvement in placebo patients. Second- and third-dayDRS scores showed a significant improvement in olanzapine patients com-pared with haloperidol patients; however, endpoint comparison was not sig-nificantly different. Both groups showed significantly earlier improvement inDRS scores than placebo-treated patients. Haloperidol-treated patients, com-pared with olanzapine-treated patients, had more frequent EPS (haloperidol,31.9%; olanzapine, 2.7%) and dry mouth (haloperidol, 16.7%; olanzapine,2.7%). EPS were most significant in patients receiving >4.5 mg haloperidoldaily. It is important to note that this study included a relatively high meandosage of haloperidol (administered parenterally), compared with olanzapineand compared with haloperidol dosages of the studies cited above, and for alonger duration. This likely explains the higher incidence of EPS and drymouth found in this study.

Another RCT compared enteral olanzapine (initiated 5 mg/day, 2.5 mgin patients over age 60; mean dosage 4.5 mg/day) to enteral haloperidol (2.5–5 mg every 8 hours, 0.5–1 mg every 8 hours in patients over age 60; meandosage 6.5 mg/day) in the treatment of delirium in surgical ICU patients(Skrobik et al. 2004). After 5 days, Delirium Index scores decreased in bothgroups, and concurrent benzodiazepine use did not differ. Of 45 haloperidol-treated patients, none had severe EPS, but six (13%) had mild EPS, comparedwith none in the olanzapine group.

Favorable results with few adverse events have been reported in threeopen-label delirium studies (total 35 patients) using quetiapine at a meandosage of 45–211 mg/day (Osbolt et al. 2008). Similarly, aripiprazole 5–15mg/day (mean dosage 9 mg/day) titrated over a 7-day period and continuedfor up to 7 months yielded favorable results, with mean response time of6 days and no adverse events (Straker et al. 2006).

A small open-label randomized trial compared intravenous dexmedeto-midine 0.2–0.7 μg/kg/hour with intravenous haloperidol 0.5–2 mg/hour indelirious, agitated, intubated ICU patients (Reade et al. 2009). Dexmedeto-midine patients were extubated sooner, were less likely to require tracheos-tomy, were released from restraints sooner, required less adjunctive propofol


sedation, and had reduced length of ICU stay compared with the haloperidol-treated patients.

In summary, a small number of RCTs suggest similar efficacy of haloperi-dol (oral or parenteral), olanzapine, and risperidone for the treatment of de-lirium; however, the limited number of trials and the limitations andvariability of the trial designs prevent firm conclusions about comparative ef-ficacy or adverse effects. Patients treated with higher dosages of haloperidol(>4.5 mg/day by injection or >7.5–15 mg/day orally) may have a higher inci-dence of EPS compared with patients treated with olanzapine and risperidoneadministered orally at more modest equivalent dosages. Dexmedetomidinemay be a promising agent for the prevention and treatment of delirium, andrandomized double-blind comparison trials are indicated.

Currently, haloperidol remains the gold standard for the treatment of de-lirium (American Psychiatric Association Work Group 1999). Haloperidolhas the advantage of being the only agent that can be given orally, intrave-nously (see next subsection), intramuscularly, and subcutaneously. A wealthof clinical experience supports the use of haloperidol over other agents in se-riously medically ill patients, and haloperidol costs less. Until adequately de-signed comparative clinical trials suggest superior efficacy or side-effectprofile for another agent, haloperidol should be the first-line treatment for de-lirium except in patients who are at elevated risk for EPS or who are allergicto haloperidol. In patients with preexisting prolonged QTc, alternatives toQTc-prolonging antipsychotics (e.g., aripiprazole, benzodiazepines, propo-fol, dexmedetomidine) should be considered first.

High-Dose Intravenous Haloperidol

Intravenous haloperidol administered at high dosages, either by bolus or bycontinuous infusion, has been used for the treatment of severely agitated pa-tients in the critical care setting. Mean dosages of haloperidol have been re-ported to be as high as 100–480 mg/day in critically ill cancer patients(Adams et al. 1986) and to approach or exceed 1,000 mg/day for several daysin agitated and difficult-to-wean ventilator patients (Riker et al. 1994), post-cardiotomy patients (K.M. Sanders et al. 1991), and lung transplant patients(Levenson 1995).

That such high dosages of haloperidol did not cause significant EPSsuggests that some patients with delirium are less vulnerable to EPS than, for


example, patients with schizophrenia. Perhaps in patients with delirium, a re-duction of CNS cholinergic function would be protective against EPS. De-spite a widespread belief that antipsychotics cause less EPS when given intra-venously than when administered intramuscularly or orally, no real evidencesupports this contention.

The primary concern with intravenous haloperidol is prolongation of theQTc interval and the potential for development of torsade de pointes (Has-saballa and Balk 2003; see also Chapter 2, “Severe Drug Reactions”). In a re-view of 223 consecutive ICU patients treated with intravenous haloperidol,Sharma et al. (1998) found that 8 patients (3.6%) developed torsade depointes, which was associated with high dosages (>35 mg), rapid infusion,and preexisting prolonged QTc (>500 msec in 84% of patients with torsadede pointes). A U.S. Food and Drug Administration (FDA; 2007) alertwarned against the off-label use of intravenous haloperidol, particularly athigher than recommended dosages, citing “at least 28 case reports of QT pro-longation and [torsade de pointes] in the medical literature, some with fataloutcome in the context of off-label intravenous use of haloperidol.” Higherdosages and intravenous administration of haloperidol appear to be associatedwith a higher risk of QT prolongation and torsade de pointes. The warningemphasizes the particular need for caution when using any formulation ofhaloperidol to treat patients who 1) have other QT-prolonging conditions, in-cluding electrolyte imbalance (particularly hypokalemia and hypomagne-semia); 2) have underlying cardiac abnormalities, hypothyroidism, or familiallong QT syndrome; or 3) are taking drugs known to prolong the QT interval(including other antipsychotic medications, tricyclic antidepressants [TCAs],and lithium; for a listing, see Arizona Center for Education and Research onTherapeutics 2009). Continuous electrocardiographic monitoring is recom-mended if haloperidol is given intravenously. Intravenous haloperidol shouldbe given no faster than 1 mg/minute to reduce cardiovascular side effects, in-cluding torsade de pointes.

Dexmedetomidine Pharmacology

Dexmedetomidine, an alpha-2 receptor agonist that decreases sympathetictone both centrally and peripherally, was approved by the FDA in 1999 for usein humans as a short-term medication (<24 hours) for analgesia and sedationin the ICU (Gertler et al. 2001). It has also been found to attenuate neuroen-


docrine and hemodynamic responses to anesthesia and surgery and to reduceanesthetic and opioid requirements. Dexmedetomidine must be administeredintravenously. It is rapidly and extensively distributed to tissues and rapidlyeliminated almost entirely via cytochrome P450 (CYP) 2D6, with a half-lifeof 2–2.5 hours (Karol and Maze 2000). This rapid distribution and fast elim-ination allow adjustment of dosage and effects. It is not known how dosage ofdexmedetomidine should be adjusted in patients with hepatic or renal impair-ment; however, infusion ranges of 0.2–0.7 μg/kg/hour have been reported incritically ill ICU patients, including those on ventilatory support and withorgan failure (Maldonado et al. 2009; Reade et al. 2009). The most commonside effects are hypotension, bradycardia, and respiratory suppression. Thedrug should be used cautiously in patients with heart and lung disease, or inthose taking vasodilators or beta-blockers. It is a major substrate and inhibitorof CYP 2D6 (see “Drug–Drug Interactions” later in this chapter).

Anticholinergic Delirium

Acetylcholine deficit is one of the critical pathogenetic mechanisms of delir-ium (Trzepacz 2000). Medications with antimuscarinic effects (e.g., benz-tropine, trihexyphenidyl, scopolamine, diphenhydramine, TCAs [especiallytertiary amine compounds]) cause delirium, and patients with impaired cho-linergic neurotransmission (i.e., Alzheimer’s disease) and other CNS insults(e.g., trauma, hypoxia, stroke) are highly susceptible to their effects. Anticho-linergic delirium is addressed by removal of the offending agent, supportivemeasures, and, in severe refractory cases, treatment with physostigmine (adults0.5–2 mg, children 0.01–0.03 mg/kg, given intravenously at ≤1 mg/minuteevery 20–30 minutes until symptoms resolve). Physostigmine was superior tobenzodiazepines for agitation associated with anticholinergic delirium (Burnset al. 2000). Donepezil has also been reported to be effective (Noyan et al.2003).

Psychotropic Drugs in the Perioperative PeriodThe question whether to discontinue a psychiatric drug prior to surgery withgeneral anesthesia is a common and complex one. In one survey of adultsprior to elective surgery, 43% admitted to taking one or more psychotropicmedications. Of these, 35% were taking antidepressants, 34% were taking


benzodiazepines, 19% were taking combinations, and 11% were taking anti-psychotics, lithium, or over-the-counter psychotropics such as melatonin(Scher and Anwar 1999). The potential risks of continuing a psychotropicdrug before surgery include adverse interactions with anesthetic agents, inter-ference with hemodynamic management (e.g., causing hypotension or hyper-tension), and postoperative complications (e.g., excessive sedation, ileus).Risks of discontinuing the drug include, at best, loss of therapeutic effect and,at worst, rebound exacerbation of the mental disorder and/or a withdrawalsyndrome. The evidence base regarding these relative risks is scanty, com-posed mostly of case reports. Practical and ethical limitations make controlledtrials unlikely.

A consensus of experts noted that the decision whether to stop a psycho-tropic drug prior to surgery should be individualized, taking into account theextent of surgery, the patient’s condition (diagnosis, comorbidities, stability),the choice of anesthetic agents, the length of preoperative fasting, and therisks of discontinuation (withdrawal, relapse) (Huyse et al. 2006). They rec-ommended that lithium, monoamine oxidase inhibitors (MAOIs), TCAs,and clozapine be discontinued prior to surgery; that selective serotonin re-uptake inhibitors (SSRIs) be continued in patients who are mentally andphysical stable; and that for all other psychotropics, an individualized deci-sion is required. Other experts caution against discontinuation, advising thatthe safest course of action for the vast majority of drug therapy is to continueit until the time of surgery, particularly drugs that can cause a withdrawal syn-drome (Noble and Kehlet 2000; Smith et al. 1996).

Seemingly contradictory literature makes establishing clear guidelines dif-ficult. For example, lithium and carbamazepine are reported both to cause re-sistance to neuromuscular blocking agents (Ostergaard et al. 1989) and toprolong their effects (Hill et al. 1977; Melton et al. 1993). Another difficultyin balancing risks is that some psychotropics may actually provide side bene-fits; for example, antipsychotics may enhance intraoperative hypothermia(Kudoh et al. 2004).

In our opinion, the risks of discontinuation usually exceed the risks ofcontinuing most psychotropic drugs. Even MAOIs can be continued with rel-ative safety prior to surgery by use of specific “MAOI-safe” anesthetic tech-niques and/or substitution of reversible MAOIs (Smith et al. 1996). Anexception is the cholinesterase inhibitors, which synergistically increase the


effects of succinylcholine and similar neuromuscular blocking agents (Russell2009) and may run the risk of causing or exacerbating postoperative delirium.Given the low risks of temporary cessation of therapy, cholinesterase inhibi-tors should be stopped prior to surgery.

In some cases, interruption of psychopharmacological therapy may be un-avoidable, such as when a patient is unable to take oral medication postoper-atively for a prolonged period. General strategies to cope with this possibilityinclude 1) allowing patients to continue their usual drugs until the day of sur-gery when possible; 2) using alternatives to the oral route of administration ifavailable (see Chapter 1, “Pharmacokinetics, Pharmacodynamics, and Princi-ples of Drug–Drug Interactions”); 3) when alternative routes are not available,substituting an alternative drug of the same or different class, which can beadministered by a nonoral route; and 4) returning gastrointestinal transittimes to normal as soon as possible to restore reliable drug absorption fromthe gut (e.g., avoiding unnecessary gastrointestinal tubes and restrictions onoral intake, and using nonopioid or opioid-reduced analgesia combined withearly oral nutrition) (Noble and Kehlet 2000).

Treatment of Preoperative AnxietyPreoperative anxiety is common in adults and children and has been treatedwith antianxiety medications, particularly benzodiazepines. Concerns havebeen expressed regarding whether preoperative sedating medication might de-lay discharge, especially because an increasing percentage of surgical proceduresare being carried out on an outpatient basis. A Cochrane review of 17 studiesfound no evidence of a difference in time to discharge from hospital in adultpatients who received anxiolytic premedication (Walker and Smith 2009).

Adults and Preoperative Anxiety

A number of randomized trials in adults in recent years have demonstrated thebenefits of benzodiazepines, although the studies vary in type of surgery,patient demographics, dosage, and timing of medication. Compared withplacebo, both oral diazepam (10 mg) in the evening before surgery and midaz-olam (1.5 mg) at least 15 minutes before surgery resulted in lower preoperativeanxiety and a reduction in the usual postoperative increase in cortisol levels(Pekcan et al. 2005). In women undergoing abdominal hysterectomy, diaz-


epam-treated patients showed lower postoperative anxiety and lower incidenceof surgical wound infection up to 30 days after surgery compared with thosegiven placebo (Levandovski et al. 2008). Another trial found that 50 mg clor-azepate the evening before surgery prevented increases in anxiety and sym-pathoadrenal activity (Meybohm et al. 2007).

Alternative medications have also been found beneficial. Both melatoninand clonidine, when given preoperatively, reduced anxiety equivalently, result-ing in less postoperative pain and less morphine consumption in women un-dergoing abdominal hysterectomy, compared with placebo (Caumo et al.2009). However, another study found that melatonin did not reduce anxietymore than placebo in elderly patients undergoing surgery (Capuzzo et al.2006). Premedication with 1,200 mg gabapentin improved (compared withplacebo) preoperative anxiety, postoperative analgesia, and early knee mobili-zation after arthroscopic knee surgery (Ménigaux et al. 2005). Preoperativegabapentin may have other benefits in addition to anxiolysis, including post-operative analgesia; attenuation of the hemodynamic response to laryngoscopyand intubation; and prevention of chronic postsurgical pain, postoperativenausea and vomiting, and delirium (Kong and Irwin 2007). However, the dataare not extensive, and another randomized trial found that although the simi-lar drug pregabalin (75–300 mg administered orally) increased perioperativesedation, it failed to reduce preoperative state anxiety or postoperative pain, orto improve the recovery process after minor elective surgery procedures (Whiteet al. 2009). Finally, in a trial in moderate- and high-risk female gynecologicalsurgery patients, Chen et al. (2008) reported that premedication with mirtaza-pine (30 mg) reduced the level of preoperative anxiety and the risk of postop-erative nausea and vomiting.

Children and Preoperative Anxiety

Anxiety regarding impending surgery occurs in up to 60% of children. Preop-erative anxiety in children has been associated with a number of problematicbehaviors, both preoperatively (e.g., agitation, crying, enuresis, the need forphysical restraint during anesthetic induction) and postoperatively (e.g., pain,sleeping disturbances, parent-child conflict, separation anxiety) (Wright et al.2007). A variety of pharmacological and nondrug interventions have beenstudied.


As in adults, most drug trials in children have been of benzodiazepines.In a Cochrane review of 61 studies of sedation for anxious children undergo-ing dental procedures, Matharu and Ashley (2006) were not able to reach anydefinitive conclusion regarding which was the most effective drug or methodof sedation.

Alternative routes of administration are more often needed in young chil-dren than in older patients (see also Chapter 1, “Pharmacokinetics, Pharma-codynamics, and Principles of Drug–Drug Interactions”). Sublingualmidazolam 0.2 mg/kg was found as efficacious as oral midazolam 0.5 mg/kg(Kattoh et al. 2008). Adverse temporary cognitive effects may occur after re-ceiving preoperative anxiolytics. A placebo-controlled trial of buccal midaz-olam (0.2 mg/kg) before anesthesia for multiple dental extractions in childrenfound that midazolam impaired reaction times and psychomotor coordina-tion at discharge, with recovery at 48 hours later. However, midazolam wasalso associated with significant postoperative anterograde amnesia (for infor-mation presented in the interval between premedication and surgery), whichpersisted at 48 hours (Millar et al. 2007).

Although midazolam is an effective anxiolytic for most children, a signif-icant minority do not benefit from it (Kain et al. 2007). One study found pre-operative clonidine or dexmedetomidine to have similar effects on anxietyand sedation postoperatively compared with midazolam; however, childrengiven either clonidine or dexmedetomidine had less perioperative sympa-thetic stimulation and less postoperative pain than those given midazolam(Schmidt et al. 2007). As in adults, there is some support for melatonin inchildren. In one trial, melatonin not only was as effective as midazolam in al-leviating preoperative anxiety in children, but also was associated with a ten-dency toward faster recovery, lower incidence of agitation postoperatively, anda lower incidence of sleep disturbance at week 2 postoperatively (Samarkandiet al. 2005).

Acute and Posttraumatic Stress in the Critical Care Setting

Posttraumatic stress symptoms and disorders can occur as a result of physicalinjury, disease phenomena, being in intensive care, and having surgery (Jack-


son et al. 2007). Although considerably less studied, acute stress disordersymptoms or early-onset posttraumatic stress disorder (PTSD) in the criticalcare setting are prevalent and appear to predict ongoing or later-onset PTSD(McKibben et al. 2008).

Psychopharmacological treatment of PTSD in the months after a severeinjury and/or ICU stay would be expected to follow usual treatment guide-lines, with SSRIs being first-line treatment. However, no RCTs have been re-ported to suggest treatment of patients with postsurgical or post-ICU PTSD.

Retrospective studies of PTSD prevention among soldiers who had sus-tained burns in combat and had at least one surgery revealed that intraopera-tive ketamine versus no ketamine (McGhee et al. 2008) was associated with asignificant reduction in incident PTSD, but pre- and intraoperative midaz-olam (McGhee et al. 2009b) and propranolol (McGhee et al. 2009a) had nosignificant relationship to PTSD. However, administration of ketamine im-mediately after a motor vehicle accident has also been found to increase PTSDincidence (Schonenberg et al. 2008), so further study is warranted. In a ret-rospective analysis of traumatic injury victims admitted to the hospital,higher morphine dosages in the week after injury were predictive of lower in-cidence of PTSD but not of major depression or other anxiety disorder, sug-gesting a beneficial effect of morphine on fear conditioning (Bryant et al.2009). A pilot RCT investigating a 14-day prevention strategy for PTSDamong hospitalized surgical trauma victims found no differences betweenpropranolol gabapentin, and placebo (Stein et al. 2007). Two RCTs haveshown that stress doses of hydrocortisone reduce PTSD symptoms after car-diac surgery (Schelling et al. 2004; Weis et al. 2006), and a very small RCTshowed similar results in septic shock (Schelling et al. 2001). In an RCT inacute adult trauma inpatients, fewer PTSD symptoms were observed in pa-tients undergoing a collaborative care intervention that included psychiatricmedication when indicated than in patients receiving usual care (Zatzick etal. 2004).

In summary, data on PTSD prevention are sparse, with studies limited bysmall sample size and retrospective data. Findings that intraoperative ket-amine, higher posttrauma morphine dosages, and stress corticosteroids aftertrauma and surgery are associated with lower rates of PTSD need to be cor-roborated by further prospective study with these agents, in addition to anti-depressants, which are virtually unstudied.


Adverse Neuropsychiatric Effects of Critical Care and Surgical DrugsDrugs used in surgery and critical care may have adverse neuropsychiatric ef-fects. These drugs are summarized in Table 15–1 and discussed below.

Nitrous Oxide

Nitrous oxide anesthesia has been associated with reversible and irreversiblecognitive impairment and psychotic symptoms; however, the causal nature of

Table 15–1. Psychiatric adverse effects of drugs used in surgery and critical care

Medication Psychiatric adverse effects

Inhalational anesthetics

Desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane

Malignant hyperthermia syndrome: delirium, autonomic instability, muscular rigidity, tremor

Neuromuscular blockers

Succinylcholine Malignant hyperthermia syndrome: delirium, autonomic instability, muscular rigidity, tremor

Nitrous oxide Psychosis, reversible and irreversible cognitive impairment

Sympathomimetic agents

Dobutamine, dopamine, epinephrine, isoproterenol, norepinephrine

Fear, anxiety, restlessness, tremor, insomnia, confusion, irritability, mania, psychosis

Vasodilators

Amrinone, isosorbide, milrinone, nesiritide, nitroglycerin, nitroprusside

Increased intracranial pressure, syncope

Intravenous sedative and anesthesia induction agents

Etomidate, midazolam, propofol

Excessive sedation, respiratory suppression, delirium (especially in combination with sedative-hypnotics and opioid analgesics)


these symptoms remains controversial because studies fail to account for mul-tiple concurrent causal factors (R.D. Sanders et al. 2008). Potential mecha-nisms proposed include antagonism of the N-methyl-D-aspartic acid receptorand disruption of cortical methionine synthase, which may lead to B12 andfolate deficiency. Women, young patients, and elderly patients with B12 defi-ciency appear to be most susceptible.

Inhalational Anesthetics and Succinylcholine

Inhalational anesthetics and succinylcholine may cause malignant hyperther-mia syndrome, which is similar to neuroleptic malignant syndrome (seeChapter 2, “Severe Drug Reactions”) in that it is characterized by delirium,autonomic instability, and rigidity. Antipsychotic medications have not beenreported to predispose to this effect. Like neuroleptic malignant syndrome,malignant hyperthermia syndrome is treated with dantrolene and supportivecare.

Sympathomimetic Amines

Sympathomimetic amines include dopamine, dobutamine, and other drugs.Central effects of these medications include fear, anxiety, restlessness, tremor,insomnia, confusion, irritability, weakness, psychotic states, appetite reduc-tion, nausea, and vomiting.

Vasodilator Hypotensive Agents

Vasodilator hypotensive agents include nitroglycerin and nitroprusside,among others. Increases in intracranial pressure can occur with central vasodi-lation. In patients whose intracranial pressure is already elevated, sodium ni-troprusside should be used only with extreme caution.

Drug–Drug InteractionsMultiple potential drug–drug interactions are possible due to the use ofpsychopharmacological agents in the critical care and perisurgical arena (seeTable 15–2). Most of these potential interactions (i.e., for antibiotics, corti-costeroids, analgesics, and cardiovascular medications) are covered in the rel-evant organ system disease chapters and in Chapter 1, “Pharmacokinetics,Pharmacodynamics, and Principles of Drug–Drug Interactions.” The focus

Surgery and

Critical Care

455

Table 15–2. Critical care and perisurgical drug–psychotropic drug interactionsMedication Interaction mechanism Effect(s) on psychotropic drugs and management

Inhalational anestheticsDesflurane, enflurane,

halothane, isoflurane, methoxyflurane, sevoflurane

Additive sedation

Additive hypotensive effect

Increased sedation with sedative-hypnotics and antihistaminic psychotropics (TCAs, antipsychotics).

Increased risk of hypotension with drugs that block alpha-1 adrenergic receptors (e.g., TCAs, MAOIs, typical and atypical antipsychotics).

Halothane: sensitization of myocardium

Arrhythmias with sympathomimetic psychotropics (NRIs, SNRIs, TCAs, psychostimulants).

Nitrous oxide Activation of supraspinal GABAA receptors

Sedative-hypnotics and propofol may block anesthetic activity of nitrous oxide.

Potentiation of noradrenergic mechanisms

Additive analgesia with noradrenergic agents (SNRIs, NRIs, TCAs).

Nondepolarizing neuromuscular blocking agentsPancuronium,

tubocurarineReversal of antinicotinic

neuromuscular blockadeCholinesterase inhibitors antagonize anesthesia due to these agents and should

be stopped 2 weeks before surgery.Unknown mechanism Lithium and carbamazepine have been found to both potentiate and inhibit

neuromuscular blockade.Depolarizing neuromuscular blocking agentsSuxamethonium

(succinylcholine)Increasing acetylcholine-

mediated neuromuscular depolarization

Cholinesterase inhibitors may prolong the duration of action of these agents.

Blockade of depolarization Psychotropics with anticholinergic properties (trihexyphenidyl, benztropine, TCAs, antipsychotics) may antagonize depolarization and reduce effectiveness.

456C



Sedative-hypnotic induction agentsEtomidate, midazolam,

propofolAdditive sedation Increased sedation with sedative-hypnotics and antihistaminic psychotropics

(TCAs, antipsychotics).Alpha-2 adrenergic sedativeDexmedetomidine Additive sedation Increased sedation with sedative-hypnotics and antihistaminic psychotropics

(TCAs, antipsychotics).Inhibits CYP 2D6 May inhibit the metabolism of psychotropics metabolized by this isoenzyme

(e.g., TCAs, mirtazapine, venlafaxine, risperidone, opioids, atomoxetine) if given chronically (see Chapter 1 in this volume), but no apparent interactions with short-term use.

Sympathomimetic inotropic and pressor agentsDopamine, epinephrine,

isoproterenol, norepinephrine

MAO inhibition

Reversal of pressor effect

Treatment with MAOIs 2–3 weeks prior to initiation of these agents may augment hypertensive effects and cause hypertensive crisis.

Risk of severe hypotension with coadministration of agents with beta-2 agonist activity (epinephrine, isoproterenol) and drugs that block alpha-1 adrenergic receptors (e.g., TCAs, typical and atypical antipsychotics). Norepinephrine should be used as a pressor agent in this situation.

Additive noradrenergic effects

With dopaminergic and noradrenergic psychotropics (e.g., bupropion, atomoxetine, duloxetine, TCAs), augmentation of hypertensive effects and CNS activation.

Dobutamine Hypokalemia Increased risk of cardiac arrhythmias with QT-prolonging agents, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium.

Table 15–2. Critical care and perisurgical drug–psychotropic drug interactions (continued)Medication Interaction mechanism Effect(s) on psychotropic drugs and management

Surgery and

Critical C

are4

57

VasodilatorsAmrinone, isosorbide,

milrinone, nesiritide, nitroglycerin, nitroprusside

Additive hypotensive effects Augmentation of hypotensive effects when combined with drugs that block alpha-1 adrenergic receptors (e.g., TCAs, MAOIs, typical and atypical antipsychotics) or with PDE5 inhibitors.

Note. CNS=central nervous system; CYP=cytochrome P450; GABAA=gamma-aminobutyric acid type A; MAO=monoamine oxidase;MAOI=monoamine oxidase inhibitor; NRI=norepinephrine reuptake inhibitor; PDE5=phosphodiesterase type 5; SNRI=serotonin–norepinephrine re-uptake inhibitor; TCA=tricyclic antidepressant.

Table 15–2. Critical care and perisurgical drug–psychotropic drug interactions (continued)Medication Interaction mechanism Effect(s) on psychotropic drugs and management


in this chapter is on anesthetic agents and intravenously administered agentsused in the coronary care setting.

Inhalational Anesthetics

Pharmacodynamic effects of inhalational anesthetics (e.g., enflurane, hal-othane, isoflurane, methoxyflurane, desflurane, sevoflurane) include excessivesedation and respiratory suppression with sedating psychotropic drugs (seda-tive-hypnotics, barbiturates, drugs with antihistaminergic properties) andhypotensive effects with alpha-1–blocking psychotropics (e.g., TCAs,MAOIs, antipsychotics). Halothane in combination with sympathomimeticpsychotropics (e.g., norepinephrine reuptake inhibitors [NRIs], serotonin–norepinephrine reuptake inhibitors [SNRIs], TCAs, psychostimulants) maycause arrhythmias secondary to halothane-induced myocardial sensitizationto these agents. Administration of anesthesia with halothane and neuromus-cular block with pancuronium in patients receiving TCAs has resulted in se-vere ventricular arrhythmias (Halothane package insert; Edwards et al. 1979).The mechanisms of neuroleptic malignant syndrome (see Chapter 2, “SevereDrug Reactions”) and malignant hyperthermia are thought to be divergent,and there are no reports of antipsychotic treatment increasing the risk of ma-lignant hyperthermia postoperatively.

Nitrous Oxide

The analgesic action of nitrous oxide is partially dependent on both the inhi-bition of supraspinal GABAA receptors and the activation of spinal GABAAreceptors. Agents that activate the supraspinal GABAA receptor, such as mi-dazolam and propofol, may interfere with nitrous oxide analgesia by inhibit-ing the activation of the descending inhibitory neurons (R.D. Sanders et al.2008). Noradrenergic agents (e.g., TCAs, SNRIs, and NRIs) and opioids maypotentiate analgesia due to nitrous oxide via its activation of locus coeruleusand opioidergic neurons.

Nondepolarizing Neuromuscular Blocking Agents

Nondepolarizing neuromuscular blocking agents (e.g., tubocurarine, pancu-ronium) act by competitive inhibition at nicotinic cholinergic receptors, pro-ducing paralysis. Cholinesterase inhibitors may antagonize this type ofneuromuscular blockade and, in fact, are used to reverse it. Cholinesterase in-


hibitors should be discontinued several weeks before surgery involving neu-romuscular blocking agents (Russell 2009). Lithium and carbamazepine mayboth potentiate and inhibit neuromuscular blockade by these agents (Meltonet al. 1993; Ostergaard et al. 1989).

Depolarizing Neuromuscular Blocking Agents

In contrast to the nondepolarizing agents, succinylcholine (suxamethonium)has acetylcholine-like actions; cholinesterase inhibitors prolong the durationof action of succinylcholine by inhibiting its plasma cholinesterase-mediatedmetabolism and increasing acetylcholine-mediated neuromuscular depolar-ization. Anticholinergic drugs may antagonize succinylcholine effects.

Sedative-Hypnotic Induction and Continuous Sedation Agents

Coadministration of sedative-hypnotic induction and continuous sedationagents (propofol, midazolam, etomidate) with CNS depressant psychotro-pics, including benzodiazepines, nonbenzodiazepine hypnotics, and antihis-taminic drugs, may synergistically result in excessive sedation and respiratorysuppression.

Dexmedetomidine

Because dexmedetomidine is a substrate and inhibitor of CYP 2D6, pharma-cokinetic interactions with some psychotropics might be expected, especiallywith prolonged infusion of this agent (see Chapter 1, “Pharmacokinetics,Pharmacodynamics, and Principles of Drug–Drug Interactions,” for a listingof CYP 2D6–interacting psychotropic drugs) (Karol and Maze 2000). Withshort-term use, dexmedetomidine does not appear to exhibit pharmacokineticinteractions. Dosage modifications of some concomitant medications (e.g.,some anesthetics, sedatives, hypnotics, antihistaminic medications, opioids)may be needed due primarily to common pharmacodynamic actions of thetwo drugs.

Sympathomimetic Agents

Sympathomimetic agents (e.g., dopamine, dobutamine, epinephrine, norepi-nephrine, isoproterenol) are often used for vasoconstriction, bronchodilatation,combination with local anesthetics, and treatment of hypersensitizing reactions.


Concurrent use of MAOIs (including tranylcypromine, phenelzine, moclobe-mide, and selegiline) with sympathomimetic agents may prolong and intensifycardiac stimulation and vasopressor effects because of increased release of cate-cholamines, which accumulate in intraneuronal storage sites during MAOItherapy. This interaction may result in headache, cardiac arrhythmias, vomit-ing, or sudden and severe hypertensive and/or hyperpyretic crises. For patientswho have been receiving MAOIs within 2–3 weeks prior to administration ofsympathomimetic agents, the initial dosage of dopamine should be reduced tono more than one-tenth of the usual dosage.

Dopamine may interact pharmacodynamically with noradrenergic agents,such as TCAs, NRIs, SNRIs, and psychostimulants, to cause a marked increasein heart rate and/or blood pressure. Patients with preexisting hypertensionmay have increased risk of an exaggerated pressor response with these drugs.Dobutamine may cause hypokalemia, so that administration of this drug withQTc-prolonging psychotropic drugs requires close cardiac and serum potas-sium monitoring. Unlike dopamine, dobutamine does not appear to be anMAO substrate (Yan et al. 2002); however, absent substantial clinical data,caution is warranted when combining dobutamine with irreversible MAOIs.

Vasodilators

The principal pharmacological action of vasodilators (isosorbide dinitrate andmononitrate, nitroglycerin, nitroprusside, milrinone, amrinone, nesiritide) isrelaxation of vascular smooth muscle and consequent dilatation of peripheralarteries and veins. Excessive hypotension may result through additive effectswhen vasodilators are used with psychotropics with alpha-1 antagonist prop-erties, such as TCAs, MAOIs, and phenothiazines; atypical antipsychotics;and phosphodiesterase type 5 inhibitors, such as sildenafil, vardenafil, andtadalafil.

Key Clinical Points

Delirium

• The differential diagnosis of delirium is broad. Prevention andtreatment require early assessment of patients at risk, identifica-tion and treatment of underlying causes (including avoiding


where possible anticholinergic, sedative-hypnotic, antihista-minic, opioid analgesic and corticosteroid drugs), environmentalintervention, and psychopharmacology.

• For the prevention of delirium, a small number of RCTs in selectpatient populations undergoing surgery support the efficacy ofolanzapine and dexmedetomidine in reducing the incidence ofdelirium and haloperidol in reducing the severity and durationof delirium.

• For the treatment of delirium not due to sedative or alcohol with-drawal, RCTs support the efficacy of haloperidol (oral or pa-renteral), chlorpromazine, olanzapine, risperidone, and dex-medetomidine, whereas benzodiazepines are less effective ordeleterious.

• Currently, haloperidol remains the gold-standard treatment fordelirium except in patients who have elevated risk for EPS, whoare allergic, or who are being considered for intravenous admin-istration and have a prolonged QTc interval.

Psychotropics in the Perioperative Period

• The decision to continue or stop a psychotropic drug in the peri-operative period should be individualized, with consideration ofthe extent of surgery, the patient’s medical condition, choice ofanesthetic agents, length of preoperative fasting and the risks ofdrug discontinuation (withdrawal or relapse of psychiatric disor-der).

• The greatest perioperative risk exists with lithium, MAOIs, TCAs,and clozapine.

Preoperative Anxiety and Posttraumatic Stress Disorder

• For preoperative anxiety in adults and children, benzodiazepinesare the most widely used agents, however, other agents such asgabapentin, and alpha-adrenergic antagonist agents such asclonidine and dexmedetomidine, may be viable alternatives.

• For PTSD secondary to illness or injury, evidence from small RCTssuggests efficacy of stress doses of hydrocortisone in reducingPTSD symptoms after cardiac surgery and septic shock. Evidence


for other agents, such as propranolol, intraoperative ketamine,and opioid analgesics, is scant and inconclusive.

Drug Interactions

• There is significant potential for pharmacodynamic and phar-macokinetic interactions between psychotropic drugs and an-esthetics and other agents used in the critical setting. In thissetting, the prescription of psychotropic drugs should be donewith caution, particularly because of the severity of medical co-morbidity and the use of multiple medications concurrently.

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469

16Organ Transplantation


Catherine C. Crone, M.D.

Marian Fireman, M.D.

Transplantation engenders many biopsychosocial stressors, resulting in ratesof anxiety and mood symptoms, delirium, and cognitive disorders in transplantcohorts that are similar to or higher than rates in other medically ill populations.Untreated psychiatric disorders can impact psychiatric as well as transplantmedical outcomes and adherence to necessary posttransplant routines. Phar-macotherapy is an essential component in the psychiatric care of many trans-plant patients.

Organ disease alters many aspects of drug pharmacokinetics, changing thebioavailability and disposition of medications and both the intended thera-peutic action and side effects. For a full review of pharmacokinetics of psycho-tropic drugs in general and in hepatic, renal, bowel, heart, and lung diseases


in particular, the reader is referred to Chapter 1, “Pharmacokinetics, Pharma-codynamics, and Principles of Drug–Drug Interactions,” and the respectivechapters on these organ systems. Our primary focus for this chapter is on keypoints in the management of psychopathology in adult transplant patients.Topics include the physiological properties of the newly transplanted organ asthis relates to drug pharmacokinetics, the psychopharmacological treatmentof psychiatric illness that arises pretransplant to posttransplant, and the neuro-psychiatric adverse effects and drug–drug interactions related to immunosup-pressant medications. Considering these pharmacological issues and the wideinterpatient variability, we provide guidelines for drug choice and dosing.

Posttransplant Pharmacological ConsiderationsPosttransplant Organ Functioning

For the majority of recipients, a newly transplanted organ functions immedi-ately such that normal physiological parameters are quickly restored andpharmacokinetic abnormalities resolve. For patients with stable liver or kid-ney functioning within the first month following transplant, the clearanceand steady-state volume of distribution of drugs have been shown to be sim-ilar to those of normal healthy volunteers (Herbert et al. 2003). Thus, mosttransplant recipients can be treated using normal therapeutic drug dosing, as-suming that patients have recovered from the immediate postoperative com-plications (e.g., sedation, delirium, ileus, ability to take oral medications).

For some recipients, however, the transplanted organ does not assume au-tonomous normal physiological functioning immediately or the organ mayassume normal functioning slowly over time. Posttransplant pharmacokineticstudies addressing these issues have been conducted mostly in liver and kid-ney recipients due to the importance of these organs in drug pharmacokinet-ics. Such studies have only investigated immunosuppressive medications dueto the need to achieve and maintain stable immunosuppressant levels to pre-vent organ rejection, the ability to monitor serum levels, and the narrow ther-apeutic range of these drugs. These data can provide general guidance onpsychotropic medication prescribing in specific types of posttransplant organdysfunction.

Primary nonfunction, occurring in 3%–4% of liver and renal transplantrecipients (Kemmer et al. 2007; U.S. Renal Data System 2008), is primary

Organ Transplantation 471

graft failure that results in death or retransplantation within 30 days of thetransplant. For liver recipients with primary nonfunction, survival beyond thefifth postoperative day is uncommon, and life support until another organ be-comes available is the focus of therapy. The intensive care unit team will oftenuse intravenous benzodiazepines, propofol, dexmedetomidine, or narcoticsfor rapid sedation and pain management.

The most common allograft complication affecting pharmacokinetics inthe immediate posttransplant period is delayed graft function (DGF). DGFoccurs in 10%–50% of liver recipients (Angelico 2005). Such patients wereshown to require one-half of the immunosuppressant dosage required bythose without DGF, and these dosing requirements did not correlate withbody weight. This finding suggests that in the early posttransplant period,metabolic capacity rather than volume of distribution is the critical factor inpharmacokinetics (Herbert et al. 2003; Luck et al. 2004).

DGF occurs in 25%–50% of renal transplant recipients and is defined asthe recipient’s requiring dialysis within the first week of transplant (Shoskesand Cecka 1998; U.S. Renal Data System 2008). Immunosuppressant phar-macokinetic studies show that DGF alters pharmacokinetics by mechanismsthat increase the free fraction of parent drugs and renally excreted metabolites(Shaw et al. 1998). Delayed renal elimination of immunosuppressants for pa-tients in severe or acute renal impairment posttransplant can result in levels3–6 times higher than those in nonimpaired recipients for both renally ex-creted drugs and their metabolites (Bullingham et al. 1998; Shaw et al. 1998).DGF also affects the binding of drugs to plasma proteins even in the absenceof hypoalbuminemia (Shaw et al. 1998).

Posttransplant Organ Rejection

Acute cellular rejection occurs in 20%–70% of liver transplant recipients,most often within the first 3 weeks posttransplant, and results in transientgraft dysfunction. Delirium may be a clinical manifestation. Acute rejectionis most commonly treated with high-dose steroids, effective in 65%–80% ofcases. Alternative therapies, required in about 15% of cases, include antibodytreatments, such as monoclonal therapy or antithymocyte globulin (Lake2003), which can cause serious neuropsychiatric side effects (see “Neuropsy-chiatric Effects of Immunosuppressant Medications and Their Treatment”later in this chapter).


Chronic graft rejection, manifested by gradual obliteration of small bileducts and microvascular changes, occurs in about 5%–10% of liver recipientsand responds poorly to changes in immunosuppression. Patients may havejaundice and/or difficult-to-manage pruritus. Loss of liver synthetic functionmay not be evident until very late in the course (Lake 2003).

An estimated 20%–60% of kidney recipients will experience an episodeof acute rejection, most often within the first 6 months after transplant. How-ever, up to 25%–30% of recipients with stable or improving renal functionwill actually be in an undetected rejection episode (Rush et al. 1998; R. Sha-piro et al. 2001). With treatment, acute or chronic rejection typically resolvesquickly with restoration of prerejection renal function, whereas undetectedsubclinical rejection can result in gradually worsening renal function overtime, with eventual graft loss (Rush et al. 1998).

Nearly 50% of heart transplant recipients will experience an episode ofacute rejection (either humoral or cellular) within the first posttransplantyear. Most episodes are treated with the addition of steroids to the baselineimmunosuppressive regimen. Ischemic injury usually occurs in the early post-transplant period, and can also cause allograft dysfunction (Michaels et al.2003). Sinus node dysfunction or atrioventricular block requiring permanentpacing occurs in 5%–19% of heart transplant recipients and may be associ-ated with rejection (Collins et al. 2003). Conduction delay may be importantfor psychotropics that can cause or worsen this phenomenon (e.g., tricyclicantidepressants [TCAs] and antipsychotics).

General Posttransplant Issues

In addition to overt DGF or rejection, some recipients will have transientphysiological abnormalities in the weeks following transplant that could alsoaffect pharmacokinetics (e.g., liver congestion and/or renal hypoperfusion inheart recipients, fluid overload in renal recipients, and liver hypoperfusionand fluid overload in liver recipients). Liver transplant patients often developpretransplant altered hemodynamics with fluid retention (i.e., ascites, periph-eral edema, pleural effusions) and/or hepatorenal syndrome. Generally, oncenormal hemodynamics are restored posttransplant, hepatorenal syndrome re-solves. Nonetheless, up to 20% of patients may develop persisting fluid reten-tion in the form of moderate to large pleural and peritoneal fluid collections,resulting in fluctuating drug volume of distribution. In addition, nearly 20%


of liver recipients require postoperative dialysis in the days to weeks followingtransplant, mostly to treat resolving hepatorenal syndrome and volume over-load (Contreras et al. 2002). Principles of psychotropic management duringhemodialysis should be employed (see Chapter 5, “Renal and Urological Dis-orders”).

In addition, underlying disease processes or other comorbid organ insuf-ficiencies that are not corrected by organ transplant may impact drug phar-macokinetics. For example, patients with cystic fibrosis who receive a lungtransplant may continue to have delayed gastric emptying, pancreatic insuffi-ciency with malabsorption, and altered liver metabolism and renal clearancethat impair normal cyclosporine kinetics (Reynaud-Gaubert et al. 1997).

Chronic graft rejection is potentially reversible in the early stages, but notonce chronic dysfunction has set in and progressive graft failure may occur.Thus, for transplant recipients, adherence to lifelong immunosuppressants iscritical. Unfortunately, for all organ types, immunosuppressant nonadher-ence is a major risk factor for rejection and may be responsible for up to 25%–30% of graft loss and late deaths after the initial recovery period (Bunzel andLaederach-Hofmann 2000; Schweizer et al. 1990). Attempts to identify andalleviate immunosuppressant side effects may improve adherence. Unfortu-nately, the treatment of most types of graft dysfunction (DGF or acute orchronic rejection) typically requires an increase in the dosage of the primarycalcineurin-inhibiting medication and/or addition of other immunosuppres-sants, including monoclonal antibodies, steroids, mycophenolate, or siroli-mus, which tend to create or exacerbate neuropsychiatric side effects (see“Neuropsychiatric Effects of Immunosuppressant Medications and TheirTreatment” later in this chapter). Additionally, depression has been impli-cated in cases of nonadherence, and mood symptoms should be elicited andtreated.

Finally, for all organ types, calcineurin-inhibiting immunosuppressantsare nephrotoxic, and chronic use results in renal failure for 10%–20% of re-cipients by 5 years posttransplant (Ojo et al. 2003). Thus, the quality of renalfunction should always be considered, especially for long-term transplant re-cipients.

With the resumption of normal graft function, psychotropic medicationsthat may have been prescribed in lower dosages pretransplant, to account fordiminished metabolism or elimination, may need to be adjusted to higher


dosages posttransplant. Another important consideration is pain manage-ment for patients taking chronic opioids pretransplant; higher than averagedosages of narcotic analgesics may be required perioperatively. In one specificexample, patients taking methadone maintenance therapy, for whom metha-done was also used as their postoperative pain medication, required an aver-age methadone dosage increase of 60% posttransplant, presumably to adjustfor chronic downregulation of μ-opiate pain receptors from chronic metha-done exposure (Weinrieb et al. 2004) and improvement in metabolism post-transplant.

Living Organ Donation Issues: Recipients and Donors

Living donor liver transplant recipients make up only 4% of liver transplantprocedures in the United States (Health Resources and Services Administra-tion Division of Transplantation 2006), but these recipients require specialpharmacological consideration. Because living donor liver transplant recipi-ents receive grafts that are 55%–60% of normal liver volume, they initiallyrequire smaller doses of medication. Pharmacokinetic studies with immuno-suppressants suggest that medication doses should be reduced by 30% com-pared with doses given to deceased donor recipients to achieve similartherapeutic levels in the early postoperative period (Jain et al. 2008). In addi-tion to the fact that a reduced-size liver clears drugs less readily, animal modelssuggest that glucuronide conjugation is impaired during the first severalweeks of hepatic regeneration (Jain et al. 2008).

Living donor liver transplant recipients can experience an uncommontechnical complication termed small-for-size syndrome (SFSS). SFSS occurswhen a partial liver graft is unable to meet the functional demands of the re-cipient, resulting in a clinical syndrome characterized by postoperative liverdysfunction. The incidence of SFSS is reported to be in the 5%–10% rangeafter partial liver transplant, but may be higher depending on the status of therecipient and the type of graft used (Tucker and Heaton 2005). SFSS is char-acterized by prolonged cholestasis, elevated liver enzymes, and coagulopathycombined with manifestations of portal hypertension such as ascites. With-out any intervention, approximately 50% of recipients with SFSS will die ofsepsis within 4–6 weeks posttransplant (Dahm et al. 2005). Using psychotro-pics in these patients requires close attention to liver function, fluid status,and coagulopathy.


For living liver donors, little is known about the rate and extent of the res-toration of hepatic function, especially following right lobe hepatectomy, aprocedure involving more extensive removal of hepatic tissue (50%–60% ofthe liver mass). Existing literature suggests that the liver mass of donors canreturn to approximately 80%–100% of baseline by several weeks to monthsfollowing donation, despite biochemical abnormalities persisting beyond2 months (Emre 2001; Nadalin et al. 2004). One preliminary study of donorliver function showed that hepatic galactose elimination capacity, a measureof liver function, was only 50% by 10 days following hepatic resection despiterapid return of liver volume (Jochum et al. 2006). By 3 months, completefunction was restored (Jochum et al. 2006).

Psychotropic considerations for live liver donors must take into accountthe time since donation and the potential for incomplete restoration of met-abolic capacity. Long-term hepatic function in liver donors is unknown butassumed to return to normal. Several studies of liver donors’ psychologicaloutcomes evaluated using specific psychiatric assessments found that substan-tial percentages of liver donors, 10%–14%, meet criteria for diagnosable de-pressive and/or anxiety disorders within the first year postdonation (Erim etal. 2006, 2007; Fukunishi et al. 2001).

Kidney donors lose half of their functional nephron mass with donor ne-phrectomy. In the year following nephrectomy, donor creatinine clearancecan decrease by 30% compared with preoperative levels, but still be withinnormal limits (Bieniasz et al. 2009). With long-term follow-up, kidney do-nors continue to have 72%–77% of predonation creatinine clearance and anincidence of proteinuria as high as 19%–31% (Najarian et al. 1992; Zafar etal. 2002). Although most donors experience a decrease in glomerular filtra-tion rate immediately after donation, the risk of end-stage renal failure is low,approximately 0.2%–0.5% (Azar et al. 2007). In one study, after 1-year fol-low-up, 9.3% of donors were prescribed antidepressants for severe depression,suggesting a substantial need for psychotropics in donors (Azar et al. 2007).

Psychotropic Medications in Transplant PatientsAlthough no psychotropic medication is absolutely contraindicated for use intransplant patients, specific precautions and careful selection are necessary.Patients in end-stage organ failure are typically more sensitive to medication


side effects. For example, patients with psychomotor retardation or cognitiveimpairment due to uremia, hypoxia, or hepatic encephalopathy often cannottolerate psychotropics with significant sedating side effects (e.g., benzodiaz-epines, mirtazapine, paroxetine). Pharmacokinetic changes (e.g., delayed ab-sorption, altered volume of distribution, impaired metabolism, reducedexcretion) caused by organ failure will also require dosing adjustments.

After transplant, drug–drug interactions become a greater concern becausepatients are maintained on a broad array of medications (e.g., immunosup-pressants, antihypertensives, antibiotics, lipid-lowering agents, hypoglycemicdrugs). In the following subsections, we provide guidance regarding the selec-tion of psychotropics by drug class with respect to specific side effects andorgan disease. These guidelines apply both to pretransplant patients with or-gan failure and posttransplant patients without complete restoration of organfunction. Because few data are available specifically on transplant patients, in-formation on nontransplant patients with advanced organ disease is included.

Antidepressants

The prevalence of depressive and anxiety disorders among transplant patientsis high and contributes to increased morbidity and mortality if left untreated.Patients often do well with antidepressant therapy, and appropriate medica-tion treatment should not be avoided due to concerns over organ disease.Antidepressants may provide additional benefits to the management of organfailure symptoms, such as nausea, anorexia, insomnia, pruritus, and intradia-lytic hypotension. Posttransplant, antidepressants can be helpful not only forprimary psychiatric disorders but also for disorders that are secondary to im-munosuppressants.


Selective serotonin reuptake inhibitors (SSRIs) are the primary choice fortransplant patients due to their relative safety. Although relatively unstudiedin posttransplant patients, citalopram, sertraline, paroxetine, and fluoxetinehave been studied to varying degrees in patients with end-stage organ disease(Gottlieb et al. 2007; Kalender et al. 2007; Lacasse et al. 2004), with generallypositive results; however, caution must be exercised due to the very limitednumber of randomized controlled trials.


SSRIs inhibit platelet activation and may prolong bleeding time. Al-though possibly beneficial for those patients with congestive heart failure whoare prone to thromboembolism, SSRIs carry some risk for patients with cir-rhosis, who are prone to bleeding due to varices, coagulopathy, and thrombo-cytopenia (Serebruany et al. 2003; Weinrieb et al. 2003). SSRIs should beused with caution in patients already taking drugs that increase bleeding risk(e.g., acetylsalicylic acid [aspirin] and other nonsteroidal anti-inflammatorydrugs, or antiplatelet agents) (Weinrieb et al. 2005).

Among the SSRIs, citalopram and escitalopram likely offer the greatest tol-erability with the fewest drug–drug interactions. Citalopram was effective formild to moderate depression in depressed lung transplant recipients (Silver-tooth et al. 2004).

Sertraline has the second fewest drug interactions of the SSRIs. It signifi-cantly reduced itch scores in cholestatic jaundice patients, independent of effectson depression (Mayo et al. 2007). In dialysis patients, it lessened intradialytichypotension, a common hemodialysis complication (Yalcin et al. 2002).

Paroxetine is generally associated with greater weight gain than otherSSRIs, which may be beneficial for poor nutritional status, a common prob-lem among patients with end-stage organ disease. In depressed patients withend-stage renal disease, paroxetine combined with psychotherapy reduced de-pression and improved nutritional status (e.g., serum albumin, predialysisblood urea nitrogen) (Koo et al. 2005). Tolerability is a concern due to parox-etine’s anticholinergic side effects and discontinuation syndrome.

Mirtazapine

Mirtazapine is a unique agent that preferentially blocks presynaptic alpha-2,histamine, and 5-hydroxytryptamine type 2 (5-HT2) and type 3 (5-HT3) re-ceptors. By blocking 5-HT3 receptors, mirtazapine provides antiemetic ef-fects, a valuable feature for transplant patients with nausea from medicationsand organ failure (Kim et al. 2004). Mirtazapine may relieve persistent pruri-tus caused by uremia or cholestasis by blockade of histamine, 5-HT2, and 5-HT3 receptors (Davis et al. 2003). It may improve appetite and promoteweight gain, which can be advantageous for some patients, but followingtransplant, mirtazapine may accentuate immunosuppressant-induced weightgain and hyperlipidemia (Kim et al. 2004; McIntyre et al. 2006). It may causeagranulocytosis, neutropenia, and other reductions in hematological parame-


ters and should be used cautiously in patients taking drugs that can causeblood dyscrasias (e.g., immunosuppressants, interferon). Although rare, theseevents can be especially serious in immunocompromised patients. Becausemirtazapine lacks inhibitory effects on cytochrome P450 (CYP) isozymes,there is little risk of drug–drug interactions (Crone and Gabriel 2004).

Bupropion

Although the activating side effects associated with bupropion can be difficultfor some patients to tolerate, activation and lack of sedation can be useful fortransplant patients with persistent fatigue. Bupropion may also be useful forsmoking cessation (Wagena et al. 2005). It can elevate blood pressure andshould be used with caution in end-stage organ disease and posttransplant pa-tients with preexisting and persistent hypertension associated with immuno-suppressants. Although the risk of seizures is low at therapeutic doses, cautioususe is required for patients at risk for seizures from other causes (e.g., hepaticencephalopathy, high-dose immunosuppression).

Serotonin-Norepinephrine Reuptake Inhibitors

Venlafaxine and duloxetine can elevate blood pressure, and caution should beexercised as with bupropion. Duloxetine has been reported to cause severeliver toxicity in rare cases (McIntyre et al. 2008; see also Chapter 4, “Gas-trointestinal Disorders”).

Nefazodone

The risk of serious hepatotoxicity and CYP 3A4 inhibition makes nefazodonean undesirable choice for transplant patients. There have been several cases ofimmunosuppressant toxicity due to nefazodone’s inhibiting CYP 3A4 (see“Drug–Drug Interactions” later in this chapter).

Trazodone

Trazodone is similar in action to nefazodone but lacks significant hepatotox-icity. The sedating side effects are helpful for persistent insomnia, but may beintolerable for patients with psychomotor slowing or cognitive impairment,common among patients with end-stage organ disease and neuropsychiatricside effects from immunosuppressants. Care is needed in those heart diseasepatients who are more prone to its orthostatic and arrhythmogenic effects.Trazodone does not appear to have effects on the CYP isozymes.


Tricyclic Antidepressants

TCAs are a secondary choice in the transplant population due to safety andtolerability issues. TCAs have significant effects on the cardiovascular system,producing quinidine-like (Type 1A) antiarrhythmic activity, orthostatic hypo-tension, intraventricular conduction delay, and increased heart rate (Fusar-Poli et al. 2006). Weight gain, changes in lipid levels, and anticholinergic sideeffects may be undesirable for transplant patients (McIntyre et al. 2008). Sec-ondary amine TCAs (desipramine, nortriptyline) are preferred over tertiaryamine TCAs due to a less severe adverse-effect profile. Nortriptyline offers theadvantage of established therapeutic drug levels and reports of safe use in sometransplant recipients (Kay et al. 1991; P.A. Shapiro 1991).

Monoamine Oxidase Inhibitors

In general, monoamine oxidase inhibitors pose an excessive risk for safety andtolerability (e.g., drug–drug interactions, potential hypertensive crises) intransplant patients. Transdermal selegiline may be an option for those treat-ment-resistant patients who are unable to take oral medications or who lackadequate bowel absorption (Pae et al. 2007; see also Chapter 3, “AlternateRoutes of Drug Administration”).

Psychostimulants

Methylphenidate and dextroamphetamine are effective for short-term treat-ment of depressive symptoms in medically ill patients. Both offer the advan-tage of rapid onset of action and are useful in reducing apathy, fatigue, andcognitive dulling. Methylphenidate was markedly effective for at least four ofeight liver transplant patients experiencing depression, apathy, and cognitiveimpairment (Plutchik et al. 1998). Although supraventricular tachycardia hasbeen reported in a heart recipient treated with methylphenidate, stimulantshave been used safely in patients with significant cardiac disease withoutmarked changes in blood pressure or heart rate (Come and Shapiro 2005;Masand et al. 1991). Nevertheless, close monitoring for elevations in bloodpressure or heart rate or for worsening congestive heart failure is necessary.

Modafinil has been used clinically in transplant patients; however, partic-ularly at doses of 400 mg/day or more, modafinil inhibits CYP 2C9 and 2C19and induces CYP 1A2, 2D6, and 3A4, which may be problematic in combi-


nation with immunosuppressants (see “Drug–Drug Interactions” later in thischapter). Armodafinil has metabolic interactions similar to those of modafinil.

No reports of atomoxetine use in transplant patients have been published.However, because of CYP 2D6 inhibition and recent warnings of hepatotox-icity, other psychostimulants are preferred.

Benzodiazepines

Benzodiazepines are effective in providing anxiolysis to transplant patients, butmay worsen sedation, respiratory suppression, preexisting cognitive impair-ment, or encephalopathy in patients with end-stage organ disease. Lorazepam,oxazepam, and temazepam require only glucuronidation and may be a saferchoice in patients with cirrhosis (Crone and Gabriel 2004) or impaired post-transplant hepatic function. Clonazepam has been successfully used to managesteroid-induced mania in transplant recipients (Viswanathan and Glickman1989).

Antipsychotic Agents

Antipsychotics are commonly used for transplant patients to manage agitationand psychosis associated with acute delirium, mood disorders secondary to im-munosuppressants (e.g., mania), and comorbid primary psychiatric disorders(e.g., bipolar disorder, schizophrenia). They can also be used for anxiolysis(e.g., in patients with advanced pulmonary disease or patients being weaned offventilators). A concern is their risk of QTc prolongation, torsade de pointes,and sudden death (Haddad and Anderson 2002; Pacher and Kecskemeti 2004;see also Chapter 6, “Cardiovascular Disorders”). Transplant patients often haveother risk factors for cardiac arrhythmia (e.g., electrolyte imbalance, renal orhepatic disease, heart failure, ventricular hypertrophy, other QTc-prolongingdrugs) (Haddad and Anderson 2002; Zareba and Lin 2003).

Haloperidol

Haloperidol is the primary typical antipsychotic used in transplant patientsdue to its varied routes of administration, therapeutic efficacy, overall tolera-bility, and few side effects. It is an excellent choice for managing agitationand/or psychosis in delirious transplant patients (see also Chapter 15, “Sur-gery and Critical Care”). In rare cases, extremely high doses of intravenoushaloperidol (>1,000 mg/day) have been safely used to control severe agitation


(Levenson 1995). Haloperidol can also treat psychosis from immunosuppres-sant neurotoxicity (see “Neuropsychiatric Effects of ImmunosuppressantMedications and Their Treatment” later in this chapter) (Tripathi and Panzer1993). Extrapyramidal side effects should be monitored in transplant patientswith encephalopathy.

Atypical Antipsychotics

Atypical antipsychotics may be employed for agitation, insomnia, anxiety,mania, and delirium associated with end-stage organ disease or posttransplantimmunosuppressant reactions; however, no literature specific to transplanthas been published. Atypical antipsychotics may cause weight gain, hyper-lipidemia, and glucose intolerance, exacerbating the similar effects of immu-nosuppressant drugs.

Mood Stabilizers

Lithium is complicated to use in patients awaiting transplant and those whoare recent recipients due to problems with fluid imbalance. Other mood sta-bilizers pose more of a challenge after transplant because they interact withimmunosuppressants, altering immunosuppressant drug levels. The choice ofmood stabilizer for a transplant patient depends on the patient’s history ofsymptoms and prior treatment and type of organ disease.

Lithium

Maintaining lithium levels within a narrow therapeutic window is compli-cated in transplant patients. In patients with dehydration, congestive heartfailure, cirrhosis, nephrotic syndrome, or cystic fibrosis, sodium retentionmechanisms are activated and lithium clearance is reduced (Thomsen andSchou 1999). Fluctuating fluid status from dehydration (due to fever, sweat-ing, or decreased intake) or fluid overload (e.g., edema, ascites) can also makemaintenance of stable nontoxic lithium levels difficult (Thomsen and Schou1999). Cyclosporine, a common immunosuppressant, increases lithium levelsby altering proximal tubular reabsorption (Vincent et al. 1987). Other drugsused before or after transplant (e.g., angiotensin-converting enzyme inhibi-tors, spironolactone, calcium channel blockers) can alter lithium levels. Lith-ium can cause renal tubular damage with loss of urine concentrating ability(see Chapter 5, “Renal and Urological Disorders”). Posttransplant, these po-


tential adverse effects of lithium must be carefully considered, especially whencombined with nephrotoxic immunosuppressant therapy. Lithium can causeweight gain, cognitive slowing, and tremor, potentially aggravating commonposttransplant problems (DasGupta and Jefferson 1990).

Valproic Acid

Valproic acid is a less desirable choice for patients with preexisting hepatic im-pairment, and its use for treatment of short-term immunosuppressant moodinstability is not advisable given its potentially serious side effects (e.g., hepa-totoxicity, thrombocytopenia, platelet dysfunction). Reduced serum albuminconcentrations due to cirrhosis, renal disease, cachexia, other catabolic states,and elevated free fatty acid concentrations in the setting of diabetes, hemodi-alysis, and hypertriglyceridemia can raise free valproic acid levels, resulting inan increased risk of sedation, cognitive slowing, and lethargy (Haroldson etal. 2000).

Carbamazepine and Oxcarbazepine

Carbamazepine may cause leukopenia and poses a rare risk of serious blooddyscrasias, including aplastic anemia and agranulocytosis, which are espe-cially concerning for patients taking immunosuppressants or those who areimmunocompromised due to end-stage organ disease (Schatzberg et al.2007). It may alter vitamin D levels and bone turnover, potentially increasingthe risk for osteoporosis from immunosuppressant therapy (Mintzer et al.2006). In patients with renal failure or cirrhosis, levels of carbamazepine andits pharmacologically active metabolite 10,11-epoxide should be closely mon-itored (Tutor-Crespo et al. 2008). Carbamazepine may induce CYP 3A4,lowering tacrolimus and cyclosporine levels (see “Drug–Drug Interactions”later in this chapter). Oxcarbazepine, while not associated with blood dyscra-sias, is a weak inducer of CYP 3A4 and can reduce immunosuppressant levels(Rosche et al. 2001; Wang and Ketter 2002). Hyponatremia has been ob-served in up to 25%–50% of patients treated with oxcarbazepine, and oxcar-bazepine use has also been associated with lower vitamin D levels andincreased bone turnover (Asconape 2002; Mintzer et al. 2006).

Gabapentin

Gabapentin can be used to treat anxiety disorders, neuropathic pain (e.g., im-munosuppressant-induced neuropathy, postherpetic neuralgia), restless legs


syndrome, and uremic pruritus (Coleman and Stadel 1999; Molnar et al.2006; Naini et al. 2007). These conditions are common in transplant pa-tients, particularly those with renal failure. Because gabapentin is renally ex-creted rather than hepatically metabolized, the dosage must be reduced inproportion to the decline in creatinine clearance (Wong et al. 1995).

Topiramate

Topiramate is generally undesirable for transplant patients because of its ten-dency to cause cognitive impairment and possible metabolic acidosis (Schatz-berg et al. 2007). Cognitive side effects are especially problematic for patientswith cognitive dysfunction due to end-stage organ disease or high-dose immu-nosuppressants.

Medications Used to Treat Substance Use Disorders

Medications to reduce cravings or block the effect of substances and poten-tially diminish relapse risk for alcohol, opioids, and tobacco have not beenstudied in transplant patients. Nevertheless, the known pharmacodynamicsof these drugs can provide guidance for their use (see Chapter 18, “SubstanceUse Disorders”).

For treating alcohol dependence, disulfiram is not advised in transplantpatients due to possible serious side effects and significant interactions withdrugs requiring CYP metabolism (e.g., posttransplant immunosuppressants)(Chick 1999; DiMartini et al. 2005; Krahn and DiMartini 2005). Acampro-sate should be used cautiously because rare cases of cardiomyopathy, heartfailure, and renal failure have occurred. In renal impairment (creatinine clear-ance 30–50 mL/min), half dose should be given. It is contraindicated for cre-atinine clearance of 30 mL/min or less (Overman et al. 2003; Savin et al.1998). Naltrexone, an opioid antagonist, is contraindicated in severe hepaticdisease and may cause hepatotoxicity, particularly at dosages of 300 mg/dayor more (Krahn and DiMartini 2005). Acute worsening of hepatic functionhas been noted when used in therapeutic doses to treat itching in patientswith hepatic failure (J. Schwartz, personal communication, March 2008).Postoperative use is contraindicated because of antagonism of opioid analge-sia. Patients surveyed following liver transplant were reluctant to use naltrex-one due to potential hepatotoxicity (Weinrieb et al. 2001).


For nicotine dependence, nicotine replacement therapies are generallycontraindicated in patients with serious heart disease due to the potential forincreasing angina and heart rate and possibly exacerbating arrhythmias. Cau-tion is advised, especially in heart transplant patients. Varenicline is renallyexcreted, and dose reductions are recommended in patients who have renalinsufficiency or those undergoing dialysis. Side effects (i.e., nausea and vom-iting) may be problematic in transplant patients.

Transplant patients undergoing methadone maintenance therapy for opi-oid dependence can be successfully managed, including through the provi-sion of adequate postoperative analgesia. In patients with renal and hepaticfailure, dose adjustment may be needed to minimize side effects and preventworsening uremic or hepatic encephalopathy; however, higher doses may berequired posttransplant due to resumption of normal metabolic capacity. Pe-rioperatively, patients undergoing methadone maintenance therapy requirecareful attention to pain control. The dose can be increased for pain controlor continued at maintenance dose with a different opioid added for acutepostoperative pain. Sedation, respiratory depression, and other symptoms ofopioid toxicity should be monitored. Drug–drug interactions are common(Indiana University Division of Clinical Pharmacology 2009). A few cases ofbuprenorphine-induced hepatotoxicity in patients with known hepatitis Chave been reported. Buprenorphine is metabolized by CYP 3A4, and drug–drug interactions must be considered (Zuin et al. 2009). Buprenorphine isnot recommended perioperatively because it may precipitate withdrawal inpatients taking opioids.

Drug-Specific Issues

Neuropsychiatric Effects of Immunosuppressant Medications and Their Treatment

Immunosuppressants commonly cause medical side effects (e.g., hyperglyce-mia, hypertension, nephrotoxicity, infections, increased risk for cancer), aswell as neuropsychiatric side effects (see Table 16–1). Patients with neuropsy-chiatric symptoms often take combinations of immunosuppressants, makingthe contribution of any specific drug to the symptoms sometimes difficult toestablish.


The mainstays of transplant immunosuppression are the calcineurin-inhibiting immunosuppressants (CIIs) cyclosporine and tacrolimus. Bothdrugs have similar neuropsychiatric side effects. Up to 40%–60% of trans-plant recipients experience mild symptoms, including tremulousness, head-ache, restlessness, insomnia, vivid dreams, photophobia, hyperesthesias/dysesthesias, anxiety, or agitation (Magee 2006; Tombazzi et al. 2006). Mod-erate to severe side effects—cognitive impairment, coma, seizures, focal neu-rological deficits, dysarthria, cortical blindness, and delirium—occur lessoften but can affect 21%–32% of patients during the early postoperativeperiod (Bechstein 2000). Neuropsychiatric effects are more common with

Table 16–1. Neuropsychiatric side effects of immunosuppressantsMedication Neuropsychiatric side effect(s)

Calcineurin inhibitors (cyclosporine/tacrolimus)

Fatigue, insomnia, anxiety, agitation, confusion, depression, hallucinations, cognitive impairment, seizures

Corticosteroids (prednisone, others)

Euphoria, depression, anxiety, agitation, insomnia, hallucinations, delusions, delirium, personality changes, cognitive impairment

Sirolimus Insomnia

Azathioprine None described

Mycophenolate Insomnia, anxiety, agitation, depression, delirium, psychosis

Monoclonal antibodies

Basiliximab, daclizumab Insomnia, fatigue

Muromonab-CD3 (OKT3) (especially in those with central nervous system or neurological disease)

Anxiety, confusion, delirium, depression, seizures

Alemtuzumab Insomnia, anxiety

Rituximab Anxiety, depression, delirium, hallucinations

Source. Alloway et al. 1998; Bajjoka and Anandan 2002; Bartynski and Boardman 2007; Bech-stein 2000; DiMartini et al. 2008; Kershner and Wang-Cheng 1989; Magee 2006; Tombazzi et al. 2006.


parenteral administration and early posttransplant, perhaps due to higher se-rum levels during this period.

CIIs have been associated with posterior reversible leukoencephalopathysyndrome, which produces a variety of symptoms depending on the locationof the lesion(s). Symptoms may include headache, visual disturbances, sei-zures, focal neurological symptoms, decreased consciousness, and coma. Pa-tients with moderate to serious symptoms should have a computed tomogra-phy scan or magnetic resonance imaging (MRI) of the brain to evaluate forcharacteristic cortical and subcortical white matter changes, typically involv-ing the parietal or occipital lobes (Bartynski and Boardman 2007). Cases havebeen reported involving the anterior brain, cerebellum, and brain stem (Bar-tynski and Boardman 2007). Specific findings on fluid-attenuated inversionrecovery (FLAIR) MRI sequences and apparent diffusion coefficient mapping(sensitive to water diffusion) are especially useful in identifying the character-istic vasogenic edema seen in posterior reversible leukoencephalopathy syn-drome (Ahn et al. 2003).

Neuropsychiatric adverse effects of high-dose corticosteroid treatment arereviewed in Chapter 10, “Endocrine and Metabolic Disorders.”

Sirolimus, a non-CII, appears to have relatively mild neuropsychiatricside effects, including tremor, insomnia, and headache. Azathioprine rarelycauses neuropsychiatric side effects. Neuropsychiatric side effects with myco-phenolate appear to be milder than those described with CIIs, but up to 20%of patients may complain of symptoms such as anxiety, depression, seizures,agitation, weakness, headache, insomnia, and tremor (Alloway et al. 1998;DiMartini et al. 2005).

Monoclonal antibodies, used for induction immunosuppression or ad-junctive therapy, have generally mild and uncommon neuropsychiatric sideeffects. Muromonab-CD3 (OKT3) is an exception; it frequently causes head-ache, tremor, agitation, and depression. It may also cause cerebral edema andencephalopathy with confusion, disorientation, hallucinations, and seizures(Alloway et al. 1998). Rituximab is associated with progressive multifocal leu-koencephalopathy (Kranick et al. 2007).

Evaluation of posttransplant neuropsychiatric symptoms must includecareful consideration of all possible etiologies, such as metabolic disturbances,infections, organ insufficiency, medication effects, and drug interactions. Ifside effects are believed secondary to CIIs, it may be necessary, if medically


possible, to decrease the dose or switch to a different agent if symptoms aresevere or life threatening. In general, symptoms resolve with reduction or dis-continuation of the CII. Anticonvulsants can successfully treat CII-inducedseizures and are not required long term. Seizures may also cease if CII dosagereduction or discontinuation is possible. Corticosteroid-induced symptomsgenerally improve dramatically as the medication is tapered after transplant.

If treatment of neuropsychiatric symptoms is needed, it is important tochoose medications with the fewest side effects, fewest active metabolites,least toxicity, and minimal side effects. Benzodiazepines may be used safelyfor a short term for sleep disturbances, anxiety, and agitation; long-term treat-ment with these agents is usually not advisable. SSRIs are generally consideredfirst-line treatment for depressive and anxiety disorders (see “Selective Seroto-nin Reuptake Inhibitors” earlier in this chapter). Haloperidol and other anti-psychotics can be used for symptoms of delirium, hallucinations, delusions,mania, mood lability, irritability, and agitation.


Drug interactions commonly occur with immunosuppressants and otherdrugs frequently required by transplant patients (e.g., antihypertensives, anti-microbials, lipid-modifying agents, antiulcer drugs, analgesics, psychotro-pics). Most immunosuppressants have significant toxicities and narrowtherapeutic indices. Glucocorticoids, CIIs, sirolimus, and corticosteroids areall CYP 3A4 substrates (Table 16–2). Inhibitors and inducers of CYP 3A4may cause clinically significant drug level changes, resulting in toxicity orinadequate immunosuppression. Glucocorticoids induce CYP 3A4 and maydecrease levels of drugs metabolized by CYP 3A4 (e.g., quetiapine) (IndianaUniversity Division of Clinical Pharmacology 2009).

Several drug interactions are particularly relevant to psychiatrists (see Ta-bles 16–3 and 16–4). Among SSRIs, paroxetine is the most potent inhibitorof CYP 2D6, which may increase the risk for drug–drug interactions. Fluox-etine has been well tolerated and successfully used in patients with cardiac dis-ease and renal failure (Gottlieb et al. 2007; Kalender et al. 2007); however, itsprolonged half-life and potential for drug–drug interactions makes it less de-sirable for the medically ill (Crone and Gabriel 2004). Both fluoxetine and itsactive metabolite, norfluoxetine, are inhibitors of CYP 1A2, 2D6, 2C19, and3A4. Because of its ability to inhibit CYP 3A4, fluoxetine theoretically could


prolong the metabolism of cyclosporine, tacrolimus, and sirolimus. However,a small study failed to detect significant changes in cyclosporine levels whenfluoxetine was used (Strouse et al. 1996). No change in cyclosporine levelsoccurred in a small group of transplant recipients treated with citalopram(Liston et al. 2001). Sertraline inhibits CYP 2D6 at doses >200 mg/day andis a weak inhibitor of CYP 3A4. Nonetheless, one study reported that cyclo-sporine clearance was inhibited by sertraline (Lill et al. 2000), but anotherstudy failed to show any significant changes in cyclosporine levels for patientstaking sertraline, paroxetine, or fluoxetine (Markowitz et al. 1998). Althoughthere are no reports of elevated immunosuppressant levels with fluvoxamine,it is the least desirable choice among SSRIs due to its risk of drug–drug inter-actions (Crone and Gabriel 2004). It is a strong inhibitor of CYP 1A2, andinhibits CYP 2C9, 2C19, and 3A4. Nefazodone, a CYP 3A4 inhibitor, hasbeen implicated in several case reports of causing toxic CII levels, leading intwo cases to acute renal insufficiency and delirium, and in two cases to ele-vated liver enzymes (Campo et al. 1998; Garton 2002; Helms-Smith et al.1996; Wright et al. 1999). St. John’s wort, a popular herbal remedy for de-pression, is an inducer of CYP 3A4 and P-glycoprotein. Use of St. John’s wortcan result in reduced levels of CIIs and has resulted in transplant rejection(Fireman et al. 2004). In summary, it appears that only antidepressants that

Table 16–2. Immunosuppressant metabolism and effects on metabolic systemsImmunosuppressant medication Metabolized by Inhibits Induces

Corticosteroids CYP 3A4 — CYP 3A4

Cyclosporine CYP 3A4P-glycoprotein

CYP 3A4P-glycoprotein

—

Sirolimus CYP 3A4P-glycoprotein

— —

Tacrolimus CYP 3A4P-glycoproteinUGT

CYP 3A4UGT

—

Note. CYP=cytochrome P450; UGT=uridine 5′-diphosphate glucuronosyltransferase.Source. Augustine et al. 2007; Fireman et al. 2004; Warrington et al. 2004.


Table 16–3. Immunosuppressant drug–psychotropic drug interactions

Medication Pharmacokinetic effectEffect(s) on psychotropic drug and management

Corticosteroids Induces CYP 3A4 Reduced levels and possibly subtherapeutic effect for pimozide, quetiapine, ziprasidone, iloperidone, fentanyl, meperidine, tramadol, buspirone, and benzodiazepines except oxazepam, lorazepam, and temazepam

Cyclosporine Inhibits CYP 3A4 Increased levels and toxicities for pimozide, quetiapine, ziprasidone, iloperidone, fentanyl, meperidine, tramadol, buspirone, and benzodiazepines except oxazepam, lorazepam, and temazepam

Inhibits P-glycoprotein Possible increase in bioavailability and toxicity for P-glycoprotein substrates including carbamazepine, lamotrigine, phenytoin, paroxetine, venlafaxine, olanzapine, quetiapine, and risperidone

Tacrolimus Inhibits CYP 3A4 Increased levels and toxicities for pimozide, quetiapine, ziprasidone, iloperidone, fentanyl, meperidine, tramadol, buspirone, and benzodiazepines except oxazepam, lorazepam, and temazepam

QT prolongation Increased QT prolongation in combination with other QT-prolonging drugs such as TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium



strongly inhibit or induce CYP 3A4 may have clinically meaningful inter-actions with immunosuppressants (i.e., inhibitors nefazodone and perhapsfluvoxamine; inducer St. John’s wort). In turn, CIIs may increase levels of psy-chotropics metabolized by CYP 3A4, whereas glucocorticoids may decreaselevels (Indiana University Division of Clinical Pharmacology 2009).

In one case, a transplant recipient’s cyclosporine level dropped 50% dueto CYP 3A4 induction by modafinil 200 mg/day (Cephalon 1998). Carba-mazepine may lower drug levels of tacrolimus and cyclosporine by causingCYP 3A4 induction (Baciewicz and Baciewicz 1989; Campana et al. 1996;Chabolla and Wszolek 2006), which can raise the risk of organ rejection dueto inadequate immunosuppression.

The immunosuppressant drugs have important pharmacodynamic inter-actions. CIIs are nephrotoxic, and nephrotoxicity may be enhanced whenCIIs are combined with aminoglycosides, amphotericin B, nonsteroidal anti-inflammatory drugs, vancomycin, and likely lithium (Alloway et al. 1998).

Table 16–4. Psychotropic drug–immunosuppressant drug interactions

Medication Pharmacokinetic effectEffect(s) on immunosuppressant drug and management

Carbamazepine, oxcarbazepine, phenytoin

Armodafinil, modafinil

Induces CYP 3A4 Increased metabolism and reduced exposure and therapeutic effect of CYP 3A4 substrates, including corticosteroids, cyclosporine, tacrolimus, and sirolimus

St. John’s wort Induces CYP 3A4 and P-gp

Reduced bioavailability and increased metabolism leading to reduced exposure and therapeutic effect of CYP 3A4 or P-gp substrates, including corticosteroids, cyclosporine, tacrolimus, and sirolimus

Fluoxetine, fluvoxamine, nefazodone

Inhibits CYP 3A4 Reduced metabolism and increased exposure and toxicities of CYP 3A4 substrates, including corticosteroids, cyclosporine, tacrolimus, and sirolimus

Note. CYP=cytochrome P450; P-gp=P-glycoprotein.


Lithium should be used only when necessary, with frequent assessment ofrenal function, creatinine clearance, and lithium levels.

Gastrointestinal symptoms (i.e., nausea, vomiting, diarrhea) are commonadverse effects of immunosuppressant medications in more than 60% of pa-tients undergoing combination therapy (Pescovitz and Navarro 2001). Gas-trointestinal symptoms should always be evaluated, especially prior toadministering psychotropics with similar adverse effects (e.g., SSRIs, ven-lafaxine).

Immunosuppressants have significant metabolic side effects (e.g., weightgain, glucose intolerance, hyperlipidemia) (Alloway et al. 1998; Augustine etal. 2007; Bajjoka and Anandan 2002). These side effects must be consideredwhen psychotropic medications with similar effects, such as some of the atyp-ical antipsychotics, are to be used. Psychotropic medications with minimalmetabolic side effects should be considered (see drug choices in “PsychotropicMedications in Transplant Patients” above).

ConclusionTransplantation is a challenging process for patients and medical professionalsalike. Patients undergo acute and chronic pathophysiological changes and willbe subjected to powerful medications with potentially serious side effects. Inaddition, psychiatric disorders are common in these patients, and the identi-fication and prompt treatment of these disorders are important aspects oftransplant care. We have reviewed the essential aspects of the transplant pro-cess relevant to pharmacotherapy. This review should provide the informa-tion necessary to deal with the psychotropic needs of this unique and complexpatient population.

Key Clinical Points• Psychiatric consultation can aid in the correct diagnosis and

choice of proper medication.• No psychotropic medications are absolutely contraindicated for

use in transplant patients, but clinicians should carefully con-sider the type of organ disease, drug, dosage, potential for sideeffects, and possible drug–drug interactions.


• Patients should begin taking low dosages, and the dosageshould be slowly titrated upward.

• Patients with organ disease often have some degree of cognitiveimpairment or encephalopathy and tend to be more sensitive tosedative and cognitive side effects of psychotropic medications.

• Selection of psychotropic medications should take into consid-eration other potential benefits a drug might provide to aidsymptoms of organ disease (e.g., additionally treating pruritus,restless legs syndrome, nausea, anorexia, fatigue).

• Encephalopathy can be mistaken for depression, psychosis, ma-nia, and anxiety disorders. Careful diagnosis is necessary toavoid use of psychotropic medications that may aggravate a pa-tient’s symptoms (e.g., worsen agitation or confusion).

• Psychotropic polypharmacy should be minimized if possible, be-cause transplant patients often take numerous drugs.

• Following transplantation, medications that inhibit or induceCYP 3A4 should be avoided if possible because most immuno-suppressants are CYP 3A4 substrates.

• Although neuropsychiatric symptoms or changes in mental sta-tus may have many possible etiologies in the early posttransplantperiod, the possibility that symptoms reflect immunosuppressivemedication side effects should always be entertained. Symptomscan diminish with a decrease in immunosuppressive medica-tions.

• Drug–drug interactions should be carefully considered, becausepatients may be taking a wide variety of medications in additionto immunosuppressants that may pose risk of significant inter-actions with psychotropics.

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17Pain Management

Michael R. Clark, M.D., M.P.H.


Pain is the most common symptom for which people seek medical treatment(Cherry et al. 2003). In nationally representative surveys conducted in theUnited States, approximately one-fourth of individuals report experiencingpain in the prior month (National Center for Health Statistics 2006), andapproximately 15%–35% report chronic pain that is focal, regional, or wide-spread (Hardt et al. 2008; Harstall and Ospina 2003). Both acute and chronicpain are associated with impairment in multiple quality-of-life and functionaldomains and are highly costly, making the treatment of pain a major personaland public health concern (O’Connor 2009).

In addition to opioids, a relatively small number of drug classes are em-ployed in the treatment of chronic pain and especially neuropathic pain con-ditions (Moulin et al. 2007). Antidepressants and anticonvulsants remain thebest studied and are first-line therapies, particularly for various painful poly-neuropathies and postherpetic neuralgia (Dworkin et al. 2007). Recent


guidelines have been released for the multidisciplinary treatment of fibromy-algia, emphasizing evidence-based pharmacological therapies (Carville et al.2008). Unfortunately, medications are generally underutilized and under-dosed. In one study of patients with neuropathic pain, 73% complained ofinadequate pain control, but 72% had never received anticonvulsants, 60%had never received tricyclic antidepressants (TCAs), 41% had never receivedopioids, and 25% had never received any of the above (Gilron et al. 2002).No algorithm can provide a simple, straightforward approach to the treat-ment of chronic pain. The disease itself may change over time such that treat-ment efficacy is altered, treatments may be selected based on previousresponse, and drugs may be combined with the expectation of pharmacolog-ical synergies and minimized liabilities. Polypharmacy for the treatment ofchronic pain also raises concerns of drug–drug interactions.

Psychiatric Comorbidity

Pain Disorder and Somatization

Although the actual diagnosis of somatization disorder is rare in patients withchronic pain, multiple pain complaints are almost always present in somati-zation disorder. Patients in whom psychological factors play a primary role inthe perception of pain typically have more sites of pain, spread of pain beyondthe area of original injury, more opioid and benzodiazepine use, and greaterinvolvement with compensation and litigation (Streltzer et al. 2000).

Substance Use

The prevalence of substance dependence or addiction in patients withchronic pain ranges from 3% to 19% (Nicholson 2003). The core criteria fora substance use disorder in patients with chronic pain include the loss of con-trol in the use of the medication, excessive preoccupation with the medicationdespite adequate analgesia, and adverse consequences associated with its use(Compton et al. 1998). However, reliance on medications that provide painrelief can result in a number of stereotyped patient behaviors that can eitherrepresent or be mistaken for addiction. Persistent pain can lead to increasedfocus on opioid medications and measures to ensure an adequate medicationsupply even in the absence of addiction. Patients understandably fear the re-

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emergence of pain and withdrawal symptoms if they run out of medication.Drug seeking behavior may be the result of an anxious patient trying to main-tain a previous level of pain control. These actions may represent pseudo-addiction that results from therapeutic dependence as well as current orpotential undertreatment, but not addiction (Kirsh et al. 2002).

Patients with substance use disorders have increased rates of chronic painand are at the greatest risk for stigmatization and undertreatment with appro-priate medications by health care practitioners (Rosenblum et al. 2003). In-tegrating care for chronic pain with innovative stepped-care models ofsubstance abuse treatment would likely improve outcomes by tailoring the in-tensity of treatment to the individual patient’s needs (Clark et al. 2008).

Depression and Distress

Physical symptoms are common in patients with major depression. Approxi-mately 60% of patients with depression report pain symptoms at diagnosis(Magni et al. 1985; von Knorring et al. 1983). Depression increases the riskof developing chronic pain (Von Korff et al. 1993), and chronic pain approx-imately doubles the incidence of depression (Patten 2001). Depressive symp-toms, even without the categorical diagnosis of major depression, are animportant comorbidity in patients with chronic pain, associated with greaterpain intensity, more pain persistence, and greater interference from pain, in-cluding more pain behaviors observed by others (Haythornthwaite et al.1991), as well as with increased risk of suicidality (Fishbain 1999; Tang andCrane 2006). Depression with comorbid pain is more resistant to treatment(Kroenke et al. 2008), but pain often subsides with improvement in depres-sive symptoms (Salerno et al. 2002). In addition to having greater efficacy forthe treatment of neuropathic pain, serotonin–norepinephrine reuptake inhib-itors (SNRIs) and TCAs are associated with faster rates of improvement andlower rates of relapse compared with selective serotonin reuptake inhibitors(SSRIs) (Rosenzweig-Lipson et al. 2007).

Anxiety, Fear, Catastrophizing, and Anger

Patients with chronic pain syndromes have increased rates of both anxietysymptoms and anxiety disorders, such as generalized anxiety disorder, panicdisorder, agoraphobia, and posttraumatic stress disorder (McWilliams et al.2003). Fear of pain, movement, reinjury, and other negative consequences


that result in the avoidance of activities promote the transition to and sustain-ing of chronic pain and its associated disabilities, such as muscular reactivity,deconditioning, and guarded movement (Asmundson et al. 1999). Pain-related cognitions such as catastrophizing and fear-avoidance beliefs are pre-dictive of poor adjustment to chronic pain (Hasenbring et al. 2001). Angerhas been reported by 70% of patients with chronic pain, with the anger di-rected at themselves (74%) and health care professionals (62%) (Okifuji et al.1999). Posttraumatic stress disorder is increasingly recognized as a comorbidcondition with significant consequences for patients with chronic pain disor-ders (Geisser et al. 1996; Liebschutz et al. 2007).

Pain Description and Management

Acute Pain

Acute pain is usually the result of trauma from surgery, injury, or exacerbationof chronic disease, especially musculoskeletal conditions. Acute pain manage-ment is usually successful with straightforward strategies such as relaxation;immobilization; analgesics, such as nonsteroidal anti-inflammatory drugs(NSAIDs), acetaminophen, and opioids; massage; and transcutaneous elec-trical nerve stimulation (Institute for Clinical Systems Improvement 2008).Acute pain management initiated as early as possible and focused on preventingthe occurrence and reemergence of pain may allow for lower total doses of an-algesics. The absence of signs consistent with acute pain, such as elevated heartrate, blood pressure, and diaphoresis, does not rule out the presence of pain.

Analgesics, especially opioids, should be prescribed only for pain relief.Although analgesia may produce other benefits, other symptoms commonlycoinciding with acute pain, such as insomnia or anxiety, should be managedseparately from pain. Sleep deprivation and anxiety may intensify the sensa-tion of pain and increase requests for more medication. Reducing anxiety andinsomnia often reduces analgesic requirements. In acute pain management,psychiatric consultation is requested when a patient requires more analgesiathan expected or has a history of substance abuse. Patients with an active orrecent history of opioid addiction and those receiving methadone mainte-nance therapy have increased tolerance to opioids and may require up to 50%higher doses of opioids. Although opioid use in these patients should be care-

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fully monitored, adequate treatment of acute pain is a priority. Inadequatedosing is significantly more common than abuse or diversion. Dosage shouldbe carefully individualized rather than based on preconceived expectations.

Selected Chronic Pain Conditions

Neuropathic Pain

Postherpetic neuralgia. Postherpetic neuralgia is pain, often described asburning, stabbing, or throbbing, that persists or recurs at the site of shinglesat least 3 months after an acute varicella zoster rash. Postherpetic neuralgia oc-curs in about 10% of patients with acute herpes zoster, occurs in more than50% of patients over age 65 who have shingles, and is more likely in indi-viduals with cancer, diabetes, or immunosuppression. Approximately 15% ofreferrals to pain clinics are for the treatment of postherpetic neuralgia(Schmader 2002).

TCAs, anticonvulsants (e.g., carbamazepine, valproic acid, pregabalin,gabapentin), and opioids are the most common effective treatments for post-herpetic neuralgia and may have potential for its prevention. Amitriptyline orgabapentin provide pain relief in 50%–60% of patients with postherpeticneuralgia (Zin et al. 2008), and a 5% lidocaine patch is approved for posther-petic neuralgia. Unless otherwise contraindicated, TCAs should be the firstchoice for treating postherpetic neuralgia, followed by gabapentin (K. J.Smith and Roberts 2007).

Diabetic peripheral neuropathy pain. Approximately 25% of patientswith diabetes mellitus will experience painful diabetic neuropathy with dura-tion of illness and poor glycemic control as contributing risk factors. Thispain is described as constant burning to episodic, paroxysmal, and lancinatingin quality, and results from axonal degeneration and segmental demyelination(Mendell and Sahenk 2003). First-line pharmacological treatments for dia-betic peripheral neuropathy pain include TCAs, SNRIs, and calcium channelmodulating anticonvulsants (Zin et al. 2008), which appear to be of compa-rable efficacy (Chou et al. 2009a; Quilici et al. 2009). Other anticonvulsantshave been shown to be effective in smaller studies.

Central poststroke pain and spinal cord injury. Pain is common afterstroke (8% of patients) or spinal cord trauma (60%–70% of patients)


(Finnerup 2008; Ullrich 2007). Symptoms of spinal cord injury pain or cen-tral poststroke pain are often poorly localized, vary over time, and includeallodynia (>50% of central poststroke pain patients), hyperalgesia, dysesthe-sias, lancinating pain, and muscle and visceral pain regardless of sensory def-icits. Pain is described as burning, aching, lacerating, or pricking.

Central poststroke pain is difficult to treat; conventional analgesics andopiates have been shown to be ineffective. Randomized clinical trials havedemonstrated efficacy for amitriptyline and for drugs that reduce neuronalhyperexcitability, including lidocaine (intravenous), mexiletine, lamotrigine,fluvoxamine, and gabapentin, but not carbamazepine, phenytoin, or topira-mate (Frese et al. 2006). Morphine is effective against allodynia but not othercomponents of central pain syndromes (Nicholson 2004). Intravenous lido-caine may be the most efficacious agent, but the need for intravenous admin-istration limits its use. Topical lidocaine may be beneficial for some patients(Hans et al. 2008).

Trigeminal neuralgia. Trigeminal neuralgia (tic douloureux) is a chronicpain syndrome with severe, paroxysmal, recurrent, lancinating pain with a uni-lateral distribution of cranial nerve V, most commonly the mandibular divi-sion (Elias and Burchiel 2002). Sensory or motor deficits are not usuallypresent. Less commonly, the facial or glossopharyngeal nerve is involved, withpain distribution to the ear, posterior pharynx, tongue, or larynx (Zakrzewskaet al. 2005). Episodes of pain can be spontaneous or evoked by nonpainfulstimuli to trigger zones, activities such as talking or chewing, or environmentalconditions. Between episodes, patients are typically pain free. Uncontrolledpain with frequent or severe prolonged attacks increases the risk of insomnia,weight loss, social withdrawal, anxiety, and depression, including suicide.

Anticonvulsants are the mainstay of pharmacotherapy for trigeminal neu-ralgia. Placebo-controlled trials identify carbamazepine as first-line treatment(number needed to treat was 1.8). Trials also support the use of oxcarbazepineand lamotrigine. Evidence is insufficient to recommend clonazepam, gaba-pentin, phenytoin, tizanidine, topical capsaicin, or valproate (Cruccu et al.2008). Given the pathophysiological similarities of trigeminal neuralgia withpostherpetic neuralgia and painful peripheral neuropathies, other medica-tions, such as the TCAs and SNRIs, would be appropriate pharmacologicaltreatments to consider.

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Complex regional pain syndrome. Complex regional pain syndrome(CRPS; formerly called reflex sympathetic dystrophy and causalgia) is an ar-ray of painful conditions characterized by ongoing spontaneous burning painprecipitated by a specific noxious trauma or cause of immobilization and of-ten with hyperalgesia or allodynia to cutaneous stimuli. Pain is regional butnot limited to a single peripheral nerve or dermatome. Often, there is evi-dence of edema, blood flow abnormalities, or sudomotor dysfunction in thepain region—usually an extremity. Motor changes, such as weakness, tremor,dystonia, and limitations in movement, are common (Harden et al. 2007).Sympathetically maintained pain is present in most, but not all, cases. Pa-tients with sympathetically maintained pain often report hyperalgesia to coldstimuli. Sympathetically maintained pain is generally considered to respondto sympathetic blockade (Pontell 2008).

Patients with CRPS often exhibit affective (46%), anxiety (27%), andsubstance abuse (14%) disorders (Rommel et al. 2001), which are generallyconsidered to be a consequence rather than a cause of chronic pain. Pharma-cotherapy for CRPS has limited success, and few randomized controlled stud-ies have been done to guide treatment selection. Symptoms often improvewith NSAIDs or corticosteroids in the acute, or inflammatory, stage of thedisease. Evidence suggests efficacy for gabapentin, pregabalin, carbamazepine,TCAs, and opioids. Increased risk for substance use disorders limits the use ofopioids to prescribing contingent on functional improvement. Randomizedcontrolled trials of calcitonin and bisphosphonates in patients with CRPSdemonstrated reduced pain and improved joint mobility. Clinical trials oflocal anesthetic sympathetic blockade, once considered the “gold standard”therapy for CRPS, have proved inconclusive (Sharma et al. 2006). Othertherapies include early intervention with reactivating physical therapies, elec-trical stimulation, and possibly even surgical sympathectomy (Pontell 2008).

Phantom limb pain. Feeling pain in a body part that has actually been re-moved occurs in 50%–80% of amputees within a year of the amputation.Phantom limb pain, considered to be neuropathic and described as stabbing,throbbing, burning, or cramping, is more intense in the distal portion of thephantom limb (Flor 2002). Phantom pain is also common after mastectomy(Peuckmann et al. 2009). Although TCAs, gabapentin, and carbamazepineare considered first-line treatments for phantom pain, no controlled trials


support their use. The benefit of these agents does not generally exceed the30% placebo response observed in other pain studies. Newer antidepressantsand anticonvulsants with generally fewer side effects may result in greater ef-fectiveness if higher doses can be tolerated by patients. However, morphine,calcitonin, and ketamine have been shown to reduce phantom pain in con-trolled studies (Halbert et al. 2002). Morphine, but not mexiletine, decreasedpostamputation pain of greater than 6 months duration (Wu et al. 2008).Controlled trials have discredited anecdotal reports of the effectiveness ofneural blockade (Manchikanti and Singh 2004).

Headache

Migraine. About 18% of women and 6% of men have migraines, with peakincidence between ages 30 and 40. Common migraine is a unilateral pulsatileheadache, which may be associated with other symptoms such as nausea,vomiting, photophobia, and phonophobia. The classic form of migraine addsvisual prodromal symptoms (Lipton et al. 2007). Placebo-controlled clinicaltrials suggest the use of NSAIDs and triptans for acute treatment of migraineattacks, and propranolol, metoprolol, flunarizine, valproate, topiramate, andTCAs as prophylactic agents (Evers et al. 2006; Keskinbora and Aydinli 2008;Mulleners and Chronicle 2008).

Chronic daily headache. Chronic daily headache affects about 5% of thepopulation and is composed of constant (transformed) migraine, medication-overuse headache, chronic tension-type headaches, new-onset daily persistentheadache, and hemicrania continua (Dodick 2006). Patients with chronicdaily headache are more likely to overuse medication, leading to reboundheadache; suffer psychiatric comorbidity such as depression and anxiety; re-port functional disability; and experience stress-related headache exacerba-tions (Lake 2001). Chronic daily headache is difficult to manage and is oftenunresponsive to medications. Placebo-controlled clinical trials are few butsupport the use of amitriptyline, gabapentin, topiramate, and botulinumtoxin type A (Dodick 2006). As with other chronic pain syndromes, empiricalsupport exists for treating patients with other agents such as the SNRIs,TCAs, and anticonvulsants. Combined medication and cognitive-behavioralpsychotherapy are more effective than either treatment alone (Lipchik andNash 2002).

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Fibromyalgia

Fibromyalgia is a chronic pain syndrome characterized by widespread muscu-loskeletal pain in all four limbs and trunk, stiffness, and exaggerated tender-ness. These symptoms are usually accompanied by poor sleep and fatigue.Fibromyalgia is diagnosed in 3.4% of women and 0.5% of men and is clus-tered in families (Arnold et al. 2004). Current research suggests that fibromy-algia may be a syndrome of dysfunctional central pain processing influencedby a variety of processes, including infection, physical trauma, psychologicaltraits, and psychopathology (Abeles et al. 2007). Guidelines for fibromyalgiatreatment have been recently released (Carville et al. 2008). Placebo-controlledtrials suggest pain reduction with cyclobenzaprine (Tofferi et al. 2004), mil-nacipran (Mease et al. 2009) (recently approved by the U.S. Food and DrugAdministration [FDA] for fibromyalgia), gabapentin, pregabalin (Arnold et al.2008), duloxetine (in females, not males), and tramadol (Crofford 2008).

Pain in Sickle Cell Anemia

Pain is the hallmark of sickle cell disease. Sickle cell pain is mainly nocicep-tive, resulting from tissue ischemia and microcirculatory vaso-occlusion bysickled or less malleable red blood cells. It may be acute or chronic, with acutepainful episodes most often affecting long bones and joints and the lowerback (Ballas 2005). Placebo-controlled trials demonstrate efficacy of NSAIDsin acute pain (Dunlop and Bennett 2006). Chronic pain and acute painfulepisodes not controlled by NSAIDs are best managed with a combination oflong-acting opioids and short-acting opioids for breakthrough pain. The ben-efits of long-term opioids must be balanced against the risks of addiction.Chronic therapy with hydroxyurea also reduces pain.

Nociceptive Pain

Tissue injury and inflammation trigger the release of local mediators of painand inflammation, including prostaglandins, serotonin, bradykinin, adeno-sine, and cytokines. These substances sensitize tissue nociceptors and producethe sensation of pain. Somatic (musculoskeletal) and visceral pain is generallynociceptive in origin but may also have neuropathic elements. Somatic painis a localized stabbing or sharp pain, whereas visceral pain is diffuse, with ach-ing, pressure, colicky, or sharp qualities. Musculoskeletal pain includes softtissue injuries, intra-articular disorders, bone pain, muscle pain syndromes,


and neck and low-back conditions. Mild to moderate nociceptive pain gen-erally responds to NSAIDs, but severe pain may require opioids. Expert con-sensus guidelines recommend topical NSAIDs, capsaicin cream, and intra-articular corticosteroids for osteoarthritis pain (Zhang et al. 2008). In anopen-label trial of lidocaine patch 5%, significant pain improvement was re-ported in patients with osteoarthritis (Gammaitoni et al. 2004).

Malignant Pain

One-third of newly diagnosed oncology patients and 65%–85% of those withadvanced disease report significant pain (Skaer 2004). Management of malig-nancy-related pain is often suboptimal; many patients receive subtherapeuticdoses of analgesics in spite of published guidelines for cancer pain manage-ment (National Cancer Institute 2010). Cancer pain may have both nocicep-tive and neuropathic components. Neuropathic pain is often managed withanticonvulsants, TCAs, SNRIs, or opioids. Mild nociceptive pain can be man-aged with acetaminophen or NSAIDs, but most patients with malignanciesexperience moderate to severe pain, generally treated with opioids. Short-act-ing opioids are used for initiation of therapy, for pain that is highly variable,or in medically unstable patients. Once analgesic requirements become stable,patients should be switched to long-half-life or sustained-release forms. Inad-equate opioid dosing often results because of fear of addiction or respiratorydepression. Patients become opioid tolerant with long-term dosing and mayneed dosage increases to maintain pain control. Particular nociceptive painsyndromes may respond to specific treatments. For example, in clinical trials,bisphosphonates reduced pain from bone metastases (Shaiova 2006).

Pharmacological Treatment

Various medications are commonly used to treat pain. A summary of some ofthese drugs, including demonstrated pain benefits and dosage ranges, is pro-vided in Table 17–1.

Opioids

Opioids reduce the sensory and affective components of pain by interactingwith mu, delta, and kappa opioid receptors located on the peripheral nervesin the central nervous system modulating pain transmission. Opioids are po-

Pain Management 511

tent analgesics for all types of neuropathic and nociceptive pain. Controversysurrounds the long-term use of opioids for chronic nonmalignant pain (No-ble et al. 2008). Evidence for the efficacy of opioids in chronic pain is consid-ered weak. Studies are generally less than 18 months in duration and arecomplicated by high rates of discontinuation due to adverse events or insuf-ficient pain relief. Opioids should be slowly tapered and discontinued if theburdens (side effects, toxicities, aberrant drug-related behaviors) outweigh theobjective benefits (analgesia, functional improvement).

Successful treatment with opioids requires the assessment and documen-tation of improvements in function and analgesia without accompanying ad-verse side effects and aberrant behaviors. Guidelines have been established forthe use of opioids for treating chronic pain (American Academy of Pain Med-icine and American Pain Society 1996). Suitable patients are those with mod-erate or severe pain persisting for more than 3 months and adversely affectingfunction or quality of life.

Before opioid therapy is initiated, additional factors, such as the patient’sspecific pain syndrome, response to other therapies, and potential for aber-rant drug-related behaviors (misuse, abuse, addiction, diversion), should beconsidered (Ballantyne and LaForge 2007). A patient’s suitability for chronicopioid therapy can be assessed with standardized questionnaires (Chou et al.2009b). Commonly used instruments include the Opioid Risk Tool (ORT);the Diagnosis, Intractability, Risk, Efficacy (DIRE) screening scale; and theScreener and Opioid Assessment for Patients in Pain (SOAPP) (all three areavailable for download at http://pain-topics.org/opioid_rx/risk.php). Treat-ment outcomes, including analgesia, activities of daily living, adverse events,and potential aberrant drug-related behaviors can be assessed with the PainAssessment and Documentation Tool (available for download at http://www.npecweb.org). The presence of aberrant drug-related behaviors shouldalways be evaluated. The Current Opioid Misuse Measure (COMM; avail-able for download at http://pain-topics.org/opioid_rx/risk.php) is used toevaluate patients who are taking opioids for concurrent signs or symptoms ofintoxication, emotional volatility, poor response to medication, addiction,health care use patterns, and problematic medication behaviors.

Clinically available opioids include naturally occurring compounds (mor-phine, codeine), semisynthetic derivatives (hydromorphone, oxymorphone,hydrocodone, oxycodone, dihydrocodeine, buprenorphine), and synthetic

http://pain-topics.org/opioid_rx/risk.php

http://www.npecweb.org

http://pain-topics.org/opioid_rx/risk.php

http://www.npecweb.org

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Table 17–1. Medications for pain managementClass/agent Dosage range Research evidence of efficacy for

AntidepressantsTCAsa

Secondary amine TCAs (desipramine, nortriptyline)

50–200 mgb Painful peripheral neuropathy, headache, migraine, trigeminal neuralgia, PHN, central pain, poststroke pain, orofacial pain, postmastectomy pain

Tertiary amine TCAs (amitriptyline, imipramine)

100–300 mgb Painful peripheral neuropathy, headache, migraine, trigeminal neuralgia, PHN, central pain, poststroke pain, orofacial pain, postmastectomy pain

SSRIsCitalopram 20–80 mg Somatoform pain disorder, irritable bowel syndrome, headache, diabetic peripheral neuropathyFluoxetine 10–80 mg Fibromyalgia, pain in rheumatoid arthritisParoxetine 10–40 mg Diabetic peripheral neuropathyAtypicalsBupropion 100–450 mg Neuropathic painMirtazapine 15–90 mg Tension-type headacheSNRIsDuloxetine 30–120 mg Diabetic peripheral neuropathy, fibromyalgiaVenlafaxine 75–450 mg Diabetic peripheral neuropathy, migraine prophylaxisAnticonvulsantsCarbamazepine 100–800 mgb Trigeminal neuralgia, diabetic peripheral neuropathy, PHN, migraineGabapentin 900–3,600 mg Diabetic peripheral neuropathy, PHN, postamputation pain, Guillain-Barré syndromeLamotrigine 25–300 mgb HIV neuropathy, central poststroke painOxcarbazepine 150–1,200 mg Diabetic peripheral neuropathyPregabalin 150–600 mg Painful diabetic neuropathy, PHN, central pain/spinal cord injury pain, fibromyalgiaTopiramate 25–400 mg Migraine, lower back pain, radicular pain, diabetic peripheral neuropathyValproate 250–2,000 mgb Neuropathic pain, migraine, cluster headache

Pain M

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ent513

OpioidsFentanyl (transdermal)MethadoneMorphine (SR)

12–100 μg/h10–80 mg15–240 mg

Acute pain, breakthrough pain, mixed efficacy in numerous chronic nociceptive pain syndromes (e.g., lower back) and neuropathic pain syndromes (e.g., PHN, peripheral neuropathies)

Oxycodone (SR) 10–160 mgOxymorphone (XR) 5–80 mgAntipsychoticsOlanzapineQuetiapine

2.5–20 mg25–300 mg

Diabetic neuropathy, PHN, trigeminal neuralgia, headache, facial pain, HIV/AIDS pain, cancer, musculoskeletal pain

Risperidone 0.5–5 mgZiprasidone 10–80 mg

Note. HIV/AIDS=human immunodeficiency virus/acquired immunodeficiency syndrome; PHN=postherpetic neuralgia; SNRIs=serotonin–norepi-nephrine reuptake inhibitors; SR=sustained release; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants; XR=extended release.aTricyclic antidepressants are often underdosed.bSerum levels can be helpful for optimizing efficacy.

Table 17–1. Medications for pain management (continued)Class/agent Dosage range Research evidence of efficacy for


opioid analgesics (fentanyl, meperidine, methadone, tramadol, pentazocine,propoxyphene). Morphine, because of its hydrophilicity, has poor oral bio-availability (22%–48%) and delayed central nervous system access and onsetof action. This delay prolongs the analgesic effect of morphine relative to itsplasma half-life, which decreases the potential for accumulation and toxicity.Morphine is a more effective epidural/spinal analgesic than oxycodone. Oxy-codone is an opioid analgesic with high oral bioavailability (>60%), a fasteronset of action, and more predictable plasma levels than morphine. In com-parison with morphine, oxycodone has similar analgesic efficacy, releases lesshistamine, and causes fewer hallucinations (Riley et al. 2008). Hydrocodone issimilar to oxycodone, with rapid oral absorption and onset of analgesia. Hy-drocodone is metabolized by N-demethylation to hydromorphone, which hasproperties similar to morphine, except lower rates of side effects. Fentanyl ishighly lipophilic with affinity for neuronal tissues and the potential for trans-dermal or transmucosal delivery. The duration of action of transdermal prep-arations is up to 72 hours, with considerable interindividual variability.Meperidine can cause seizures and an agitated delirium, believed to be causedby accumulation of the active metabolite normeperidine, which has anticho-linergic properties. This is particularly a concern in patients with renal insuf-ficiency, because normeperidine is eliminated by the kidneys.

Methadone warrants special consideration in the treatment of chronicpain because of its low cost, high bioavailability, rapid onset of action, slowhepatic clearance, multiple receptor affinities, lack of neurotoxic metabolites,and incomplete cross-tolerance with other opioids. However, compared withother opioids, methadone has significantly greater risk of inadvertent over-dose due to longer time for adaptation with oral use and greater variation inplasma half-life (15–120 hours) (Sandoval et al. 2005). Extensive tissue dis-tribution and prolonged half-life prevents withdrawal symptoms when dosedonce a day. However, elimination is biphasic, and the more rapid eliminationphase equates with analgesia that is limited to approximately 6 hours. Re-peated dosing, with accumulation in tissue, may increase analgesia durationto 8–12 hours. Therefore, it should usually be given twice daily. Methadonehas been shown to be effective for chronic pain in a study of 100 patients,with a mean duration of treatment of 11 months (Peng et al. 2008).

The most common side effect of chronic opioid therapy is decreased gas-trointestinal motility, causing constipation, vomiting, and abdominal pain.

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Oral opioids differ in their propensity to cause symptoms of gastrointestinaldysmotility (Heiskanen and Kalso 1997). Transdermal opioids (fentanyl,buprenorphine) have fewer gastrointestinal side effects than oral opioids (Tas-sinari et al. 2008). Meperidine is not preferred in patients with acute pancre-atitis, because all opioids are equally likely to cause spasm of the sphincter ofOddi (Thompson 2001).

Long-term opioid administration may result in analgesic tolerance or opi-oid-induced hyperalgesia (Mitra 2008). When tolerance develops, coadmin-istration of other analgesics, opioid rotation to a more potent agonist, orintermittent cessation of certain agents may restore analgesic effect (Dumasand Pollack 2008; Mercadante 1999; Vorobeychik et al. 2008). Opioid rota-tion from morphine or hydromorphone may be beneficial because the 3-glucuronide metabolites of either drug can accumulate within the cerebrospi-nal fluid and produce neuroexcitatory effects, such as allodynia, myoclonus,delirium, and seizures (M.T. Smith 2000). Rotation to mixed agonist–antag-onist opioids (buprenorphine, pentazocine) may precipitate withdrawalsymptoms in patients undergoing chronic opioid therapy.

Antidepressants

The analgesic properties of antidepressants are underappreciated (Barkin andFawcett 2000). The neurobiology of pain suggests that all antidepressantswould be effective for treatment of chronic pain (McCleane 2008). TheTCAs and SNRIs, in particular, are prescribed for many chronic pain syn-dromes, including diabetic neuropathy, postherpetic neuralgia, central pain,poststroke pain, tension-type headache, migraine, and oral-facial pain (Saartoand Wiffen 2007). The analgesic effect of antidepressants is independent oftheir antidepressant effect and is mediated primarily by the blockade of re-uptake of norepinephrine and serotonin, increasing their levels and enhanc-ing the activation of descending inhibitory neurons in the dorsal horn of thespinal cord (Mico et al. 2006). Antidepressants may also produce antinoci-ceptive effects by other mechanisms. For example, TCAs block a subtype ofsodium channels implicated in neuropathic pain (Dick et al. 2007).

Tricyclic Antidepressants

Meta-analyses of randomized controlled trials concluded that TCAs are themost effective agents for neuropathic pain and are effective for headache syn-


dromes. TCAs have been shown in controlled trials to effectively treat centralpoststroke pain, postherpetic neuralgia, painful diabetic and nondiabeticpolyneuropathy, and postmastectomy pain syndrome, but not spinal cordinjury pain, phantom limb pain, or pain in human immunodeficiency virus(HIV) neuropathy. TCA agents are equally effective for pain, but secondaryamine TCAs (e.g., nortriptyline) are better tolerated than tertiary agents (e.g.,amitriptyline) (Dworkin et al. 2007; Finnerup et al. 2005). Antidepressantsgenerally produce analgesia at lower dosages and with earlier onset of actionthan expected for the treatment of depression (Rojas-Corrales et al. 2003).However, lack of analgesic effect—for example, in spinal cord injury pain—may be due to inadequate dosing. Chronic pain of postherpetic neuralgia anddiabetic peripheral neuropathy has been successfully treated with TCAs ataverage dosages of 100–250 mg/day (Max 1994; Onghena and Van Houden-hove 1992). In contrast, a U.S. health insurance claims database found thatthe average dosage of TCAs for the treatment of neuropathic pain in patientsages 65 and older was only 23 mg/day (Berger et al. 2006), suggesting unre-alized potential for additional pain relief.

Serotonin–Norepinephrine Reuptake Inhibitors

Duloxetine, venlafaxine, desvenlafaxine, and milnacipran inhibit the presyn-aptic reuptake of serotonin, and to a lesser extent norepinephrine, with fewerside effects than TCAs. In placebo-controlled trials, venlafaxine significantlyreduced neuropathic pain following breast cancer treatment (Tasmuth et al.2002) and decreased allodynia and hyperalgesia associated with neuropathicpain (Yucel et al. 2005). Studies also suggest that venlafaxine is effective foratypical facial pain and migraine prophylaxis (Forssell et al. 2004; Ozyalcin etal. 2005). Response increases with increasing dosage; venlafaxine 150–225mg/day produced a greater percentage of reduction in pain than 75 mg/day(50% vs. 32%) in a placebo-controlled study of painful diabetic neuropathy(Rowbotham et al. 2004). Duloxetine possesses analgesic efficacy in preclini-cal models and in clinical populations such as those with fibromyalgia andpainful diabetic neuropathy (Arnold et al. 2005; Wernicke et al. 2006).Guidelines for the treatment of neuropathic pain recommend duloxetine asan effective treatment (Argoff et al. 2006). The efficacy of duloxetine in pain-ful diabetic neuropathy increases with increasing pain but is not related to theseverity of diabetes or neuropathy (Ziegler et al. 2007). Milnacipran signifi-

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cantly improved symptoms of fibromyalgia including pain, physical function-ing, and patient global impression of change in a large placebo-controlled trial(Mease et al. 2009).


In clinical trials, the efficacy of SSRIs in chronic pain syndromes has been in-consistent and disappointing, especially in the treatment of neuropathic pain(Finnerup et al. 2005). In a Cochrane review, Moja et al. (2005) found SSRIsto be no more efficacious than placebo for migraine and less efficacious thanTCAs for tension-type headache. Fluoxetine improved outcome measures inwomen with fibromyalgia (Rani et al. 1996) and was comparable to amitrip-tyline at significantly reducing rheumatoid arthritis pain (Arnold et al. 2002).Citalopram improved irritable bowel syndrome symptoms independent of ef-fects on anxiety and depression (Tack et al. 2006). Patients with pain disorderexperienced significant analgesic effects, independent of changes in depres-sion, with citalopram but not with the noradrenergic reuptake inhibitorreboxetine (Aragona et al. 2005). Paroxetine and citalopram, but not fluoxe-tine, have shown benefit for painful diabetic peripheral neuropathy in con-trolled studies (Goodnick 2001). Despite better efficacy, TCAs increasecatecholamines, which diminish insulin sensitivity and may exacerbate glu-cose intolerance. In contrast, increased serotonergic function improves sensi-tivity to insulin, making SSRIs an alternative for some patients with diabetes.Also, in a comparison study of gabapentin, paroxetine, and citalopram forpainful diabetic peripheral neuropathy, patients reported better satisfaction,compliance, and mood with SSRIs, with similar efficacy for pain (Giannop-oulos et al. 2007). Overall, although not recommended as a first-line therapyfor chronic pain, SSRIs are a recommended alternative to TCAs or SNRIs,with a favorable risk-benefit profile.

Novel Antidepressants

Few controlled trials have examined the efficacy of novel antidepressants intreating pain syndromes. Mirtazapine decreased the duration and intensity ofchronic tension-type headache in a controlled trial with treatment-refractorypatients (Bendtsen and Jensen 2004). In a controlled trial of patients withneuropathic pain, sustained-release bupropion decreased pain intensity andinterference of pain on quality of life (Semenchuk et al. 2001). Although sev-


eral reports suggest efficacy for trazodone in treating chronic pain, controlledstudies do not support its use in patients with chronic pain (Goodkin et al.1990).

Anticonvulsants

Anticonvulsants are effective for treating a variety of neuropathic pain syn-dromes, including trigeminal neuralgia, diabetic neuropathy, postherpeticneuralgia, and migraine prophylaxis (Tremont-Lukats et al. 2000). The num-ber needed to treat ranges from <2 to 4 for anticonvulsants, with better com-pliance when compared with TCAs because of fewer adverse effects (Finnerupet al. 2005).

First-Generation Anticonvulsants

Phenytoin was first reported as a successful treatment for trigeminal neuralgiain 1942 (Bergouignan 1942). Carbamazepine is the most widely studied anti-convulsant effective for neuropathic pain (Tanelian and Victory 1995). Val-proic acid is most commonly used in the prophylaxis of migraine but is alsoeffective for neuropathic pain (Jensen et al. 1994). Valproate was effective asa prophylactic treatment in over two-thirds of patients with migraine andalmost 75% of those with cluster headache (Gallagher et al. 2002). Improve-ment occurred in frequency of headache, duration or headache-days permonth, intensity of headache, use of other medications for acute treatment ofheadache, the patient’s opinion of treatment, and ratings of depression andanxiety (Kaniecki 1997; Klapper 1997; Rothrock 1997).

Second-Generation Anticonvulsants

Newer anticonvulsants were developed to target novel pharmacologicalmechanisms for the suppression of nociceptive processes. Gabapentin dem-onstrated analgesic efficacy in placebo-controlled trials of diabetic peripheralneuropathy pain, postherpetic neuralgia, and postamputation phantom limbpain (Backonja et al. 1998; Bone et al. 2002; Chandra et al. 2006). A retro-spective analysis found patients with chronic pain more likely to respond withgabapentin if allodynia was a feature of their neuropathic pain (Gustorff et al.2002). Gabapentin significantly decreased the pain associated with Guillain-Barré syndrome as well as the concomitant consumption of fentanyl (Pandeyet al. 2002). Pregabalin, a gabapentin analog with rapid onset of action and

Pain Management 519

better bioavailability, is effective for the treatment of painful diabetic neurop-athy, postherpetic neuralgia, and central neuropathic pain associated with spi-nal cord injury (Siddall et al. 2006; Sonnett et al. 2006; van Seventer et al.2006). In patients with postherpetic neuralgia, flexible dosing strategies re-sulted in fewer discontinuations, higher final dosage, and slightly better painrelief compared with fixed-dose schedules (Stacey et al. 2008). In a meta-anal-ysis of controlled trials, Wiffen and Rees (2007) found that lamotrigine pro-duced positive but disappointing results for pain associated with HIV-relatedneuropathy and central poststroke pain, and was without significant effect ondiabetic neuropathy pain, trigeminal neuralgia, or intractable neuropathicpain. Gabapentin and pregabalin are renally excreted.

Next-Generation Anticonvulsants

Topiramate offers the advantages of minimal hepatic metabolism and un-changed renal excretion, few drug interactions, a long half-life, and the un-usual side effect of weight loss. Topiramate is effective for migraine prophylaxis(Silberstein et al. 2006) and for pain reduction from chronic low-back pain,lumbar radiculopathy, and diabetic neuropathy (Donofrio et al. 2005;Khoromi et al. 2005; Muehlbacher et al. 2006). A randomized, placebo-con-trolled trial of oxcarbazepine for painful diabetic neuropathy found that about35% of patients treated with oxcarbazepine experienced >50% improvementin their pain compared with 18% given placebo (Dogra et al. 2005). Tiaga-bine, vigabatrin, retigabine, levetiracetam, and zonisamide are new anticon-vulsants with a spectrum of pharmacological actions and antinociceptiveeffects in animal models, but few clinical studies exist to support their use as afirst-line therapy for patients with chronic pain (Cutrer 2001; Marson et al.1997). Although variable, adverse drug reactions from these agents can causesignificant cognitive impairment. In an open-label trial with various chronicpain conditions, tiagabine was found to be similar to gabapentin in pain re-duction but to result in greater improvement in sleep quality (Todorov et al.2005). Zonisamide was not effective in a controlled trial for diabetic neurop-athy pain, and the drug was poorly tolerated (Atli and Dogra 2005).

Combinations of anticonvulsants with complementary mechanisms ofaction may increase effectiveness and decrease adverse effects of treatment. Pa-tients with multiple sclerosis or trigeminal neuralgia who had failed treatmentwith carbamazepine or lamotrigine at therapeutic dosages due to intolerable


side effects were given gabapentin as an augmentation agent (Solaro et al.2000). Gabapentin was titrated to pain relief with no new side effects up to amaximum dosage of 1,200 mg/day, at which time either carbamazepine orlamotrigine was tapered until side effects were no longer present. When anti-convulsants were combined with tramadol, synergistic effects were found forinhibiting allodynia and blocking nociception (Codd et al. 2008).

Benzodiazepines

Benzodiazepines are commonly prescribed for insomnia, anxiety, and spastic-ity in patients with chronic pain, but no studies demonstrate any benefit forthese target symptoms, and the drugs may be counterproductive in these pa-tients (King and Strain 1990; Taricco et al. 2000). Benzodiazepines decreasedpain in only a limited number of chronic pain conditions, such as trigeminalneuralgia, tension headache, and temporomandibular disorders (Dellemijnand Fields 1994). Clonazepam may provide long-term relief for the episodiclancinating variety of phantom limb pain (Bartusch et al. 1996). Benzodiaz-epines can cause sedation and cognitive impairment, especially in elderly pa-tients (Buffett-Jerrott and Stewart 2002). In patients with chronic pain, theuse of benzodiazepines, but not opioids, was associated with decreased activitylevels, higher rates of health care visits, increased domestic instability, depres-sion, and more disability days (Ciccone et al. 2000). Combining benzodiaz-epines with opioids may be countertherapeutic and potentially dangerous.Studies of methadone-related mortality found high rates of benzodiazepineuse, with the cause of death being attributed to a combination of drug effects,especially in patients receiving methadone for chronic pain (Caplehorn andDrummer 2002).

Antipsychotics

Antipsychotics have been studied in a variety of chronic pain conditions, in-cluding diabetic neuropathy, postherpetic neuralgia, headache, facial pain,pain associated with acquired immunodeficiency syndrome (AIDS) and can-cer, and musculoskeletal pain. A meta-analysis of 11 controlled trials suggeststhat some antipsychotics have analgesic efficacy in headache (haloperidol)and trigeminal neuralgia (pimozide) (Seidel et al. 2008). In an open-labelstudy, the addition of quetiapine to patients’ existing but ineffective fibromy-algia treatment regimen did not decrease pain but produced significant im-

Pain Management 521

provements on the Fibromyalgia Impact Questionnaire and quality-of-lifemeasures (Hidalgo et al. 2007). Studies of ziprasidone and olanzapine showedbeneficial effects but low response rates and poor tolerability (Calandre et al.2007; Rico-Villademoros et al. 2005). Results are difficult to interpret be-cause comorbid depressive, anxiety, and sleep disorders in patients with fibro-myalgia might respond to treatment with atypical antipsychotics.

Local Anesthetics

Local anesthetic agents act as membrane stabilizers in hyperactive neuronscarrying nociceptive information. Topical lidocaine has been approved for thetreatment of postherpetic neuralgia and does not produce significant serumlevels (Argoff 2000). Results are mixed in studies treating HIV neuropathypain (Cheville et al. 2009; Davies and Galer 2004; Estanislao et al. 2004).Oral mexiletine is an effective treatment for neuropathic pain in patients withpainful diabetic neuropathy, peripheral nerve injury, alcoholic neuropathy,and phantom limb, but not in patients with cancer-related pain (Chabal et al.1992; Davis 1993; Jarvis and Coukell 1998; Kalso et al. 1998; Nishiyama andSakuta 1995). Mexiletine decreased not only reports of pain but also the ac-companying paresthesias and dysesthesias (Dejgard et al. 1988). Mexiletinedecreased pain and sleep disturbances associated with painful diabetic neur-opathy (Oskarsson et al. 1997). Analgesic effect did not correlate with plasmamexiletine levels.

Calcium Channel Blockers

The most commonly prescribed calcium channel blocker for chronic pain isverapamil, which has proved effective in the treatment of migraine and clusterheadaches (Lewis and Solomon 1996; Markley 1991). Intrathecal ziconotide,a neuron-specific calcium channel blocker, has been approved for the inter-ventional treatment of refractory pain of cancer or AIDS. It has potent anal-gesic, antihyperesthetic, and antiallodynic activity, as well as synergisticanalgesic effects when administered with morphine, without producing tol-erance (Christo and Mazloomdoost 2008).

Capsaicin

Topically applied capsaicin has moderate to poor efficacy in the treatment ofchronic musculoskeletal or neuropathic pain. However, it may be useful as an


adjunct or sole therapy for a small number of patients who are unresponsiveto or intolerant of other treatments (Mason et al. 2004).

Drug–Drug InteractionsIn this section, we review only drug interactions between psychotropic drugsand opioids, triptans, NSAIDs, and local anesthetics. (Selected interactionsare listed in Table 17–2.) Most pharmacokinetic interactions between paindrugs and psychotropic drugs result from psychotropic drug–mediated inhi-bition or induction of cytochrome P450 (CYP)–mediated drug metabolism.Many opioids are metabolized by CYP 2D6, an enzyme significantly inhib-ited by fluoxetine, paroxetine, moclobemide, and bupropion. The triptanantimigraine medications rizatriptan, sumatriptan, and zolmitriptan undergometabolism by monoamine oxidase type A. Monoamine oxidase inhibitors(MAOIs) increase the levels of these drugs and possibly their toxicity. Mexi-letine, a CYP 1A2 inhibitor, may inhibit metabolism of olanzapine and clo-zapine. NSAIDs, including cyclooxygenase isoenzyme 2 (COX-2) inhibitorsbut not acetylsalicylic acid (aspirin), may precipitate lithium toxicity by re-ducing its excretion (Hersh et al. 2007). Valproate inhibition of glucuronida-tion increases lamotrigine levels several-fold and may cause toxicities unlesslamotrigine dosage is reduced by at least 50% (Gidal et al. 2003). See Chapter1, “Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug In-teractions,” for a general discussion of drug interactions.

Pharmacodynamic interactions also occur between pain medications andpsychotropic agents. The phenylpiperidine series opioids, meperidine (pethi-dine), fentanyl, tramadol, methadone, dextromethorphan, and propoxy-phene are weak serotonin reuptake inhibitors and may precipitate serotoninsyndrome in combination with MAOIs (including some fatalities) (Choongand Ghiculescu 2008; Gillman 2005) and SSRIs (Ailawadhi et al. 2007; Ranget al. 2008). Morphine, codeine, oxycodone, and buprenorphine are lesslikely to precipitate serotonin toxicity with MAOIs, TCAs, SSRIs, or SNRIs.The constipating effects of opioids are additive in combination with drugspossessing anticholinergic activity, including TCAs and anticholinergicagents used to treat extrapyramidal symptoms (e.g., trihexyphenidyl, benztro-pine). Methadone is associated with prolonged QTc (Ehret et al. 2007),which is exacerbated in the presence of CYP 3A4 inhibitors (e.g., fluvox-

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Table 17–2. Pain drug–psychotropic drug interactions

Pain drugMechanism of interaction

Clinical effect(s) and management

OpioidsDextromethorphan,

fentanyl, meperidine (pethidine), methadone, propoxyphene, tramadol

Increased serotonin activity (have serotonin reuptake inhibitor activity)

Possible serotonin syndrome or hyperpyrexia when combined with SSRIs, SNRIs, MAOIs, or TCAs. Avoid concurrent use, discontinue offending opioid. Consider morphine for pain management.

Methadone Prolonged QT interval

Potentiates QT prolongation induced by TCAs or antipsychotics (typical and atypical). May lead to cardiac arrhythmias or torsade de pointes. Avoid concurrent use. Consider other opioid analgesic.

NSAIDsCelecoxib (and other

COX-2 inhibitors), ibuprofen, naproxen

Reduced renal blood flow

Reduced lithium elimination, leading to lithium toxicity.

Monitor lithium levels, reduce lithium dose. Consider ASA.

Antimigraine agentsAlmotriptan, eletriptan,

frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan

Serotonin agonist activity

Possible serotonin syndrome in combination with SSRIs, SNRIs, MAOIs, or TCAs. Use with caution. Instruct patient about symptoms.

Local anestheticsMexiletine Inhibition of

CYP 1A2Increased levels of olanzapine or

clozapine, possibly increasing toxicity. Avoid concurrent use. Reduce antipsychotic dose.

Note. ASA=acetylsalicylic acid (aspirin); COX-2=cyclooxygenase isoenzyme 2; CYP= cyto-chrome P450; MAOIs=monoamine oxidase inhibitors; NSAID=nonsteroidal anti-inflammato-ry drugs; SNRIs=serotonin–norepinephrine reuptake inhibitors; SSRI=selective serotoninreuptake inhibitors; TCAs=tricyclic antidepressants.


amine, fluoxetine, nefazodone) and other QT-prolonging agents (e.g., TCAs,typical and atypical antipsychotics). A 2006 FDA alert warns of possible sero-tonin syndrome precipitated by the combined use of SSRIs or SNRIs andtriptan antimigraine medications (Evans 2007).

Key Clinical Points

Medication Selection

• Functional outcomes should be determined prior to initiatingtherapy.

• SNRIs and TCAs are first-line therapies.• Anticonvulsants are second-line therapies.• Atypical antipsychotics and opioids are third-line therapies.• If possible, serum levels should be optimized.

Medication Combinations

• The following medication combinations may increase analgesiceffect:– SNRI + anticonvulsant– SNRI + antidepressant– SNRI + anticonvulsant + opioid– Antidepressant + atypical antipsychotic– Antidepressant + anticonvulsant 1 + anticonvulsant 2 with a

different mechanism– Antidepressant + mood-stabilizing anticonvulsant

Cautions

• MDD is underdiagnosed and undertreated, so patients shouldbe treated aggressively if disabling pain persists.

• Opioids should be avoided in the presence of MDD.• Short-acting pain medications should be avoided in the pres-

ence of MDD.• The dosage of opioids should not be increased if two successive

increases provide no benefit.• SSRIs have utility in pain management; they should not be

avoided.

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Drug Interactions

• Serum levels can provide useful insights into real-world interac-tions.

• Gabapentin, pregabalin, and topiramate are primarily renallyexcreted.

• Caution is needed when combining valproate and lamotrigine;the lamotrigine dosage should be reduced by ≥50%.

• CYP 2D6 inhibitors, including several antidepressants, inhibitopioid metabolism.

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18Substance Use Disorders

José Maldonado, M.D., F.A.P.M., F.A.C.F.E.



Abuse and dependence of substances, including alcohol, tobacco, prescrip-tion drugs, and illicit drugs, complicate the treatment of patients who aremedically ill. The 2007 National Survey on Drug Use and Health (SubstanceAbuse and Mental Health Services Administration 2008) identified the inci-dence of substance abuse in the United States among those ages 12 and olderas follows: heavy alcohol use, 6.9%; binge drinking, 23.3%; tobacco use, 28%;and nonmedicinal use of prescription psychotherapeutics, 2.8% (includingpain relievers alone at 2.1%). Complications of ongoing substance abuse, in-cluding intoxication, overdose (suicidal or unintentional), withdrawal, andlong-term organ system damage (e.g., hepatic failure, dementia), lead inevi-tably to medical hospitalization. Among medically hospitalized psychiatric


consultation patients, substance use disorders are diagnosed in 36% of patientsunder age 60 and nearly 9% of patients over age 60 (Schellhorn et al. 2009),underscoring the importance of this issue across the life span. Substance-induced mood disorder is more prevalent in medically serious suicide attemptsthan in attempts with no medical sequelae (Elliott et al. 1996).

In this chapter, we discuss the management of alcohol abuse and with-drawal; drugs for the treatment of alcohol, nicotine, and opioid dependence;and the use of these medications in medically ill patients. Psychiatric adverseeffects and drug interactions of these agents are listed in Tables 18–1 and 18–2, later in this chapter.

Drugs for Substance Intoxication

No antidotes exist for most drug intoxications. Opioids are the clearest excep-tion. Opioid overdose is treated with the opioid antagonist naloxone. It isgiven intravenously and has no major contraindications in patients who aremedically ill. However, patients with chronic pain who have been taking opi-oids chronically may wake up extremely agitated and in severe pain after beinggiven naloxone.

For the treatment of acute benzodiazepine intoxication, flumazenil, a ben-zodiazepine antagonist, is available. Flumazenil is short acting, and sedationmay recur after an initial response. Flumazenil has also been used to treat he-patic encephalopathy based on an increase in endogenous benzodiazepine re-ceptor ligands in this condition. Two systematic reviews of the literatureconcluded that treatment of hepatic encephalopathy with flumazenil producedsignificant symptomatic improvement, but the benefit was short lived, with nosignificant benefit on recovery or survival (Als-Nielsen et al. 2004; Goulenoket al. 2002). Nausea and vomiting are its most common side effects, but flu-mazenil’s major risk is that it may provoke withdrawal seizures in patients withbenzodiazepine dependence. Flumazenil should not be administered to coma-tose patients when the identity of the ingested drug(s) is not certain.

Flumazenil was without significant cardiovascular effects in patients withstable ischemic heart disease. Rapid intravenous infusion of flumazenil athigher than currently recommended doses produced no abnormal changes incardiovascular parameters in high-risk cardiac patients (Croughwell et al.

Substance Use Disorders 539

1990; Griffiths et al. 1993). Slow infusion has been suggested to avoid cardiacadverse effects (Weinbroum et al. 2003). However, use of flumazenil in pa-tients with carbamazepine or chloral hydrate overdose or who show electro-cardiographic abnormalities suggestive of a tricyclic antidepressant (TCA)overdose can induce treatable cardiac dysrhythmias (Weinbroum et al. 1997).Flumazenil should be withheld in patients with a history or evidence of sei-zures, or in those who have overdosed on drugs that decrease seizure thresholdor are tachydysrhythmogenic, or in those who have an electrocardiogram sug-gestive of overdose of these drugs (e.g., QRS prolongation suggesting overdoseon TCAs) (Weinbroum et al. 2003). Provocation of fear and panic attacks hasbeen reported when administered to patients with a history of panic disorder(Roche 2007).

Drugs for Substance Use Disorders

Medications for the treatment of substance abuse, including medications usedto prevent withdrawal, to reduce cravings, and to block the effect of sub-stances and potentially diminish relapse risk for alcohol, opioids, and tobacco,have received relatively little study in patients who are medically ill. Neverthe-less, the known adverse effects, pharmacokinetics, and pharmacodynamics ofthese drugs can provide guidance for their use.

Alcohol Use Disorders

Alcohol and its medical consequences are a major concern for hospitalized pa-tients, particularly surgical and intensive care unit (ICU) patients. Amongtrauma patients, 40%–50% are intoxicated at the time of injury (Gentilelloet al. 1995). Alcohol abuse and dependence are found in 10%–14% of ICUpatients, and the presence of alcoholism is associated with a doubling of mor-tality (Moss and Burnham 2006). Alcohol abuse and withdrawal are associ-ated with increased risk for infections; cardiopulmonary insufficiency; cardiacarrhythmia; bleeding disorders; need for mechanical ventilation; and longer,more complicated ICU stays (O’Brien et al. 2007). Of the medical-surgicalpatients known to be alcohol dependent, most will develop significant symp-toms of alcohol withdrawal, requiring pharmacological intervention (Saitzand O’Malley 1997).


Alcohol Withdrawal Syndrome

Alcohol withdrawal syndrome (AWS) occurs after a period of absolute or, insome cases, relative abstinence or attempted self-tapering from alcohol.Therefore, patients can experience AWS even though they may have a highblood alcohol level on presentation. AWS usually begins within 6–24 hoursbut may occur as late as 10 days after alcohol cessation in habituated individ-uals (Hall and Zador 1997). Tremors, nervousness, irritability, nausea, andvomiting are the earliest and most common signs. Uncomplicated withdrawalnormally subsides in 5–7 days without treatment; however, residual symp-toms of sympathetic nervous system activity (e.g., insomnia, anxiety, tachy-cardia) may persist for 2 weeks or more.

Withdrawal seizures are generalized motor seizures, occurring in up to25% of patients experiencing AWS, usually between 7 and 38 hours after arelative or absolute abstinence, but they may occur up to a week later. Risk ofwithdrawal seizures is increased with hypomagnesemia, respiratory alkalosis,hypoglycemia, and hypernatremia. In patients with withdrawal seizures, two-thirds will have multiple seizures, and 2% will develop status epilepticus.About one-third of patients who develop seizures go on to develop alcoholwithdrawal delirium (delirium tremens).

Delirium tremens appears 1–3 days after absolute or relative abstinencefrom alcohol intake, reaching a peak intensity on the fourth or fifth day. Themortality rate is about 1% if treated and up to 20% if untreated or if comor-bid with major medical illness. Consistent clinical predictors of the develop-ment of delirium tremens are prior history of delirium tremens and pulse rate>100–120 beats per minute (Lee et al 2005). Delirium tremens is typically anagitated hyperactive delirium—that is, mental status changes with associatedcognitive impairment—with pronounced autonomic hyperactivity (includ-ing fever and increased heart rate and blood pressure); it is often accompaniedby visual (although sometimes tactile) hallucinations or other perceptual dis-tortions. The duration of confusion may persist days to weeks after resolutionof the physical symptoms of withdrawal. Death may result from infections,cardiac arrhythmia, shock, hyperpyrexia, or suicide in response to hallucina-tions or delusions.

The most commonly used measures of alcohol withdrawal severity in-clude the Alcohol Withdrawal Assessment Scale (Wetterling et al. 1997) and


the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar)(Sullivan et al. 1989).

Management of Alcohol Withdrawal

No single standardized protocol is used for the treatment of alcohol with-drawal, and standardized monitoring of patients’ withdrawal severity is notcommon practice (Saitz et al. 1995).

Before initiating any specific treatment for alcohol withdrawal, a thor-ough assessment of the patient’s medical condition is required to identifyacute (i.e., dehydration, hypoglycemia, subdural hematoma, Mallory-Weisstear, gastritis) and long-term (e.g., cirrhosis, malnutrition, neuropathy) se-quelae of alcohol abuse. Admission blood alcohol level and toxicology screen-ing are indicated, the latter to identify other abused substances (particularlybenzodiazepines and opioids) that may complicate the withdrawal syndromeand its treatment.

A 100-mg dose of thiamine hydrochloride should be given parenterallybefore the administration of dextrose-containing solutions, to avoid precipi-tating acute Wernicke-Korsakoff syndrome (a medical emergency). Thiamine100 mg/day (administered intravenously, intramuscularly, or orally) shouldbe continued indefinitely, because no data are available to indicate how longit is required. Folate and other B vitamins should also be supplemented daily.Fluid and electrolytes should be replaced as needed. Most patients in alcoholwithdrawal can be managed with supportive care alone. However, malnour-ished alcoholic patients may be hypoglycemic, and when they receive intrave-nous glucose, they are at high risk for the refeeding syndrome, includinghypophosphatemia and hypomagnesemia.

Benzodiazepines are the mainstay of alcohol withdrawal treatment. In pa-tients who are medically ill, short-acting benzodiazepines are preferred, par-ticularly those requiring only Phase II glucuronidation, such as lorazepam.Lorazepam has no active metabolites; can be administered by multiple routes,including intravenous drip; and can be easily titrated upward or downwardbased on symptom severity. Symptom-driven protocols in the general hospitaland ICU setting call for frequent AWS severity measurement, followed by dos-ing per protocol of lorazepam, and have been shown to reduce time to symp-tom control, amount of sedative required, and time spent receivingbenzodiazepine infusion, compared with historical control subjects (DeCarolis


et al. 2007). Lorazepam appears to have longer duration of seizure controlcompared with diazepam (Alldredge et al. 2001). When standing lorazepam isrequired, dosing should be administered at least every 4 hours; when tapered,the dose per administration should be decreased, but the timing should notchange because breakthrough symptoms may occur with longer intervals.Once lorazepam-treated patients are stabilized, and they have no severe liverdisease and are reliably taking oral medication (generally for 2–4 days),lorazepam can be switched to an equivalent dosage of a longer-acting agentsuch as chlordiazepoxide or clonazepam. This change will allow for wideningthe dosing interval and autotapering if the patient leaves the hospital prema-turely. For this reason, some experts also advocate the use of phenobarbital.However, this medication is less desirable in patients who are severely medi-cally ill, including those who are at greater risk for respiratory suppression,those with impaired liver function, and those receiving polypharmacy. Alterna-tively, a slow titration off lorazepam is also an acceptable treatment method.

Several drugs in other classes, including anticonvulsants (e.g., carbamaz-epine), beta-blockers (e.g., propranolol), alpha-2 agonists (e.g., clonidine,dexmedetomidine), and propofol, have been reported as effective in a fewsmall studies or case series, but patients were usually experiencing mild with-drawal and had minimal medical comorbidity, and validated instruments forassessing withdrawal were often not used. Thus, no definite conclusions canbe drawn about the effectiveness and safety of the use of these drugs for alco-hol withdrawal (Polycarpou et al. 2005), and none are recommended as first-line therapy, especially in medically ill patients. A review of 57 randomizedtrials of benzodiazepines compared with placebo or other drugs found thatbenzodiazepines offered a large benefit against alcohol withdrawal seizurescompared with placebo and offered a significant benefit for seizure controlwhen compared with nonanticonvulsants, but not when compared with anti-convulsants (Ntais et al. 2005). An anticonvulsant should be added if seizuresare not adequately controlled with benzodiazepines.

Beta-blockers and alpha-2 agonists may serve as adjunctive treatments forautonomic hyperactivity that is not fully responding to benzodiazepine man-agement. Beta-blockers reduce autonomic manifestations of acute alcoholwithdrawal, and most arrhythmias that patients have during AWS are respon-sive to them (Mayo-Smith et al. 2004). However, beta-blockers do not miti-gate the central nervous system effects, especially delirium and seizures. Beta-


blockers are contraindicated in patients with asthma, chronic obstructive pul-monary disease, hypoglycemia, bradycardia, and atrioventricular block, aswell as some forms of heart failure.

The alpha-2 adrenergic agonist clonidine has been found to be effective inmanaging the physical (i.e., autonomic hyperactivity) as well as psychological(i.e., anxiety) symptoms associated with AWS (Baumgartner and Rowen1991; Bjorkqvist 1975; Braz et al 2003; Dobrydnjov et al 2004; Nutt andGlue 1986; Manhem et al. 1985; Walinder et al. 1981; Wilkins et al. 1983).In fact, transdermal clonidine patch has been found to be more effective thanchlordiazepoxide (Baumgartner and Rowen 1991) and diazepam (Dobrydn-jov et al. 2004) in all withdrawal symptoms. Clonidine is contraindicated inpatients with bradycardia and atrioventricular block. It is important to mon-itor for hypotension during clonidine therapy and then to taper clonidinegradually to avoid hypertensive rebound (Gowing et al. 2004). In addition toorthostatic hypotension, side effects of clonidine include sedation, dry mouth,and constipation; these are more likely at higher doses. There are several re-ports (although no controlled studies) of the effectiveness of dexmedetomi-dine (Baddigam et al. 2005; Darrouj et al. 2008; Maccioli 2003; Rovasalo2006), but use of this agent is limited to the ICU.

Continuous infusion of propofol has been reported to be effective fordelirium tremens in ICU patients who are refractory to lorazepam, but con-trolled studies are lacking (McCowan and Marik 2000).

The addition of an antipsychotic on an as-needed basis may be useful inseverely agitated patients or in those experiencing severe hallucinosis that isnot responding to an adequate benzodiazepine regimen. Because they canlower seizure threshold, antipsychotic agents should not be administeredalone to patients with AWS.

Although intravenous ethanol has been reported to be effective for thetreatment of withdrawal symptoms (Dissanaike et al. 2006), as well as less se-dating than benzodiazepines, no controlled trials have been reported. Intra-venous alcohol has a relatively narrow therapeutic index and is toxic, and itsuse seems to give a mixed message to alcoholic patients. Therefore, intrave-nous alcohol is inappropriate for treatment or prevention of AWS in patientswho are medically ill (Hodges and Mazur 2004).

The alcohol-dependent patient with cirrhosis who presents with acutewithdrawal presents a therapeutic dilemma. Benzodiazepines and barbiturates


are contraindicated in patients with cirrhosis because these drugs can precip-itate hepatic encephalopathy, but untreated delirium tremens has a high riskof morbidity and mortality. A prudent plan is to treat with lorazepam for thereasons outlined above, but to use the lowest effective dosage.

New data are finally accumulating on the use of antidepressant agents forthe management of AWS. Carbamazepine is the most studied antiepilepticagent. Randomized double-blind studies have suggested that carbamazepine isequal in efficacy to lorazepam in decreasing the symptoms of alcohol with-drawal and superior to lorazepam in preventing posttreatment relapse to drink-ing and reducing withdrawal-related anxiety symptoms (Malcolm et al. 2002).A Cochrane review suggests that carbamazepine has a small but statistically sig-nificant protective edge over benzodiazepines (Polycarpou et al. 2005). Otheragents studied in this class include valproic acid (Reoux et al. 2001), topira-mate (Krupitsky et al. 2007), and gabapentin (Bozikas et al. 2002).

Anticraving and Abstinence-Promoting Medications for Alcohol Dependence

Disulfiram (Antabuse) inhibits the enzyme aldehyde dehydrogenase, elevat-ing levels of aldehydes in the liver, thus inducing the “Antabuse reaction,”which consists of flushing, headache, nausea, weakness, dizziness, anxiety,vertigo, and ataxia. Disulfiram is not advised in most patients with seriousmedical illnesses because of the potential for serious cardiac, hepatic, and neu-rological effects. For example, disulfiram is contraindicated in severe myocar-dial disease or coronary occlusion. Multiple cases of hepatitis, both cholestaticand fulminant types, as well as hepatic failure resulting in transplantation ordeath, have been reported with disulfiram. In patients with preexisting liverdisease, the inactivation of aldehydes is impaired, leading to excessive accu-mulation of acetaldehyde and making a disulfiram reaction more severe. Di-sulfiram may cause a variety of neurological symptoms that mimic multiplesclerosis (e.g., optic neuritis, polyneuritis). Many oral medications in liquidform and some intravenous infusions contain small amounts of alcohol,which would provoke the disulfiram reaction.

Acamprosate, a structural analog of gamma-aminobutyric acid and gluta-mate, is thought to interact with these neurotransmitter systems in the centralnervous system to attenuate glutamatergic excitation that occurs with absti-nence, and thus to reduce alcohol craving. In randomized controlled trials,acamprosate has been found to reduce craving and to increase and maintain


abstinence rates compared with placebo (Mann et al. 2004). It can be initiatedimmediately after detoxification and managed in a structured alcoholism treat-ment program. Acamprosate’s primary side effects are diarrhea and anxiety,usually only at high doses. Rare cases of cardiomyopathy, heart failure, andrenal failure have occurred. Acamprosate is renally eliminated, not hepaticallymetabolized, so it can be used in patients with liver disease (U.S. Departmentof Health and Human Services 2005). However, in renal impairment (creati-nine clearance 30–50 mL/minute), dosage must be reduced by half. It is con-traindicated in patients with creatinine clearance ≤30 mL/minute (Herve et al.1986). Acamprosate has few known drug interactions. Compared with disul-firam and naltrexone, which have multiple contraindications, acamprosatemay be a good choice for patients with medical comorbidity, especially thosetaking other medications.

Naltrexone, an opioid antagonist used to reduce alcohol craving, is sub-ject to a U.S. Food and Drug Administration black-box warning contraindi-cating its use in severe hepatic disease and warning of possible hepatotoxicitywhen administered above the recommended dosage (Alkermes 2009). Severalstudies support its hepatic safety at the recommended dosage for the treat-ment of alcoholism (Yen et al. 2006). However, acute worsening of hepaticfunction has been noted when used in therapeutic dosages to treat itching inpatients with hepatic failure (McCabe 2006). Postoperative use is contraindi-cated, because naltrexone will block postoperative opioid analgesia.

Drugs for Opioid Withdrawal

Methadone is the most widely used drug for treatment of opioid withdrawal;its use in patients with particular medical illnesses is discussed in Chapter 17,“Pain Management.” Methadone’s risk for QT prolongation is of particularconcern when given intravenously, especially if the patient is receiving otherdrugs that can increase the QT interval. In patients with renal and hepatic fail-ure, dosage adjustment may be needed to minimize side effects and preventworsening uremic or hepatic encephalopathy. Perioperatively, patients whowere undergoing chronic methadone maintenance therapy require careful at-tention to pain control. The dose can be increased for pain control or contin-ued at maintenance dose with a different opioid added for acute postoperativepain. Sedation, respiratory depression, and other symptoms of opioid toxicityshould be monitored. Drug–drug interactions are common (Cherpitel 2007).


Buprenorphine, a mixed agonist–antagonist opioid used for treatment ofopioid dependence, has a lower potential for causing respiratory depressionand QTc prolongation (Wedam et al. 2007) than methadone. A few cases ofbuprenorphine-induced hepatotoxicity have occurred in patients with knownhepatitis C. Buprenorphine is metabolized by cytochrome P450 (CYP) 3A4,and drug–drug interactions must be considered (Moss and Burnham 2006).Buprenorphine is not recommended perioperatively because it may precipi-tate withdrawal in patients previously taking opioids and will block agonistopioids given for postoperative analgesia. Clonidine is another option formitigating signs of opioid withdrawal, and its contraindications are the sameas when used for AWS.

Naltrexone’s risks in the medically ill patient with opioid dependence arethe same as in alcohol dependence, except that the potential for blocking opi-oid analgesia is even greater in the former (see “Anticraving and Abstinence-Promoting Medications for Alcohol Dependence,” earlier in this chapter).

Drugs for Nicotine Dependence

Nicotine replacement therapy (NRT) is often used in medically hospitalizedsmokers to treat acute nicotine withdrawal symptoms and to treat dependence(Rigotti et al. 2008). NRT is safe in patients with hypertension and stable car-diovascular disease (Joseph and Fu 2003). NRT is generally contraindicated inpatients with acute heart disease because of the potential for increasing heartrate, angina, and possibly arrhythmias. Caution is advised, especially in hearttransplant patients.

Bupropion and varenicline reduce nicotine craving. Because bupropionmay lower the seizure threshold, especially at rarely given doses of >450 mg/day, it is relatively contraindicated in patients with epilepsy or a recent seizure,and should be used with caution in patients at risk for seizures (e.g., those atrisk for acute alcohol withdrawal).

Varenicline is a nicotinic receptor partial agonist approved as an aid tosmoking cessation. Because of its partial agonist properties, varenicline relievesthe symptoms of nicotine withdrawal and cigarette craving while blocking thereinforcing effects of nicotine in patients who relapse (Rollema et al. 2007). Se-rious psychiatric adverse effects, including depression, mania, psychosis, hallu-cinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety,and panic, as well as suicidal ideation, suicide attempt, and completed suicide,


have been reported in patients with and without mild psychiatric disorders,and have prompted a black-box warning. Patients with preexisting psychiatricillness receiving varenicline should be closely monitored because the drug mayworsen existing psychopathology. Clinical trials have not investigated its safetyin patients with serious psychiatric illness, such as schizophrenia, bipolar dis-order, or major depressive disorder (Pfizer 2009), or in patients with seriousmedical illness. Varenicline is renally excreted, and dose reductions are recom-mended in patients with renal insufficiency or undergoing dialysis. It is with-out significant drug interactions. Side effects (i.e., nausea and vomiting) maybe problematic in patients who are medically ill. Rare cases of angioedemaleading to respiratory compromise, Stevens-Johnson syndrome, and erythemamultiforme have been reported with varenicline (Pfizer 2009).

Psychiatric Adverse Effects of Drugs Used in Substance Use DisordersA variety of drugs used in treating substance use disorders have neuropsychi-atric adverse effects. These effects are summarized in Table 18–1.

Drug–Drug InteractionsAcamprosate and varenicline are without significant pharmacokinetic druginteractions. Drug interactions between other drugs used to treat substanceabuse and psychotropic drugs are listed in Table 18–2. See Chapter 1, “Phar-macokinetics, Pharmacodynamics, and Principles of Drug–Drug Interac-tions,” for a detailed discussion of drug interactions.


Table 18–1. Neuropsychiatric adverse effects of drugs that treat substance abuseMedication Neuropsychiatric adverse effect(s)

Acamprosate Common: anxiety, insomniaSerious: suicidality, depression

Alpha-2 agonists (e.g., clonidine, dexmedetomidine)

Common: drowsiness, sedation, nervousness, agitation, sexual dysfunction

Serious: depression

Anticonvulsants (e.g., carbamazepine, valproic acid, topiramate)

Common: depression, sedation, confusion, fatigue, appetite/weight changes

Serious: seizure exacerbation, suicidality, psychosis, delirium

Barbiturates (e.g., phenobarbital)

Common: drowsiness, somnolence, dependenceSerious: suicidality, respiratory depression

Benzodiazepines (e.g., lorazepam, diazepam)

Common: sedation, lethargySerious: dependence, seizures, depression, delirium,

impaired memory

Beta-blockers (e.g., propranolol)

Common: depression, insomnia, disorientation, sexual dysfunction

Buprenorphine Common: sedation, insomnia, withdrawal symptoms, depression

Serious: seizures, respiratory depression

Bupropion Common: anxiety, insomnia, weight lossSerious: seizures, suicidality, worsening depression, agitation,

psychosis, hallucinations, paranoia

Disulfiram Common: alcohol–disulfiram reaction, drowsinessSerious: psychosis, respiratory depression, seizures

Flumazenil Common: agitation, anxiety, fatigue, confusionSerious: seizures, re-sedation (due to short half-life),

benzodiazepine withdrawal syndrome

Naltrexone Common: insomnia, anxiety, fatigue, somnolenceSerious: suicidality, depression, opioid withdrawal syndrome

Propofol Common: respiratory depression, sedation, cognitive impairment

Serious: propofol infusion syndrome, opisthotonus, unconsciousness


Key Clinical Points• Alcohol withdrawal syndrome (AWS) occurs after a period of ab-

solute or, in some cases, relative abstinence or attempted self-tapering from alcohol. Therefore, patients can experience AWSeven though they may have a high blood alcohol level on pre-sentation.

• The mortality rate of delirium tremens is about 1% when timelytreated, but it may be as high as 20% in nontreated patients.

• Although benzodiazepines are considered the treatment ofchoice for alcohol withdrawal, several drugs in other classes, in-cluding anticonvulsants (e.g., carbamazepine), beta-blockers(e.g., propranolol), alpha-2 agonists (e.g., clonidine, dexmedeto-midine), and propofol, have shown effectiveness and promise.

• Nicotine replacement therapy is safe in patients with hyperten-sion and stable cardiovascular disease but is generally contrain-dicated in patients with acute heart disease because of thepotential for increasing heart rate, angina, and arrhythmias.

• Because most available pharmacological agents used to treataddiction or prevent withdrawal syndromes have considerablepotential for neuropsychiatric side effects, providers must usecaution when prescribing them.

Varenicline Common: insomnia, abnormal dreams, appetite changes, somnolence, emotional disturbances

Serious: suicidality, depression, agitation, behavioral disturbances, exacerbation of underlying psychiatric disorder, seizures, hallucinations

Source. McEvoy 2008.

Table 18–1. Neuropsychiatric adverse effects of drugs that treat substance abuse (continued)Medication Neuropsychiatric adverse effect(s)

550C



Table 18–2. Psychotropic drug–drugs for substance abuse interactionsMedication Interaction mechanism Effect(s) on psychotropic drugs and management

Buprenorphine See Methadone below Similar drug interaction profile to methadone (see below), although generally attenuated effects, particularly less concomitant sedation and QT prolongation.

Opioid antagonism May induce withdrawal in patients on opioid analgesics and methadone.

Clonidine Additive hypotensive effect Increased risk of hypotensive effects with antipsychotics, TCAs, and MAOIs; increased risk of dry mouth and eyes with TCAs and antipsychotics.

Inhibits norepinephrine release Clonidine may decrease the therapeutic effect of TCAs and NRIs, including atomoxetine. Similarly, TCAs and NRIs may decrease the effects of clonidine.

Disulfiram Inhibits CYP 2E1, 1A2, and possibly other CYP enzymes

Increased levels and toxicity of phenytoin (and possibly mephenytoin and fosphenytoin), olanzapine, and risperidone.

Inhibits acetaldehyde metabolism

Many oral medications in liquid form and some intravenous infusions contain small amounts of alcohol, which would provoke a disulfiram reaction.

Inhibits dopamine beta-hydroxylase

Increased seizure potential with illicit cocaine use.

Flumazenil GABA antagonism Flumazenil is contraindicated in patients receiving a benzodiazepine for control of intracranial pressure or status epilepticus, or in cases of TCA overdose.

Methadone Opioid antagonism Decreased methadone effect and possibly withdrawal in combination with naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine.

Induces CYP 3A4 Decreased serum levels of methadone and possible withdrawal in combination with phenytoin, St. John’s wort, phenobarbital, carbamazepine, rifampin, and some antiretroviral medications (see Chapter 12, “Infectious Diseases”).

Inhibits CYP 3A4 Increased serum levels of methadone and potential excessive sedation and respiratory suppression with CYP 3A4 inhibitors such as fluvoxamine and nefazodone.

Sub

stance U

se Disord

ers551

Potentiation of opioid sedation Coadministration with benzodiazepines or strong antihistamines (e.g., tertiary amine TCAs, quetiapine, diphenhydramine) can potentiate opioid sedation.

QT prolongation Additive risk for QT prolongation and electrolyte disturbances with psychotropics that increase QT interval, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium (see also Chapter 6, “Cardiovascular Disorders”).

Naltrexone Opioid antagonism Naltrexone blocks the effect of opioids administered for pain, cough and diarrhea. Use of naltrexone should be avoided in patients dependent on opioids for control of severe pain.

Unknown Naltrexone increases area under the plasma concentration–time curve of acamprosate by 25%.a

Note. CYP=cytochrome P450; GABA=gamma-aminobutyric acid; MAOIs=monoamine oxidase inhibitors; NRIs=norepinephrine reuptake inhibi-tors; TCAs=tricyclic antidepressants.aAcamprosate product monograph (Prempharm 2007).

Table 18–2. Psychotropic drug–drugs for substance abuse interactions (continued)Medication Interaction mechanism Effect(s) on psychotropic drugs and management


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557

IndexPage numbers printed in boldface type refer to tables or figures.

Abacavir, 376Absorption, and pharmacokinetics, 9,

10, 11, 115, 185.See also Malabsorption

Acamprosatealcohol dependence and, 199, 483,

544–545drug–drug interactions and, 547,

551medical side effects of, 483neuropsychiatric adverse effects of,

548ACE inhibitors, and drug–drug

interactions, 30, 202Acetaminophen, 36Acetazolamide, 203, 217, 219Acne, 408, 415Acromegaly, 306Acute pain, 504–505Acyclovir, 377, 393Addison’s disease, 306Administration, alternative routes of.

See also Transdermal patchfor antidepressants, 89–91for antipsychotics, 91–92for anxiolytics and sedative-

hypnotics, 87–89for children, 451for cognitive enhancers, 94

intramuscular form of, 81intravenous form of, 80–81for mood stabilizers, 92–93for psychostimulants, 94reasons for, 79, 80, 94–95rectal form of, 81, 86sublingual form of, 81for surgical patients, 449

Adverse cutaneous drug reactions (ACDRs), 415–420

Adverse effects of medications. See also Anticholinergic effects; Drug–drug interactions; Drug reactions; Extrapyramidal symptoms; Neuroleptic malignant syndrome; Serotonin syndrome

of chronic opioid therapy, 514–515medication compliance and

minimization of, 8pharmacodynamics and, 4, 7psychiatric manifestations of

antibiotic therapy for infectious diseases, 375–377,393–394

cancer treatments, 247–251cardiac medications, 183–184critical care and surgical drugs,

453–454dermatological agents, 420–422


Adverse effects of medications, psychiatric manifestations of (continued)

endocrine treatments, 320–324gastrointestinal medications,

130, 131immunosuppressant medications

for organ transplantation, 484–487

neurological drugs, 289–291obstetric and gynecological

agents and procedures, 355–358

renal and urological agents, 161–162, 163

respiratory medications, 216–219rheumatological medications,

433, 434substance use disorder drugs,

547, 548–549psychotropic drugs and

cancer risk, 244–247cardiovascular disorders, 187endocrinological disorders,

313–320gastrointestinal disorders,

123–126neurological disorders, 286–289renal and urological disorders,

164–166respiratory disorders, 225–227rheumatological disorders,

434–435sexual dysfunction, 166, 319,

326, 355Adverse Event Reporting System

database (Food and Drug Administration), 245

Affective disorders, and complex regional pain syndrome, 507

Aggression, and testosterone replacement therapy, 323–324

AgitationAlzheimer’s disease and, 273–274traumatic brain injury and, 277–278

Agranulocytosis, 64–66, 295Albumin, 12, 13Albuterol, 217, 228Alcohol and alcohol use disorders.

See also Substance use disordersinterferon-alpha therapy and

abstinence from, 122medications for treatment of, 199,

483, 539–545plasma levels of albumin and, 13renal drug reactions to, 60

Alcohol Withdrawal Assessment Scale, 540

Alcohol withdrawal syndrome (AWS), 540–545

Aldosterone, and drug–drug interactions, 37

Alemtuzumab, 252, 485Alfentanil, 36, 202, 203Alfuzosin, 169, 171, 172, 173Alkylating agents, 249Almotriptan, 294, 523Alopecia areata, 408, 414, 417Alosetron, 137Alpha-adrenergic blocking agents, 183Alpha-glucosidase inhibitors, 321Alpha-lipoic acid, 1045-alpha reductase inhibitors, 162, 163,

172Alpha-1 acid glycoprotein, 12, 13Alpha-1 adrenergic antagonists, 162,

163, 167, 169, 455, 456, 457Alpha-2 adrenergic sedatives, 456Alpha-2 agonists, 290, 542, 543, 548

Index 559

Alprazolamanxiety in cancer patients and, 242diabetic patients and, 309drug–drug interactions and, 34hepatic insufficiency and, 119nonoral preparations of, 82seizures and, 49systemic clearance of, 19

Alprenolol, 35Alternative medications, and anxiety in

preoperative patients, 450. See also Herbal medicines; Melatonin; St. John’s wort

Alternative routes. See AdministrationAltretamine, 249Alzheimer’s disease

anticholinergic medications and, 24treatment of psychiatric symptoms

of, 272–274Amantadine

adverse psychiatric effects of, 290, 377drug–drug interactions and, 292,

294, 295renal insufficiency and, 157

American Psychiatric Association, 272Amiloride, 168, 316Aminoglycosides, 375Aminophylline, 217Aminotransferase, and drug-induced

liver injury, 128Amiodarone

drug–drug interactions and, 183,202, 205

neuropsychiatric side effects of, 184pharmacokinetics and, 30

Amisulpride, 104Amitriptyline

drug–drug interactions and, 26, 30,168, 382, 383, 410

gastric bypass surgery and, 113incontinence and, 114–115neuropathic pain and, 505, 506nonoral preparations of, 82, 90pain management and, 512rheumatological disorders and, 432systemic clearance of, 19

Amlodipine, 35Amoxapine, 26, 287Amphetamines

drug–drug interactions and, 26,135, 168, 295

gastrointestinal adverse effects of, 125pregnancy and, 352

Amphotericin B, 377Amprenavir, 34, 381Amrinone, 453, 457Analgesic agents, 455, 504Anastrozole, 250Anemia

drug reactions and, 65fatigue in cancer patients and, 243

Anesthetic agents. See also Inhalational anesthetics

discontinuation of psychotropic drugs before surgery and, 448

pain management and local forms of, 521, 523

psychiatric adverse effects of, 453Anger, and chronic pain, 504Angioedema, 408Angiotensin-converting enzyme

inhibitors, 183, 184Angiotensin II receptor blockers, 202Antacids, 23, 133Antianginal drugs, and drug–drug

interactions, 30, 202Antiarrhythmic agents, 53, 183, 184,

202, 204


Antibioticsadverse psychiatric effects of,

375–377, 393–394drug–drug interactions and,

378–384, 410Lyme disease and, 373neuropsychiatric side effects of, 218

Anticholinergic effectsatypical antipsychotics and, 67delirium in hospitalized patients

and, 447drug–drug interactions and, 24,

134, 169, 228, 455gastrointestinal symptoms and, 124,

134metabolic reactions and, 68neurological symptoms and, 287neuropsychiatric symptoms and,

217, 218renal and urological symptoms and,

165respiratory disorders and, 221, 228,

229Anticoagulants, and drug–drug

interactions, 30Anticonvulsants

adverse psychiatric effects of, 290,548

alcohol withdrawal syndrome and, 542

diabetic peripheral neuropathy and, 505

drug–drug interactions and, 30,292, 294, 295, 327

epilepsy and, 284, 285gastrointestinal reactions and, 56hematological reactions and, 65HIV/AIDS patients and, 395pain management and, 512, 518–520

pancreatitis and, 129psychiatric adverse effects of, 289,

291rectal administration of, 93renal insufficiency and, 156trigeminal neuralgia and, 506

Antidepressants. See also Tricyclic antidepressants


breastfeeding and, 353cancer risk and, 246cardiac reactions to, 50, 187,

188–193central nervous system reactions to,

42, 43diabetic patients and, 308drug–drug interactions and

cardiac medications, 204–205dermatological medications, 411endocrine medications, 325, 327gastrointestinal medications, 136neurological drugs, 294pharmacokinetics of, 26, 30–31renal and urological drugs, 60,

61, 165, 172endocrinological adverse effects of,

313functional dyspepsia and, 108gastrointestinal adverse effects of, 124hematological reactions to, 65hepatic insufficiency and, 118hypothyroidism and, 309inflammatory bowel disease and,

112–113irritable bowel syndrome and, 114liver injury and, 127neurological adverse effects of, 287,

294

Index 561

nonoral preparations of, 82–83,89–91

organ transplantation and, 476–480pain management and, 512,

515–518pancreatitis and, 129pregnancy and, 344, 346, 348–349renal disease and, 153, 154, 157,

159respiratory disorders and, 220–221rheumatological disorders and,

432–433sexual dysfunction and, 166xerostomia and, 105

Antidiarrheal agents, 31, 130, 133Antiemetics

chemotherapy-induced nausea and vomiting, 260

drug–drug interactions and, 134hyperprolactinemia and, 319neuroleptic malignant syndrome

and, 40, 41psychiatric adverse effects of, 130

Antiepileptic agents, 350Antifungal agents, 377, 410Antihelminthic agents, 377, 393Antiherpetic agents, 377Antihistamines, 411, 421, 551.

See also DiphenhydramineAntihyperlipidemics, 31, 203Antihyponatremics, 31Anti-infective agents, 227Antimetabolites, 249Antimicrobials, 32. See also AntibioticsAntimigraine drugs, 32, 523Antimuscarinic effects, and delirium, 447Antinauseants, 134Antineoplastic agents, 33Antiparkinsonian agents, 33, 157, 292

Antiplatelet agents, 30Antipsychotics.

See also Atypical antipsychoticsbreastfeeding and, 353cancer risk and, 244–245cardiac effects of, 187, 193–196,

205central nervous system reactions to,

41, 42, 43corticosteroids and, 323drug–drug interactions and

cardiac medications, 205dermatological medications, 411endocrine medications, 326, 327gastrointestinal medications, 136neurological medications, 293,

295obstetrics/gynecology drugs, 359pain management, 523pharmacokinetics of, 26, 33–34renal and urological medications,

60, 61, 165, 173dysphagia and, 105endocrinological adverse effects of,

313extrapyramidal symptoms and, 286gastrointestinal reactions and, 56,

124heatstroke induced by, 67, 68, 69hematological reactions and, 64, 65hepatic insufficiency and, 119HIV/AIDS patients and, 390hyperemesis gravidarum and, 110hyperprolactinemia and, 317,

319–320hyperthyroidism and, 310–311intravenous administration of, 81metabolic reactions and, 68, 70,

316–317, 318, 319–320


Antipsychotics (continued)mortality of elderly patients with

dementia-related psychosis and, 47–48, 195, 224, 273

neuroleptic malignant syndrome and, 40

neurological adverse effects of, 287,295

nonoral preparations of, 83, 91–92organ transplantation and, 480–481pain management and, 513,

520–521Parkinson’s disease or Lewy body

dementia, 45pregnancy and, 347, 349–350renal insufficiency and, 155, 159respiratory disorders and, 223–224ventricular arrhythmias and sudden

cardiac death, 49, 50, 52xerostomia and, 105

Antiretroviral agentsdepression and, 394drug–drug interactions and, 34,

380HIV-associated mania and, 388neuropsychiatric side effects of, 377,

385Antispasmodics


psychiatric adverse effects of, 131,161–162, 163

Antithyroid antibodies, 340Antithyroid medications, 321Antitubercular drugs, 218, 374, 375,

378Antiviral agents, 376–377, 380.

See also Antiretroviral agents

Anxiety and anxiety disorders. See also Anxiolytics

Alzheimer’s disease and, 273cancer patients and, 242–243complex regional pain syndrome

and, 507diabetes and, 308–309epilepsy and, 284–285HIV/AIDS patients and, 387–388hyperthyroidism and, 310menopause and, 343organ transplantation and, 475pain and, 503premenstrual exacerbation of,

342–343renal disease patients and, 150respiratory disease patients and,

214–215, 222stroke and, 276surgery and preoperative patients

and, 449–451Anxiolytics

breastfeeding and, 353cancer risk and, 245cardiovascular disorders and,


34–35gastrointestinal adverse effects of,

124globus hystericus and, 106hepatic insufficiency and, 119–120neurological adverse effects of, 287nonoral preparations of, 82, 87–89pregnancy and, 344–345, 346renal disease and, 155, 159–160respiratory disorders and, 221–222

Apathetic hyperthyroidism, 310

Index 563

Apathy, and central nervous system disorders, 285

Aprepitant, 130, 136, 137Aquaporin-2, and lithium, 62Arformoterol, 217Aripiprazole

cardiac effects of, 194, 196delirium in hospitalized patients

and, 444drug–drug interactions and, 33, 202hyperprolactinemia and, 320nonoral preparations of, 83renal insufficiency and, 155

Arizona Center for Education and Research on Therapeutics, 167, 259, 291, 446

Armodafinildrug–drug interactions and, 137,

174, 254, 360, 490gastrointestinal adverse effects of,

125hepatic insufficiency and, 121organ transplantation and, 490pharmacokinetics and, 37renal insufficiency and, 157

Arrhythmiascardiac drug reactions and, 49, 50,

52gastrointestinal drug interactions

and, 136neurological drug interactions and,

292renal and urological drug

interactions and, 168, 173, 174surgical and critical care drugs and,

456Arsenic trioxide, 252Asenapine

drug–drug interactions and, 33

nonoral preparations of, 83, 92renal insufficiency and, 155sublingual form of, 81

Asparaginase, 249, 251, 252, 256Asthma, 214, 215, 223Atazanavir, 34, 376Atomoxetine

drug–drug interactions andcardiac medications, 202dermatological medications, 411gastrointestinal medications,

133, 137neurological agents, 295obstetric/gynecology drugs, 360oncology drugs, 253, 255renal and urological drugs, 174

gastrointestinal adverse effects of, 125

hepatic insufficiency and, 121pharmacokinetics and, 37renal insufficiency and, 157respiratory disorders and, 224

Atopic dermatitis, 407, 413Atorvastatin, 31Atrioventricular block, and heart

transplant, 472Atropine, 217, 218, 228Attapulgite, 133Atypical antipsychotics

anticholinergic activity of, 67cancer risk and, 245cardiac effects of, 205drug–drug interactions and, 173,

205, 295, 326, 360endocrinological adverse effects of,

313extrapyramidal symptoms and, 286gastrointestinal adverse effects of,

124


Atypical antipsychotics (continued)hepatic insufficiency and, 118–119HIV/AIDS patients and, 389, 391neurological adverse effects of, 287,

295nonoral preparations of, 83, 91organ transplantation and, 481psychogenic polydipsia and, 152renal insufficiency and, 155

Autoimmune thyroiditis, 385Azathioprine, 434, 436, 485, 486Azithromycin, 372Azole antifungals, 410

Bacterial infectionsneuroborreliosis and, 372–373neurosyphilis and, 373pediatric autoimmune

neuropsychiatric disorders associated with streptococcal infections (PANDAS) and, 372

plasma levels of albumin in pneumonia and, 13

tuberculosis in central nervous system and, 374

Barbituratesneuropsychiatric adverse effects of,

548renal disease and, 160respiratory disorders and, 222

Bariatric surgery, 111Basal ganglia disorders, 282Basiliximab, 485Beck Depression Inventory, 191Behavior, benzodiazepines and

disinhibition of, 289. See also Aggression; Agitation; Anger; Apathy; Compliance

Bendroflumethiazide, 163

Benzodiazepinesalcohol withdrawal treatment and,

541–542antipsychotics administered in

conjunction with, 91anxiety before surgery and,

449–450, 451anxiety in cancer patients and, 242cardiac effects of, 188drug–drug interactions and

antibiotics, 379, 380, 381, 383cardiac medications, 202, 203dermatological medications, 410endocrine medications, 327gastrointestinal medications, 135immunosuppressant drugs, 489neurological medications, 292oncology medications, 253pharmacokinetics of, 26renal and urological drugs, 170substance abuse treatments, 551

functional dyspepsia and, 108hematological reactions to, 65hepatic encephalopathy and, 117HIV/AIDS patients and, 387–388,

391hyperthyroidism and, 310intoxication with, 538–539intravenous administration of, 81, 87neuroleptic malignant syndrome

and, 44neurological adverse effects of, 287,

289neuropsychiatric adverse effects of,

548organ transplantation and, 480pain management and, 520pregnancy and, 345, 346rectal administration of, 88

Index 565

renal disease and, 155, 160respiratory disorders and, 221–222,

226seizures and, 49sublingual administration of, 88–89xerostomia and, 105

Benztropinedrug–drug interactions and, 26gastrointestinal adverse effects of,

124neurological adverse effects of, 287renal and urological adverse effects

of, 165Beta-adrenergic blocking agents, 183Beta-agonists


neuropsychiatric adverse effects of, 216, 217, 218

Beta-blockersalcohol withdrawal syndrome and,


201, 204, 206hyperthyroidism and, 310neuropsychiatric effects of, 184, 548psychogenic polydipsia and, 152respiratory disorders and, 218traumatic brain injury and, 278

Beta-lactam agents, 375Biguanides, 321Bioavailability


pharmacokinetics and, 7, 9, 11, 115, 257

Biological response modifiers, and dermatological disorders, 422

Biotransformation, 15

Biperiden, 26, 124Bipolar disorder, 307, 310, 314Bisoprolol, 35Bisphosphonates, 507, 510Black box warnings

on antipsychotics and metabolic syndrome, 316

on antipsychotic use in elderly patients with dementia, 195, 224, 273

on naltrexone and severe hepatic disease, 545

on triptans in combination with serotonergic antidepressants, 296

on varenicline and preexisting psychiatric illness, 547

Blood dyscrasias, 64Blood pressure, and drug–drug

interactions, 200. See also Hypertension; Hypotension

Body dysmorphic disorder, 406, 408Bone marrow suppression, and

clozapine, 295Borrelia burgdorferi, 372Bortezomib, 249Brain tumors, psychiatric symptoms of,

238Breast cancer, 240, 258, 319, 320Breastfeeding, approach to

psychopharmacology during, 352–354

Bromazepam, 34Bromocriptine, 19, 321Bronchodilators

drug–drug interactions and, 35, 228neuropsychiatric side effects of, 216,

217, 218


Brugada syndrome, 50Budesonide, 136Bufuralol, 35Buprenorphine

drug–drug interactions and, 550neuropsychiatric adverse effects of,

548nicotine dependency and, 546organ transplantation and, 484

Bupropionbariatric surgery and, 112, 113breastfeeding and, 353cancer patients and, 241, 255cardiac adverse effects of, 187, 191,

193, 204drug–drug interactions and

antibiotics, 380, 382, 383cardiac medications, 204gastrointestinal medications, 136neurological drugs, 294obstetric/gynecological drugs,

360oncology drugs, 253, 255renal and urological medications,

172gastrointestinal adverse effects of, 124hepatic insufficiency and, 118inflammatory bowel disease and, 113interferon-alpha and, 123multiple sclerosis and, 279neurological adverse effects of, 287,

294neuropsychiatric adverse effects of,

548nicotine dependence and, 546organ transplantation and, 478pain management and, 512, 517pharmacokinetics of, 30pregnancy and, 346

psoriasis and, 414renal insufficiency and, 154seizures and, 49, 288systemic clearance of, 19

Burning mouth syndrome (BMS), 104, 409

Burns, and plasma levels of albumin and alpha-1 acid glycoprotein, 13

Buserelin, 356Buspirone

Alzheimer’s disease and, 273drug–drug interactions and

antibiotics, 379, 383cardiac drugs, 202, 203dermatological drugs, 410gastrointestinal medications, 135immunosuppressants, 489neurological drugs, 292pharmacokinetics of, 26, 34renal and urological drugs, 170

functional dyspepsia and, 108gastrointestinal adverse effects of,

124hepatic insufficiency and, 119HIV/AIDS patients and, 387neurological adverse effects of, 287renal insufficiency and, 155respiratory disorders and, 222systemic clearance of, 19

Butyrophenones, 52, 226

Cabergoline, 321Caffeine, and drug–drug interactions,

37Cachexia, and plasma levels of alpha-1

acid glycoprotein, 13Calcineurin-inhibiting

immunosuppressants, 473, 485–487

Index 567

Calcitonin, 507Calcium acetate, 169Calcium carbonate, 169Calcium channel blockers, 35, 203,

204, 521Cancer.

See also Breast cancer; Chemotherapy; Pancreatic cancer; Prostate cancer

drug–drug interactions and, 251–260

HIV-associated neuropsychiatric disorders and, 377

malignant pain and, 510nausea and vomiting in, 110–111neuropsychiatric adverse effects of

oncology treatments, 247–251plasma levels of alpha-1 acid

glycoprotein and, 13psychiatric symptoms in patients

with, 237, 238–239psychopharmacological treatment of

psychiatric disorders in patients with, 239–244

testosterone replacement therapy and, 324

Cannabinoids, and drug–drug interactions, 37

Capecitabine, 252Capsaicin, 104, 521–522Captopril, 30Carbamazepine


breastfeeding and, 354cardiac adverse effects of, 187, 197,

206discontinuation of prior to surgery,

448

drug–drug interactions andantibiotics, 379, 380, 382, 383cardiac medications, 206dermatological medications, 410endocrine drugs, 325gastrointestinal medications, 137immunosuppressants, 490neurological medications, 292,

294, 295obstetrical/gynecology drugs, 360oncology drugs, 252, 254, 255pharmacokinetics of, 30renal and urological drugs, 168,

170, 174surgical and critical care drugs,

455endocrinological adverse effects of,

313gastrointestinal adverse effects of,

124, 125hematological reactions to, 64hepatic insufficiency and, 120HIV/AIDS patients and, 388neurological adverse effects of, 287,

292nonoral preparations of, 84, 93organ transplantation and, 482, 490pain management and, 512, 518pregnancy and, 347, 350–351renal insufficiency and, 156, 158renal and urological adverse effects

of, 165, 174respiratory disorders and, 224, 225,

227, 229seizures and, 49systemic clearance of, 19trigeminal neuralgia and, 506xerostomia and, 105ziprasidone and, 25


Carbimazole, 321Carbonic anhydrase inhibitor diuretics,

23, 168, 171Carboplatin, 252Cardiac glycosides, and drug–drug

interactions, 35, 203Cardiac Randomized Evaluation of

Antidepressant and Psychotherapy Efficacy (CREATE) trial, 190

Cardiomyopathy, 51, 54–55Cardiovascular disorders.

See also Cardiovascular system; Heart disease; Stroke

comorbidity of psychiatric disorders with, 181

differential diagnosis of psychiatric problems in, 182–183

drug–drug interactions and, 199–201, 202–206

hyperprolactinemia and, 319, 320metabolism and, 18neuropsychiatric side effects of

medications for, 183–184pharmacokinetics and, 184–186psychotropic medication use in,

187–199sildenafil and, 395

Cardiovascular system, and drug reactions, 49–55. See also Arrhythmias; Cardiovascular disorders; QTc prolongation; Torsade de pointes

Ceftriaxone, 373 Celecoxib, 523Celiac disease, 112Central nervous system.

See also Central nervous system disorders

drug reactions and, 40–49

heatstroke and, 67tuberculosis in, 374

Central nervous system (CNS) depressants, 135

Central nervous system disorders. See also Central nervous system

adverse effects of psychotropic drugs and, 286–289

apathy and, 285dementia and, 272–275drug–drug interactions and,

291–296epilepsy and, 283–285frequency of, 271Huntington’s disease and, 282–283multiple sclerosis and, 278–280Parkinson’s disease and, 280–282pathological laughter and crying,

285–286sexual disinhibition and, 286stroke and, 275–276traumatic brain injury and, 276–278

Central poststroke pain, 505–506Cephalosporins, 375Cerebral edema, and hyponatremia, 63Cerebrovascular adverse events, and

antipsychotics for elderly patients with dementia-related psychosis, 47–48

Cesarean section, and antipsychotics, 350

Cetuximab, 252Chemotherapy

drug metabolism and, 256–257nausea and vomiting induced by,

110–111neuropsychiatric adverse effects of,

247–248, 250–251renal elimination of drugs and, 257

Index 569

Child-Pugh score (CPS), 116–117Children. See also Infants

cyclic vomiting syndrome and, 109pancreatitis as reaction to valproic

acid in, 58PANDAS and recurrent

streptococcal infections in, 372prenatal exposure to carbamazepine

and cognitive impairment in, 351

preoperative anxiety and, 450–451rectal administration of

benzodiazepines for seizures in, 88

transdermal methylphenidate for, 94Chloramphenicol, 32Chlordiazepoxide

gastrointestinal drug interactions and, 134

hepatic insufficiency and, 119renal insufficiency and, 155systemic clearance of, 19

Chlorothiazide, 163Chlorpheniramine, 411Chlorpropamide, 37Chlorpromazine

agranulocytosis and, 64anemia and, 66delirium in hospitalized patients

and, 443drug–drug interactions and, 34, 133HIV/AIDS patients and, 391liver toxicity and, 127nonoral preparations of, 83rheumatological disorders and, 434seizures and, 48systemic clearance of, 19

Cholinesterase inhibitorsadverse psychiatric effects of, 290

Alzheimer’s disease and, 272cancer patients and, 242cardiac effects of, 198, 206discontinuation of prior to surgery,

448–449drug–drug interactions and

cardiac medications, 201, 202,203, 206

gastrointestinal medications, 134

respiratory medications, 228surgical and critical care drugs,

455, 458–459gastrointestinal adverse effects of,

125hepatic insufficiency and, 120multiple sclerosis and, 278Parkinson’s disease and, 282renal disease and, 156, 160–161respiratory disorders and, 224–225traumatic brain injury and, 277

Chronic daily headache, 508Chronic fatigue syndrome, 392Chronic obstructive pulmonary disease,

214Chronic renal insufficiency, 58–59,

60Cigarettes. See Smoking cessation Cimetidine, 36, 131, 133Ciprofloxacin, 32, 375, 379Cirrhosis. See also Hepatic cirrhosis

alcohol-dependent patients and, 543–544

drug monitoring and dosage reductions in, 117

metabolism and, 18selective serotonin reuptake

inhibitors and, 477Cisplatin, 252, 257


Citalopramcardiac effects of, 190, 192drug–drug interactions and, 26, 477irritable bowel syndrome and, 114nonoral preparations of, 82, 90pain management and, 512, 517respiratory disorders and, 220systemic clearance of, 19traumatic brain injury and, 277

Clarithromycin, 32, 375, 379, 410Clidinium, 134Clinical Antipsychotic Trials of

Intervention Effectiveness—Alzheimer’s Disease (CATIE-AD), 273–274

Clinical Global Impression of Change scale, 273

Clinical Global Impressions Improvement Scale, 189

Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), 541

Clomiphene, 356Clomipramine

drug–drug interactions and, 26, 30,294

nonoral preparations of, 82seizures and, 49

Clonazepamanxiety in cancer patients and, 243burning mouth syndrome and, 104drug–drug interactions and, 34gastric bypass surgery and, 113hepatic insufficiency and, 119HIV/AIDS patients and, 389, 390nonoral preparations of, 82organ transplantation and, 480pain management and, 520systemic clearance of, 19

Clonidineadverse psychiatric effects of, 290alcohol withdrawal syndrome and,

543anxiety in preoperative patients and,

450, 451drug–drug interactions and, 204,

205, 550systemic clearance of, 19

Clorazepate, 19, 450Clozapine

anemia and, 66cardiac effects of, 193, 195discontinuation of prior to surgery,

448drug–drug interactions and

antibiotics, 379, 381, 382cardiac drugs, 202gastrointestinal medications, 133neurological agents, 292, 295oncology drugs, 253pain medications, 523pharmacokinetics of, 34

gastric bypass surgery and, 113gastrointestinal adverse effects of,

124hepatic insufficiency and, 118infectious disease and, 394myocarditis and, 54–55neutropenia and, 64, 66Parkinson’s disease and, 281renal insufficiency and, 155rhabdomyolysis and, 70seizures and, 48systemic clearance of, 19urological effects of, 166

Coagulation disorders, and drug monitoring, 66

Cocaine, and colonic toxicity, 129–130

Index 571

Codeine, 19, 36, 202, 379Cognitive dysfunction

Alzheimer’s disease and, 272anticholinergics for overactive

bladder and, 162antihistamines and, 421cancer patients and, 244epilepsy and, 283–284HIV-associated neuropsychiatric

disorders and, 377multiple sclerosis and, 278neurological adverse effects of, 289organ transplantation and, 476Parkinson’s disease and, 280prenatal exposure to valproic acid

and, 351renal disease and, 151respiratory disorders and, 216stroke and, 275traumatic brain injury and, 276–277

Cognitive enhancerscardiac effects of, 198drug–drug interactions and, 26, 36,

293nonoral preparations of, 85, 94respiratory disorders and, 224–225

Colchicine, 36Colonic toxicity, 129–130Combined therapy. See PsychotherapyComorbidity, psychiatric

anxiety in cancer patients and, 242burning mouth syndrome and, 104cardiovascular disorders and, 181chronic pain and, 502–504dermatological disorders and, 405,

408diabetes and, 306–307functional dyspepsia and, 107–108

Complete blood count (CBC), 64, 66

Complex regional pain syndrome (CRPS), 507

Compliance, with medicationroutes of administration and, 79, 80,

94–95strategies to maximize, 8–9

COMT inhibitors, 290Conduction delay, and heart transplant,

472Congestive heart failure, 55, 184, 312,

477Conivaptan, 31, 162, 163, 170, 171,

172, 173, 174Constipation, 115, 126Contraceptives. See Oral contraceptivesCorticosteroids. See also Steroids

complex regional pain syndrome and, 507


psychiatric adverse effects of, 130,216, 217, 321–323, 420, 434,485

immunosuppressant drug interactions and, 488, 489

PTSD in hospitalized surgical trauma patients and, 452

Cortisol, and drug–drug interactions, 37

Co-trimoxazole, 32Creatine phosphokinase (CPK), and

rhabdomyolysis, 70, 71Creatinine, and drug elimination,

18–20, 475Crohn’s disease, 112Current Opioid Misuse Measure

(COMM), 511Cushing’s disease, 306Cutaneous delusions, 406


Cutaneous dysesthesias, 409Cutaneous excoriation, 412Cyclic vomiting syndrome, 109–110Cyclobenzaprine, 36, 509Cyclophosphamide, 254, 255, 259,

434Cycloserine, 375Cyclosporine

bioavailability of paclitaxel and, 257drug–drug interactions and, 489,

490organ transplantation and, 481,

485–486, 488, 489, 490pharmacokinetics and, 36psychiatric side effects of, 422, 434

CYP 2D6 substrates, 17Cystic fibrosis, 214, 219, 473Cytarabine, 249Cytochrome P450 (CYP) 3A4 enzymes

drug absorption and, 9, 10, 11drug–drug interactions and, 20–21,

30–38, 171drug elimination and, 15, 17

Cytomegalovirus, 392

Dacarbazine, 259Daclizumab, 485Dactinomycin, 33Dapsone, 375Darifenacin, 162, 169, 172Darunavir, 34, 381Dasatinib, 33, 252, 256Daunorubicin, 252Death, asthma and risk of, 223.

See also Mortality; Sudden deathDehydroepiandrosterone (DHEA),

386, 387Delavirdine, 376, 380Delayed graft function (DGF), 471

Deliriumalternative routes of drug

administration and, 80anticholinergic drugs and, 24, 421chemotherapy and, 247corticosteroids and, 322HIV/AIDS patients and, 390–391neurological adverse effects of

psychotropic drugs and, 289in postsurgical and critical care

patients, 440–47posttransplant organ rejection and,

471renal failure and, 150

Delirium Rating Scale (DRS), 441, 442, 444

Delirium tremens, 540Delusions

central nervous system disorders and, 282, 283

dermatological disorders and, 409Dementia.

See also Alzheimer’s disease; Dementia with Lewy bodies; Frontotemporal dementia; Vascular dementia

hormone replacement therapy and, 357–358

neurosyphilis and, 373Dementia-related psychosis, 42, 47–48,

273–274Dementia with Lewy bodies (DLB),

44–45, 274–275Denileukin, 252Depolarizing neuromuscular blocking

agents, 455, 459Depression

Alzheimer’s disease and, 272–273antiretroviral medications and, 394

Index 573

cancer patients and, 238, 239–242, 250

corticosteroids and, 322, 323dermatological disorders and,

420–421diabetes patients and, 307–308epilepsy and, 284HIV/AIDS patients and, 385–387 Huntington’s disease and, 282–283hyperthyroidism and, 310inflammatory bowel disease and,

112interferon-alpha and, 122isotretinoin and, 420–421menopause and, 343multiple sclerosis and, 278–279organ transplantation and, 473, 475pain symptoms and, 503Parkinson’s disease and, 280–281polycystic ovarian syndrome and,

340pregnancy and, 340–341premenstrual exacerbation of,

342–343renal disease and, 150respiratory disorders and, 215rheumatological disorders and,

432–433stroke and, 275–276traumatic brain injury and, 277

Dermatitis artefacta, 407Dermatological disorders

adverse psychiatric effects of dermatological agents, 420–422

differential diagnosis of psychiatric manifestations of, 406–408

drug–drug interactions and, 410–411, 422–423

drug reactions to psychotropic agents and, 415–420

exacerbation of by psychotropic medications, 419–420

pharmacotherapy for psychiatric manifestations of, 409, 412–415

psychiatric and psychosocial comorbidity in, 405

Desflurane, 453, 455Desipramine

cancer patients and, 240diarrhea and, 115drug–drug interactions and, 26, 30,

382multiple sclerosis and, 278pain management and, 512Parkinson’s disease and, 281renal failure and, 159systemic clearance of, 19

Desvenlafaxinedrug–drug interactions and, 26, 30gastrointestinal adverse effects of,

124hepatic insufficiency and, 118renal insufficiency and, 154respiratory effects of, 226

Developmental and Reproductive Toxicology (DART) Database, 344

Dexamethasone, 37Dexmedetomidine

delirium in hospitalized patients and, 442, 443, 444–445, 446–447

drug–drug interactions and, 456,459

Dextroamphetamine, 26, 85, 94Dextromethorphan, 523


Diabetes. See also Nephrogenic diabetes insipidus

gastroparesis and, 109gestational, 350metabolic drug reactions and, 69plasma levels of albumin and, 13psychogenic polydipsia and, 151treatment of psychiatric symptoms

and, 306–309Diabetic ketoacidosis, 68, 69Diabetic peripheral neuropathy, 308,

505Diagnosis, Intractability, Risk, Efficacy

(DIRE) screening scale, 511Dialyzable psychotropics, 153, 158Diarrhea, 115, 125–126Diazepam

anxiety before surgery and, 449–450delirium in hospitalized patients


133gastroesophageal reflux disorder and,

107hepatic insufficiency and, 119nonoral preparations of, 82, 86systemic clearance of, 19

Diclofenac, 36Dicyclomine, 131, 134Didanosine, 376Diet. See also Foods

alcoholism and, 541celiac disease and, 112constipation and, 115

Differential diagnosisof neuroleptic malignant syndrome,

44of psychiatric symptoms

in cancer patients, 238–239

in cardiovascular patients, 182–183

in dermatological disorder patients, 406–408

in diabetes patients, 307in HIV-infected patients, 374,

377, 385in renal disease patients,

150–152in reproductive disorder patients,

340–342in respiratory disease patients,

214–216of rhabdomyolysis, 71

Digoxin, 35, 183, 184, 203Diltiazem, 35, 203Dimenhydrinate, 131, 134Diphenhydramine



pregnancy and, 345psychiatric adverse effects of, 131,

421systemic clearance of, 19

Diphenoxylate, 130Discontinuation.

See also Withdrawalof antipsychotics, 223, 323of opioids, 511of psychotropic drugs before surgery,

448–449Disease. See Infectious diseases; Medical

conditionsDisopyramide, 30, 202Distribution, and pharmacokinetics,

11–14, 185, 251, 256Disulfiram, 483, 544, 548, 550

Index 575

Diuretics. See also Osmotic diuretics; Thiazide diuretics


hyponatremia and, 162neuropsychiatric effects of, 183, 184pharmacokinetics and, 186

Dobutamine, 453, 456, 460Dolasetron, 131, 134, 136Domperidone

breast milk production and, 357drug–drug interactions and, 131,

135, 359pharmacokinetics of, 36psychiatric adverse effects of, 131

Donepeziladverse psychiatric effects of, 290Alzheimer’s disease and, 272cancer patients and, 242, 244delirium in hospitalized patients

and, 442, 443, 447drug–drug interactions and, 26, 293hepatic insufficiency and, 120multiple sclerosis and, 278renal insufficiency and, 156respiratory disorders and, 224systemic clearance of, 19

Dopamine agonistsadverse psychiatric effects of, 289,

290Parkinson’s disease and, 280 psychiatric adverse effects of, 321renal disease and, 161

Dopamine antagonists, 41, 44Dopamine dysregulation syndrome,

289Dose and dosages

antipsychotics and metabolic syndrome, 317

cardiovascular disorders and, 192compliance and use of minimum

effective, 8delirium as side effect of

chemotherapy and, 247of haloperidol for delirium in

hospitalized patients, 445–446liver disease and, 116–121of lorazepam for alcohol withdrawal

syndrome, 542protein binding and, 14renal disease and, 153smoking and, 219–220of venlafaxine for pain, 516

Dothiepin, 432Doxazosin, 162, 163, 172, 173Doxepin

dermatological disorders and, 413, 414

drug–drug interactions and, 26, 31,410

nonoral preparations of, 82, 90systemic clearance of, 19

Doxorubicin, 33Dronabinol, 131, 135Droperidol

drug–drug interactions and, 135, 136nonoral preparations of, 83, 91psychiatric adverse effects of, 131

Drug administration. See Administration

Drug–drug interactions, and psychotropic medications

antibiotics and, 378–384, 394–395cancer therapy and, 251–260cardiovascular drugs and, 199–201,

202–206central nervous system disorders

and, 291–296


Drug–drug interactions, and psychotropic medications (continued)

dermatological disorders and, 410–411, 422–423

endocrine system and, 324, 325–327

gastrointestinal drugs and, 132, 133–137

obstetric and gynecological drugs and, 358–360

organ transplantation and, 476, 487–491

pain management and, 522–524Phase II UGT-mediated conjugation

and, 17–18pharmacodynamics of, 24–25pharmacokinetics of, 20–23, 25, 26,

30–38renal and urological medications

and, 166–171, 172–174respiratory drugs and, 227–229rheumatological medications and,

435, 436substance abuse drugs and, 547,

550–551surgical and critical care drugs and,

454–460Drug elimination, and

pharmacokinetics, 14–20, 185,257

Drug hypersensitivity syndrome (DRESS), 417, 418

Drug hypersensitivity vasculitis, 418–419

Drug-induced lupus, 434–435. See also Systemic lupus erythematosus

Drug-induced pigmentation, 416

Drug reactions. See also Adverse effectscardiovascular system and, 49–55central nervous system and, 40–49dermatological conditions and,

415–420gastrointestinal system and, 55–58hematological system and, 64–66metabolism and, 66–71obstetric and gynecological care and,

354–355renal toxicity and, 58–64

Drug-seeking behavior, and pain control, 503

Drugs and Lactation Database (LactMed), 353

Duloxetinecardiac effects of, 191, 204drug–drug interactions and

cardiac drugs, 204gastrointestinal medications, 136obstetric/gynecology drugs, 360oncology drugs, 255pharmacokinetics of, 31renal and urological drugs, 172

fibromyalgia and, 509gastrointestinal adverse effects of,

124hepatic insufficiency and, 118liver injury and, 127organ transplantation and, 478pain management and, 512, 516renal insufficiency and, 154rheumatological disorders and, 433

Dutasteride, 162, 163, 172Dyspnea, and opioids, 225Dysphagia, 105–106

Eating disorders, 341, 342, 408Ebstein’s anomaly, 350

Index 577

Ecstasy. See 3,4-methylenedioxymethamphetamine (MDMA)

Eczema, 407, 413Edema, and renal disease, 152Education, and medication compliance,

8Efavirenz

drug–drug interactions and, 380insomnia and, 391pharmacokinetics of, 34psychiatric adverse effects of, 376,

385Elderly patients.

See also Alzheimer’s diseaseantipsychotics for dementia-related

psychosis and mortality of, 47–48, 195, 224, 273

delirium and hip fracture in, 440sleep–wake cycle disturbance and

postoperative delirium in, 442–443

syndrome of inappropriate antidiuretic hormone secretion and, 63

Eletriptan, 32Electrocardiographs (ECGs), and

psychotropic drugs with cardiac effects, 53, 55

Electroconvulsive therapy (ECT)neuroleptic malignant syndrome

and, 44pregnancy and, 344, 347

Electroencephalograms, and differential diagnosis of encephalopathies and depression, 183

Electrolytes, and drug–drug interactions, 168, 551

Eletriptan, 294, 523

Emtricitabine, 376Endocrine disorders

adverse effects of psychiatric medications and, 313–320

diabetes mellitus and, 306–309drug–drug interactions and, 324,

325–327hypogonadal disorders and,

312–313pheochromocytoma and, 311psychiatric side effects of treatments

for, 320–324psychiatric symptoms of, 305, 306thyroid disorders and, 309–311

Endocrinopathies, and HIV/AIDS patients, 385

End-stage renal disease (ESRD), 150. See also Renal disease

Enflurane, 453, 455Enhancing Recovery in Coronary Heart

Disease (ENRICHD) trial, 190Enoxacin, 32, 379Entacapone, 290, 294Epidemiology. See PrevalenceEpilepsy

anxiety and, 284–285caution on use of psychotropics in

patients with, 288cognitive deficits and, 283–284depression and, 284drug-induced seizures and, 48mania and, 284plasma levels of alpha-1 acid

glycoprotein and, 13Epinephrine, 217, 453, 456Eplerenone, 168, 172Epstein-Barr virus infection, 392Ergotamine, 32Erythema multiforme (EM), 417–418


Erythromycindrug–drug interactions and, 379,

395, 410pharmacokinetics of, 32psychiatric adverse effects of,

375Escitalopram, 26, 192, 477Esomeprazole, 37, 131, 133Esophageal disorders

alternative routes of drug administration and, 80

psychotropic medications and treatment of, 106–111

Esophageal motility disorders, 107Estradiol, 37Estrogen, and drug–drug interactions,

37, 358, 359, 360. See also Hormone replacement therapy

Estrogen receptor modulators, 356Eszopiclone



hepatic insufficiency and, 120HIV/AIDS patients and, 391menopause and, 343renal insufficiency and, 155

Ethambutol, 375Ethanol, and alcohol withdrawal

syndrome, 543Ethinyl estradiol, 37Ethionamide, 375Ethopropazine, 26Ethosuximide, 19, 30, 292Etomidate, 453, 456Etoposide, 33, 252Exanthematous rashes, 415–416

Excretion, and drug elimination, 14–20

Exfoliative dermatitis, 417, 418Extrapyramidal symptoms

adverse neurological effects of psychotropic drugs, 286, 288

gastrointestinal drug–psychotropic drug interactions and, 135

haloperidol and patients with delirium, 445–446

neurological drug–psychotropic drug interactions and, 293,295

obstetrical drug–psychotropic drug interactions and, 359

psychotropic drugs for drug-induced, 26

Fatigue. See also Chronic fatigue syndrome

cancer patients and, 238, 243–244multiple sclerosis and, 280Parkinson’s disease and, 282

Felbamate, 30, 292, 294, 295Felodipine, 35Fenofibrate, 31Fentanyl

bioavailability of, 11drug–drug interactions and, 36,

252, 253, 489, 523pain management and, 513, 514,


Fenugreek, 357Fibromyalgia, 509Finasteride, 162, 163, 172, 422First-pass metabolism, and drug

absorption, 9, 115

Index 579

Fixed drug eruptions, 416Flavoxate, 163Flecainide, 30, 168Fluconazole, 32, 383Fluid-attenuated inversion recovery

(FLAIR) MRI sequences, 486Flumazenil

benzodiazepine intoxication and, 538–539

central nervous system reactions and, 43, 49

drug–drug interactions and, 550neuropsychiatric adverse effects of,


Flunitrazepam, 82, 87, 133Fluoroquinolones, 3755-Fluorouracil, 252Fluoxetine

breastfeeding and, 353cancer patients and, 240, 241, 255cardiac effects of, 189, 204diabetic patients and, 308drug–drug interactions and

cardiac medications, 204gastrointestinal medications,

136neurological drugs, 294obstetrics/gynecology

medications, 360oncology drugs, 255organ transplantation drugs,

487–488, 490pharmacokinetics of, 31renal and urological drugs, 172

gastric bypass surgery and, 113nonoral preparations of, 83,

90–91

organ transplantation and, 487–488, 490

pain management and, 512, 517systemic clearance of, 19

Flupenthixol, 83Fluphenazine, 84Flurazepam, 19, 119Flurbiprofen, 36Fluvastatin, 31, 203Fluvoxamine

drug–drug interactions and, 31,136, 204, 294, 325, 490

nifedipine and, 21organ transplantation and, 490respiratory disorders and, 229systemic clearance of, 19

Folate supplementation, 351, 541Food and Drug Administration (FDA).

See Adverse Event Reporting System; Black box warnings

Foods. See also Dietdrug–drug interactions and, 37–38,

380MAOIs and, 21, 53–54

Formoterol, 217Fosamprenavir, 376, 381Foscarnet, 377Fosphenytoin, 292, 294, 295Frontotemporal dementia, 275Frovatriptan, 32, 294, 523Functional dyspepsia, 107–108Furosemide, 203

Gabapentinadverse psychiatric effects of, 290anxiety in preoperative patients and,

450fibromyalgia and, 509


Gabapentin (continued)hepatic insufficiency and, 120menopause and, 343neuropathic pain and, 505organ transplantation and, 482–483pain management and, 512, 518,

520pregnancy and, 345renal and biliary excretion of, 16renal insufficiency and, 156, 158

Galactogogues, 356, 357Galactorrhea, and antipsychotics, 359Galantamine

adverse psychiatric effects of, 290drug–drug interactions and, 26, 293nonoral preparations of, 85renal disease and, 156, 160–161

Ganciclovir, 377Gastric bypass surgery, 111–112Gastric disorders, 106–111Gastroesophageal reflux disease

(GERD), 106–107Gastrointestinal disorders

adverse effects of psychiatric drugs and, 123–126

drug–drug interactions and, 132, 133–137

esophageal and gastric disorders, 106–111

immunosuppressant medications and, 491

intestinal disorders and, 111–115liver disorders and, 115–123oropharyngeal disorders and,

104–106psychiatric side effects of

gastrointestinal medications, 130, 131

psychotropic drug–induced complications of, 126–130

Gastrointestinal motility modifiers, 36Gastrointestinal system, and drug

reactions, 55–58. See also Gastrointestinal disorders

Gastroparesis, 108–109Gefitinib, 33, 258Gemfibrozil, 31, 203Gepirone, 31Gestational diabetes, 350Glatiramer, 290Glimepiride, 37, 325Glipizide, 37, 325Globus hystericus, 106Glomerular filtration rate (GFR), 19–20Glossodynia, 409, 412Glucocorticoids, 135, 487Glyburide, 37, 325Glycopyrrolate, 131, 134Gold, and rheumatological medications,

434Gonadotropin-releasing hormone

agonists, 342, 356Goserelin, 356Gout therapy, 36Granisetron, and drug–drug

interactions, 131, 134, 136, 137Grapefruit juice, 38Graves’ disease. See Autoimmune

thyroiditis; HyperthyroidismGrepafloxacin, 32Group A beta-hemolytic streptococci

(GABHS), 372Growth hormone disorders, 306Growth hormone–inhibiting hormones,

321, 324, 326Guanfacine, 290

Index 581

Hallucinationscentral nervous system disorders

and, 282, 283Parkinson’s disease and, 281renal failure and, 150

Halothane, 453, 455, 458Haloperidol

cardiac effects of, 194, 196delirium in hospitalized patients

and, 441, 443, 444, 445–446drug–drug interactions and, 34extrapyramidal symptoms and, 286hepatic insufficiency and, 119HIV/AIDS patients and, 390, 391hyperprolactinemia and, 319lithium–neuroleptic encephalopathy

and, 45nonoral preparations of, 84organ transplantation and, 480–481renal insufficiency and, 155systemic clearance of, 19

Hamilton Rating Scale for Depression (Ham-D), 189, 191

Hashimoto’s thyroiditis, 309Headache, and chronic pain, 508–510Health care. See Intensive care units;

Medical conditions; Surgery and critical care

Heart block, 50Heart disease. See also Cardiovascular

disease; Congestive heart failuremetabolism and failure of, 18pharmacokinetics and failure of,

185, 186use of psychotropic drugs in patients

with, 53, 187–199, 200, 478Heart transplant, 472Heatstroke, and antipsychotics, 67, 68, 69

Hematological reactions, to psychotropic drugs, 64–66

Hemodynamics, and liver transplant, 472

Hepatic cirrhosis, 13.See also Cirrhosis

Hepatic disease. See also Liver diseaseblack box warning on naltrexone

and, 545metabolism and, 18

Hepatic encephalopathy, 116Hepatic insufficiency, 118–121Hepatitis, and metabolism, 18Hepatitis C virus (HCV), 121–123Hepatocellular jaundice, 128Hepatotoxicity, and gastrointestinal

reactions to psychotropic drugs, 56, 57, 126–128

Herbal medicines, and drug–drug interactions, 37–38.See also Alternative medications; Melatonin; St. John’s wort

Herpes encephalitis (HSE), 392–393Herpes zoster, 505Hexobarbital, 35Hip fractures, delirium in elderly

patients with, 440His-Purkinje conduction system, 52Histamine H2 antagonists, 36, 131, 421

Histrelin, 356HIV/AIDS, psychopharmacological

treatments in patients with, 374, 377, 385–391, 395

HIV-associated mania, 388–389Homoharringtonine, 252Hormonal contraceptives, 355–356, 415Hormone replacement therapy (HRT),

343, 357–358. See also Estrogen


Hormone therapy, and cancer patients, 250. See also Testosterone

5-HT3 antagonists, 134

Huntington’s disease, 282–283Hydrochlorothiazide, 163Hydrocodone, 19, 36, 514Hydrocortisone, 37, 452Hydroflumethiazide, 163Hydromorphone, 19, 515Hydrophilic drugs, 12Hydroxychloroquine, 434Hydroxyurea, 509Hydroxyzine, 411Hyoscyamine, 134Hyperammonemia, and valproate, 292Hyperammonemic encephalopathy, 56,

58Hypercalcemia, 315Hyperemesis gravidarum, 110,

340–341Hyperhidrosis, 419–420Hypernatremia, 164–165, 482Hyperparathyroidism, 306, 311, 315Hyperprolactinemia

antipsychotics and, 244, 245, 246–247, 317, 319–320

drug–drug interactions and, 326, 359psychiatric symptoms of, 306

Hyperpyrexia, 523Hypertension. See also Blood pressure

antidepressants and, 191drug–drug interactions and, 204,

205, 254, 295, 380monoamine oxidase inhibitors and,

51, 53–54Hyperthyroidism, 306, 310–311, 315Hyperventilation syndrome, 214Hypnotics, nonoral preparations of, 82.

See also Sedative-hypnotics

Hypoalbuminemia, 14Hypoglycemia, 325, 541.

See also Oral hypoglycemicsHypogonadism, 306, 312–313Hypokalemia, 168Hypomagnesemia, 168Hyponatremia

drug–drug interactions and, 200, 168, 205

renal drug reactions and, 60, 62–64, 151, 164

thiazide diuretics and, 162Hyponatremic encephalopathy, 63Hypotension. See also Blood pressure;

Orthostatic hypotensionanticancer drugs and, 260antipsychotics and, 193drug–drug interactions and, 168,

173, 204, 293, 455, 456, 457Hypothyroidism

interferon-alpha and, 122lithium-induced, 314–315, 325mood and cognitive problems in, 182plasma levels of albumin and, 13psychiatric symptoms of, 306,

309–310

Ibuprofen, 523Ibutilide, 205Idarubicin, 252Idiopathic localized cutaneous

dysesthesias, 407Ifosfamide


neuropsychiatric adverse effects of, 248

pharmacokinetics of, 33, 259renal elimination of drugs and, 257

Index 583

Iloperidonedrug–drug interactions and, 136,

173, 252, 253, 360, 489hepatic insufficiency and, 118pharmacokinetics of, 34renal insufficiency and, 155

Imatinib, 33, 253, 256, 258Imipenem, 375Imipramine

cancer patients and, 240drug–drug interactions and, 26, 31,

168, 410HIV/AIDS patients and, 385, 386irritable bowel syndrome and, 114nonoral preparations of, 83pain management and, 512systemic clearance of, 19

Immunoglobulin, 434Immunomodulators, 290Immunosuppressive agents


neuropsychiatric effects of organ transplantation medications and, 484–487

posttransplant organ rejection and, 473

Incontinence, 114–115, 166Indapamide, 163, 168, 173Indinavir, 34, 376, 381Infants. See also Children; Pregnancy;

Teratogenicitybenzodiazepines and, 345lithium and, 351, 354psychopharmacology during

lactation and, 352–354selective serotonin reuptake

inhibitors and, 349

Infectious diseasesadverse psychiatric effects of

antibiotics and, 393–394bacterial forms of, 372–374drug–drug interactions and,

394–395parasitic infections and, 393psychiatric symptoms as part of,

371viral forms of, 374, 377, 385–393

Infertility treatment, 356Inflammatory bowel disease (IBD), 13,

112–113Infliximab, 112Inhalational anesthetics, 453, 454, 455,

458Inositol, and psoriasis, 419Insomnia, 224, 343, 391, 478Insulin, and drug–drug interactions,

325, 326Intensive care units (ICUs), 440, 446,

539. See also Surgery and critical care

Interferon(s)drug metabolism and, 256psychiatric adverse effects of, 248,

249, 250, 290Interferon-alpha (IFN-),

neuropsychiatric effects of, 121–123, 249, 250, 253, 256

Interferon-alpha-2a, 376, 385Interferon-beta-1a/1b, 290, 291Interleukin-2, 248, 249, 253, 256–257Intestinal disorders, 111–115Intoxication, and substance use

disorders, 538–539Intracranial pressure, and vasodilator

hypotensive agents, 454


Intramuscular administrationof antidepressants, 90of antipsychotics, 91–92of anxiolytics and sedative-

hypnotics, 87–88properties of, 81of testosterone, 387

Intranasal administration, 86, 89, 92Intravenous administration

of antipsychotics, 91, 445–446of anxiolytics and sedative-

hypnotics, 87of mood stabilizers, 93properties of, 80–81

Iproniazid, 213Irinotecan, 33, 254, 255, 258–259Irritable bowel syndrome, 113–114,

131, 133Ischemic cerebrovascular disease, 183Isoflurane, 453, 455Isoniazid, 32, 229, 375, 378Isoproterenol, 217, 453, 456Isosorbide, 202, 453, 457Isotretinoin, 250, 415, 420–421Isradipine, 35Itraconazole, 23, 32, 383, 410

Kaolin, 133Ketoconazole, 32, 377, 383, 410Ketamine, 452Kidney. See also Renal disease

drug elimination and, 14–15, 18–20, 23

organ transplantation and, 470–471, 472, 475

Klüver-Bucy syndrome, 392

Labetalol, 35

Laboratory testsof hepatic enzymes and liver

functions, 127–128for neuroleptic malignant syndrome,

44Lactam antibiotics, 375Lamivudine, 376Lamotrigine

adverse psychiatric effects of, 290breastfeeding and, 354cardiac effects of, 196–197dermatological disorders and, 418drug–drug interactions and, 30, 382gastrointestinal adverse effects of,

124hepatic insufficiency and, 120HIV/AIDS patients and, 389nonoral preparations of, 84, 93pain management and, 512, 519phase II metabolism of, 16pregnancy and, 347, 351renal insufficiency and, 156, 158systemic clearance of, 19trigeminal neuralgia and, 506valproate and, 21–22

Lanreotide, 321Lansoprazole, 37, 131, 133Lanthanum carbonate, 169Lapatinib, 33Laryngeal dystonia, 223Leflunomide, 434Leukopenia, and carbamazepine, 482Leukotriene inhibitors, 217, 219, 228Leuprolide, 356Levalbuterol, 217Levetiracetam, 19, 290, 291Levodopa, 290, 292, 295Levofloxacin, 32, 375

Index 585

Lidocainedrug–drug interactions and, 30neuropathic pain and, 505, 506nociceptive pain and, 510pain management and, 521

Linezolidcentral nervous system reactions to,

42drug–drug interactions and, 380,

395pharmacokinetics of, 32serotonin syndrome and, 46

Lipophilic drugs, 11–12Lisdexamfetamine, 26Lithium

bariatric surgery and, 112, 113breastfeeding and, 354cancer and, 245–246cardiac adverse effects of, 187, 196corticosteroids and, 323cystic fibrosis and, 219dermatological disorders and, 419discontinuation of prior to surgery,


cardiac medications, 200endocrine medications, 325gastrointestinal drugs, 137immunosuppressants, 491neurological medications, 292,

294obstetric/gynecology drugs, 360oncology drugs, 252, 254pain medications, 523renal and urological drugs, 174surgical and critical care drugs,

455endocrinological adverse effects of,

313, 314–315

gastrointestinal adverse effects of, 124, 125

heart failure and elimination of, 186hematological reactions and, 66hepatic insufficiency and, 120HIV/AIDS patients and, 388hypernatremia and, 164–165hyperthyroidism and, 310hypothyroidism and, 310, 314–315lithium–neuroleptic encephalopathy

and, 41, 45–46multiple sclerosis and, 279nephrogenic diabetes insipidus and,

62, 316neuroleptic malignant syndrome and

coadministration with antipsychotics, 40

neurological adverse effects of, 287,289, 294

nonoral administration of, 92–93organ transplantation and, 481–482,

491pregnancy and, 344, 347, 350renal and biliary excretion of, 16renal disease and, 156, 158, 160,

165renal reactions to, 58–59, 60, 165,

174seizures and, 43, 49steroid-induced neuropsychiatric

reactions and, 322xerostomia and, 105

Lithium–neuroleptic encephalopathy, 41, 45–46

Liver disease. See also Cirrhosis; Hepatic disease

dosing and, 116–121drug elimination and, 19–20drug-induced failure of, 57


Liver disease (continued)organ transplantation and, 470–471,

472, 474pharmacokinetics and, 115–116psychotropic drug–induced forms

of, 126–128Living organ donation, 474–475LJP394, 434Local anesthetics, 521, 523Loop diuretics, 168, 171, 186Loperamide, 31, 130Lopinavir, 34, 382Lorazepam

alcohol withdrawal treatment and, 541–542, 544

anxiety in cancer patients and, 242–243

delirium in hospitalized patients and, 443

drug–drug interactions and, 35, 135hepatic insufficiency and, 119HIV/AIDS patients and, 387–388,

390, 391nonoral preparations of, 82, 87, 88,

89organ transplantation and, 480phase II metabolism of, 16sublingual form of, 81

Lormetazepam, 82Lovastatin, 31, 203Loxapine, 84Lundbeck Institute, 80Lupus cerebritis, 433.

See also Drug-induced lupus; Systemic lupus erythematosus

Lyme disease, 372–373

Macrolide antibiotics, 375, 410

Magnetic resonance imaging, and paraneoplastic limbic encephalitis, 239

Major depression, and chronic respiratory disease, 215

Malabsorption, and alternative routes of administration, 80

Malignant hyperthermia syndrome, and inhalational anesthetics, 454, 458

Malignant pain, 510Mania

corticosteroids and, 322, 323epilepsy and, 284HIV/AIDS patients and, 388–389Huntington’s disease and, 283hyperthyroidism and, 310multiple sclerosis and, 279stroke and, 276traumatic brain injury and, 277

MAO-B inhibitors, 290Maprotiline

drug–drug interactions and, 26, 31,133, 294

neurological adverse effects of, 287nonoral preparations of, 83

Maraviroc, 34Medical conditions. See also Cancer;

Cardiovascular disorders; Central nervous system disorders; Dermatological disorders; Diabetes; Endocrine disorders; Epilepsy; Gastrointestinal disorders; Infectious diseases; Pain and pain management; Renal disease; Reproductive disorders; Respiratory disorders; Rheumatological disorders; Urological disorders

Phase II metabolism and, 18

Index 587

plasma levels of albumin and alpha-1 acid glycoprotein and, 13

Medical emergency, hyponatremic encephalopathy as, 63

Meglitinides, 321Melatonin, 222, 450, 451Memantine

Alzheimer’s disease and, 272cardiac effects of, 198drug–drug interactions and, 26,

134, 168, 202, 203gastrointestinal adverse effects of, 125hepatic insufficiency and, 120renal disease and, 156, 160–161

Menopause, psychiatric manifestations of, 341, 343, 357

Meperidinedrug–drug interactions and, 168,

252, 253, 380, 489, 523pain management and, 514, 515,

523pharmacokinetics of, 36systemic clearance of, 19

Mephenytoin, 133Metabolic syndrome

antipsychotics and, 194, 316–317, 318

psoriasis and, 414Metabolism and metabolic disorders

cardiovascular disorders and, 185chemotherapeutic agents and,

256–257, 258drug–drug interactions and, 21–22,

167, 171, 206drug elimination and, 14–20drug reactions and, 66–71immunosuppressant drugs and, 491renal disease and, 152–153

Metabolites, 15

Metaproterenol, 217Metformin, 317Methadone and methadone

maintenance therapydrug–drug interactions and

antibiotics, 379, 380, 381, 395drugs for substance abuse,

550–551pain medications, 522, 523, 524pharmacokinetics of, 36renal and urological drugs, 168

opioid withdrawal and, 545organ transplantation and, 474, 484pain management and, 513, 514,

520, 522, 523, 524systemic clearance of, 19

Methamphetamine, 26, 85Methicillin-resistant Staphylococcus

aureus, 395Methimazole, 321Methotrexate, 258, 33, 252, 255, 434Methotrimeprazine, 84Methoxyflurane, 453, 455Methscopolamine, 131, 134Methylene blue, 2483,4-methylenedioxymethamphetamine

(MDMA), 395Methylphenidate

cancer patients and, 241–242, 243, 244

cardiac effects of, 198drug–drug interactions and, 26,

135, 295, 479hepatic insufficiency and, 121nonoral preparations of, 85, 86, 94organ transplantation and, 479Parkinson’s disease and, 282renal insufficiency and, 157respiratory effects of, 225, 226, 227


Metoclopramidedrug–drug interactions and, 135,

359, 360gastroparesis and, 109psychiatric adverse effects of, 131,

356, 357Metolazone, 163Metoprolol, 35Metronidazole, 32, 375Mexiletine, 30, 202, 521, 523Mianserin, 240Miconazole, 32, 384Midazolam

anxiety before surgery and, 449, 451delirium in hospitalized patients


170, 383, 456nonoral preparations of, 82, 87, 89psychiatric adverse effects of, 453systemic clearance of, 19

Migraine, 508Milnacipran, 509, 516–517Milrinone, 453, 457Mineralocorticoids, 325Mirtazapine

anxiety in preoperative patients and, 450

cancer patients and, 241cardiac effects of, 191, 204depression and nausea in cancer

patients, 111drug–drug interactions and, 26, 31,

133, 204, 292gastrointestinal adverse effects of, 124gastroparesis and, 109hepatic insufficiency and, 118hyperemesis gravidarum and, 110nonoral preparations of, 83, 90, 91

organ transplantation and, 477–478pain management and, 512, 517renal insufficiency and, 154respiratory disorders and, 220

Mitoxantrone, 252, 290Mixed alpha- and beta-agonists, 216,

217, 218Moclobemide

cardiac effects of, 204drug–drug interactions and, 136,

172, 204, 255, 294, 360pharmacokinetics of, 31psoriasis and, 414

Modafinilcancer patients and, 242, 243, 244,


cardiac medications, 202, 203gastrointestinal drugs, 137obstetrics/gynecology drugs, 360oncology drugs, 254organ transplantation drugs, 490pharmacokinetics of, 37renal and urological drugs, 174

gastrointestinal adverse effects of, 125hepatic insufficiency and, 120neuropsychiatric side effects of, 217,

219organ transplantation and, 479–480respiratory disorders and, 224systemic clearance of, 19

Molindone, 390Monitoring, of therapeutic drugs.

See also Laboratory testscompliance and, 9liver disease and, 116of metabolic status in patients taking

antipsychotics, 318Monoamine oxidase (MAO), 54

Index 589

Monoamine oxidase inhibitors (MAOIs)

cardiovascular reactions to, 51,53–54, 187, 191, 205

discontinuation of prior to surgery, 448

drug–drug interactions andcardiac medications, 205endocrine drugs, 325neurological medications and,

292, 294nondepolarizing neuromuscular

blocking agents, 460organ transplantation, 479pain medications, 522renal and urological drugs, 173surgical and critical care drugs

and, 456hepatic insufficiency and, 118hypoglycemic effects of, 307neurological adverse effects of, 287,

294organ transplantation and, 479pain management and, 522pharmacokinetic interactions and,

21renal insufficiency and, 154serotonin syndrome and, 46

Monoclonal antibodies, 249, 485, 486Montelukast, 217, 219Montgomery-Åsberg Depression Rating

Scale, 240Mood. See also Anger

hormonal contraceptives and, 355hormone replacement therapy and,

357Mood stabilizers.

See also Carbamazepine; Lithiumbreastfeeding and, 354

cancer risk and, 245–246cardiac adverse effects of, 187,

196–197, 206drug–drug interactions and, 137,

174, 206, 294, 325endocrinological adverse effects of,


124–125hepatic insufficiency and, 120neurological adverse effects of, 287,

294nonoral preparations of, 84, 92–93organ transplantation and, 481–483pregnancy and, 344, 347, 350–352renal disease and, 160renal and urological adverse effects

of, 165, 174respiratory disorders and, 224self-induced dermatoses and,

412–413Morphine


neuropathic pain and, 506pain management and, 514, 515phantom limb pain and, 508serotonin syndrome and, 46stress in surgical patients and, 452systemic clearance of, 19

Mortality. See also Death; Sudden death; Suicide and suicidal ideation

antipsychotics in elderly patients with dementia-related psychosis and, 47–48

dementia-related psychosis and, 42drug hypersensitivity syndrome and,

418


Moxifloxacin, 375Mucosal dysesthesias, 409, 412Mucosal sensory syndromes, 407Multiple sclerosis, 278–280Muromonab-CD3 (OKT3), 485, 486Muscle relaxants, and drug–drug

interactions, 36Musculoskeletal pain, 509–510Mycobacterium tuberculosis, 374Myocardial infarction, and plasma levels

of alpha-1 acid glycoprotein, 13Myocardial Infarction and

Depression—Intervention Trial (MIND-IT), 191

Myocarditis, 51, 54–55, 195Myoglobinuria, 70, 71Mycophenolate, 434, 485

Nabilone, 131, 135Nafarelin, 356Nafcillin, 32Naloxone, 538Naltrexone, 199, 483

alcohol dependence and, 199, 483, 545

black box warning on hepatic disease and, 545

drug–drug interactions and, 551hepatic disease and, 483neuropsychiatric adverse effects of,

548opioid withdrawal and, 546

Naproxen, 36, 523Naratriptan, 294, 523Natalizumab, 290Nateglinide, 325National Survey on Drug Use and

Health, 537

Nausea and vomitingadverse effects of psychiatric drugs

and, 123, 125causes and treatment of, 109–111chemotherapy and, 260

Nefazodonedrug–drug interactions and

cardiac medications, 204endocrine drugs, 325gastrointestinal medications, 136oncology drugs, 255organ transplantation drugs,

490pharmacokinetics of, 31renal and urological drugs, 172


hepatic insufficiency and, 118HIV/AIDS patients and, 386liver injury and, 127organ transplantation and, 478, 488renal insufficiency and, 154

Nelfinavir, 34, 382Nephrectomy, 475Nephritic syndrome, and plasma levels

of alpha-1 acid glycoprotein, 13Nephritis, and plasma levels of albumin,

13Nephrogenic diabetes insipidus (NDI),

59, 60, 62, 316Nephrotic syndrome, and plasma levels

of albumin, 13Nephrotoxicity, and

immunosuppressant drugs, 490Nesiritide, 453, 457Neural tube defects, and carbamazepine,

351Neurocysticercosis, 393

Index 591

Neuroleptic malignant syndrome (NMS)central nervous system drug

reactions and, 40, 41, 44, 45dysphagia and, 105

Neuroleptic Malignant Syndrome Information Service, 44

Neuroleptic Sensitivity Syndrome, 41,44–45

Neuromuscular blockers, 453, 455Neuropathic pain, 505–508Neurosyphilis, 373Neurotic excoriations, 406Neurotoxicity, and lithium–neuroleptic

encephalopathy, 45–46Neutropenia, 64–66Nevirapine, 34, 376, 380Nicardipine, 35Nicotine dependence, 546–547.

See also Smoking cessationNicotine replacement therapy (NRT),

484, 546Nifedipine

drug–drug interactions and, 35, 203fluvoxamine and, 21hypertensive crisis and, 54

Nilotinib, 33, 252, 256Nilutamide, 253, 256Nimodipine, 35Nisoldipine, 35Nitrazepam, 19Nitrogen mustards, 248, 249Nitroglycerin, 453, 457Nitroprusside, 453, 457Nitrous oxide, 453–454, 455, 458Nizatidine, 131Nociceptive pain, 509–510Noncardiac chest pain, and esophageal

disorders, 107Nonclassic alkylating agents, 248, 249

Nondepolarizing neuromuscular blocking agents, 455, 458–459

Non-nucleoside reverse transcription inhibitors, 376

Nonsteroidal anti-inflammatory drugs (NSAIDs)

complex regional pain syndrome and, 507

drug–drug interactions and, 23, 36,436, 522, 523

migraine and, 508pain management and, 508, 509,

510, 522, 523rheumatological disorders and, 434,

436Norepinephrine, 453, 456Norfloxacin, 32, 379Nortriptyline

breastfeeding and, 353cardiac effects of, 189, 192diabetic patients and, 307–308drug–drug interactions and, 26, 31,

383, 479organ transplantation and, 479pain management and, 512Parkinson’s disease and, 281poststroke depression and, 276renal failure and, 159systemic clearance of, 19

NPO (nothing per oral) orders, 80Nucleoside reverse transcription

inhibitors, 376

Obsessive-compulsive disorder, 372, 407Obstetrics/gynecology.

See Pregnancy; Menopause; Reproductive disorders

Obstructive sleep apnea (OSA), 214,215, 219, 223


Octreotide, 321, 324, 327Ofloxacin, 32, 375Olanzapine

cardiac effects of, 196corticosteroids and, 323delirium in hospitalized patients

and, 442, 443–444, 445drug–drug interactions and

antibiotics, 379, 382cardiac drugs, 202gastrointestinal medications, 133neurological agents, 292oncology drugs, 253pain medications, 523pharmacokinetics of, 34

gastric bypass surgery and, 113hepatic insufficiency and, 119HIV/AIDS patients and, 390hyperprolactinemia and, 319mortality associated with

antipsychotics in elderly patients with dementia-related psychosis, 47

nonoral preparations of, 83pain management and, 513renal insufficiency and, 155rhabdomyolysis and, 70systemic clearance of, 19

Omeprazole, 37, 131, 133Oncology. See CancerOndansetron, and drug–drug

interactions, 31, 134, 136, 137Onychophagia, 406Onychotillomania, 406–407Opiates

central nervous system reactions and, 42

drug–drug interactions and, 26, 36,202, 254

renal drug reactions and, 60, 61Opioid Risk Tool (ORT), 511Opioids


drugs for withdrawal from, 545–546pain management and, 504–505,

509, 510–511, 513, 514–515, 520, 522, 523

respiratory disorders and, 225treatment of overdose, 538

Oral contraceptives, 355–356, 358, 360, 415

Oral disintegrating tablets (ODTs), 92Oral hypoglycemics, 37, 320–321, 325,

326Organ transplantation

drug–drug interactions and, 487–491neuropsychiatric side effects of

immunosuppressants for, 484–487

posttransplant pharmacological considerations and, 470–475

psychotropic medications and, 475–484

Oropharyngeal disorders, 104–106Orthostatic hypotension.

See also Hypotensionantipsychotics and, 193mirtazapine and, 191

Osmotic demyelination, and hyponatremia, 63

Osmotic diuretics, 168, 203Osteoarthritis, 432–433, 510Osteoporosis, 319, 320, 482Ovariectomy, 357Oxazepam


Index 593

hepatic insufficiency and, 119organ transplantation and, 480phase II metabolism of, 16systemic clearance of, 19

Oxcarbazepineanemia and, 66drug–drug interactions and

cardiac medications, 206gastrointestinal medications, 137obstetric/gynecology drugs, 360oncology drugs, 254organ transplantation drugs, 490renal and urological drugs, 168,


125hepatic insufficiency and, 120organ transplantation and, 482pain management and, 512, 519renal insufficiency and, 156renal and urological adverse effects

of, 165systemic clearance of, 19trigeminal neuralgia and, 506

Oxybutynin, 163, 169, 171, 172Oxycodone, 36, 513, 514Oxygen therapy, and respiratory

disorders, 216Oxymorphone, 513

Paclitazel, 33, 257Pain Assessment and Documentation

Tool, 511Pain and pain management

categories and treatment of, 504–510drug–drug interactions and, 522–524organ transplantation and, 474pharmacological treatment of,

510–522

prevalence of, 501psychiatric comorbidity and,

502–504undertreatment of, 502, 503

Paliperidonedrug–drug interactions and, 136,

173, 295, 360hepatic insufficiency and, 119nonoral preparations of, 83renal insufficiency and, 155, 159

Palonosetron, and drug–drug interactions, 131, 134, 136, 137

Pancreatic cancer, and plasma levels of alpha-1 acid glycoprotein, 13

Pancreatitisgastrointestinal reactions to

psychotropic drugs and, 56, 58, 128–129

plasma levels of albumin and, 13Pancuronium, 455, 458Pancytopenia, 66Panic attacks, and dermatological

conditions, 406Panic disorder

cardiovascular disorders and, 182noncardiac chest pain and, 107

Pantoprazole, 37, 131Paraneoplastic limbic encephalitis

(PLE), 239Paranoid delusions, and Parkinson’s

disease, 281Parasitic infections, 393Parasitosis, delusional, 409Parathyroidectomy, 315Parkinsonian hyperthermia syndrome,

41Parkinsonism, drug-induced, 105Parkinson’s disease

atypical antipsychotics and, 295


Parkinson’s disease (continued)behavioral problems and dopamine

receptor stimulation, 289cognitive deficits and, 280depression and, 280–281neuroleptic sensitivity syndrome

and, 44–45psychosis and, 281–282

Paroxetineburning mouth syndrome and, 104cancer patients and, 240, 255cardiac effects of, 189, 204drug–drug interactions and

antibiotics, 381cardiac medications, 204gastrointestinal medications, 136obstetric/gynecology drugs, 360oncology drugs, 253, 255pharmacokinetics of, 31renal and urological drugs, 172

gastric bypass surgery and, 113gastrointestinal adverse effects of,

124inflammatory bowel disease and,

112–113irritable bowel syndrome and, 114itraconazole and, 23menopause and, 343organ transplantation and, 477pain management and, 512, 517psoriasis and, 414renal insufficiency and, 154, 159respiratory disorders and, 220–221rheumatological disorders and, 432systemic clearance of, 19

Paroxysmal supraventricular tachycardia, 182

Pathological laughter and crying, 285–286

Pathways Study, 308Pediatric autoimmune neuropsychiatric

disorders associated with streptococcal infections (PANDAS), 372

Pegvisomant, 321, 326Penicillamine, 434Penicillin, 372, 373, 375Pentamidine, 377Peptic ulcer disease, 108Pericarditis, 51, 54–55Perimenopause, 341, 342Perphenazine, 34P-glycoprotein (P-gp) efflux transport

pump, 9, 10, 11, 23Phantom limb pain, 507–508Pharmacodynamics

adverse effects and, 4, 7anticancer drugs and, 259–260concentration–response relationship

in, 4, 6, 7definition of, 4drug–drug interactions and, 24–25,

360, 522drug–receptor interactions and, 7overview of issues in, 4pain medications and, 522relationship between

pharmacokinetics and, 5renal disease and, 153urological agents and, 166–167

Pharmacokineticsabsorption and, 9, 10, 11bioavailability and, 7, 9, 11, 115,

257cancer therapy and, 251, 256–259cardiovascular disorders and,

184–186definition of, 4

Index 595

drug distribution and, 11–14drug–drug interactions and, 20–23,

25, 26, 30–38, 358, 360, 394drug elimination and, 14–20liver disease and, 115–116posttransplant organ functioning

and, 470–475relationship between

pharmacodynamics and, 5renal disease and, 152–153renal and urological agents and, 167,

171respiratory disorders and, 219–220

Phase I and Phase II metabolism, 15, 16,17–18, 21, 186

Phenelzine, 31, 113, 294Phenobarbital, and drug–drug

interactions, 35, 229, 292, 294,325

Phenothiazinesbeta-blockers and, 201cardiac effects of, 194colonic toxicity of, 130hematological reactions to, 64respiratory effects of, 226, 227

Phentolamine, 54Phenylbutazone, 36Phenylephrine, 217Phenylpropanolamine, 217Phenytoin

cardiac effects and, 206drug–drug interactions and

antibiotics, 380, 381, 383, 384cardiac medications, 202, 203,

206endocrine drugs, 325gastrointestinal medications,

133, 137neurological drugs, 292, 294

obstetrics/gynecology drugs, 359, 360

oncology medications and, 252,253, 254

organ transplantation drugs, 490pharmacokinetics of, 30renal and urological drugs, 174

organ transplantation and, 490pain management and, 518respiratory effects of, 226systemic clearance of, 19therapeutic drug monitoring and, 14

Pheochromocytoma, 306, 311Phosphate binders, 169, 171Phosphodiesterase type 5 (PDE5)

inhibitorscardiovascular disorders, 199drug–drug interactions and, 169,

171, 172, 173, 187, 457Photosensitivity reactions, and

dermatological conditions, 416Physostigmine, 447Pimozide

delusional parasitosis and, 409drug–drug interactions and

antibiotics, 379, 381dermatological medications,

410, 423gastrointestinal medications,

135, 136neurological drugs, 292obstetrics/gynecology drugs, 360oncology drugs, 252, 253organ transplantation drugs, 489pharmacokinetics of, 34renal and urological drugs, 170,

173renal drug reactions to, 60, 173

Pindolol, 35


Pioglitazone, 37, 325Pipotiazine, 84Pirbuterol, 217Platelet abnormalities, and drug

reactions, 66Polycystic ovarian syndrome, 340, 355Polypharmacy, and drug–drug

interactions, 20, 21, 25Polyserositis, 55Porphyria, 420Posaconazole, 32Posterior reversible

leukoencephalopathy syndrome, 486

Postherpetic neuralgia, 505Postpartum thyroiditis, 340Poststroke depression, 275–276Posttraumatic stress disorder

chronic pain and, 504critical care patients and, 451–452dermatological disorders and, 408renal disease and, 150

Pramipexole, 157, 290, 293, 295Pravastatin, 31Prazepam, 82Prednisolone, 37Prednisone, 37, 485Pregabalin

anxiety in preoperative patients and, 450

fibromyalgia and, 509pain management and, 512,

518–519renal and biliary excretion of, 16renal insufficiency and, 156, 158

Pregnancydepression and, 341–342management of psychiatric disorders

during, 343–345, 348–352

nausea and vomiting, 110plasma levels of albumin and, 13psychiatric issues related to, 340–341teratogenicity of psychiatric

medications, 346–347Premenstrual dysphoric disorder

(PMDD), 340, 342Prevalence

of anxiety in cancer patients, 242of anxiety in diabetic patients,

308–309of chronic pain, 501of cutaneous drug reactions, 415of delirium in hospitalized patients,

440of depression in epilepsy, 284of depression in Parkinson’s disease,

280of depression in renal disease

patients, 150of lithium-induced hyperthyroidism

and hypothyroidism, 314, 315of neuropsychiatric disorders in

patients with rheumatological disorders, 431

of poststroke depression, 275of preexisting psychiatric disorders in

cancer patients, 238of psychiatric disorders in HIV-

infected patients, 374of psychiatric and psychosocial

comorbidity in dermatological conditions, 405, 408

of psychiatric symptoms of corticosteroids, 322

of psychiatric symptoms in diabetes patients, 306–307

of psychosis in HIV/AIDS patients, 389

Index 597

Preventionof delirium in hospitalized patients,

441–443of PTSD in hospitalized surgical

trauma victims, 452of substance use disorders, 537–538

Primary psychogenic polydipsia, 62Primidone, 294Probenecid, 36Procainamide, 202Procarbazine

chemotherapeutic agents and, 257drug–drug interactions and, 249,

254, 255, 259, 260pharmacokinetics of, 33

Prochlorperazine, 86, 131, 134Procyclidine, 26Prodrugs, 15, 259, 260Progesterone, and drug–drug

interactions, 37Progressive renal insufficiency, 59Promethazine, 131, 134Propafenone, 30, 202Propofol, 442, 455, 543, 548Propoxyphene, 523Propranolol


hyperthyroidism and, 310psychiatric adverse effects of, 453

Propylthiouracil, 321Prostate cancer, 324Protease inhibitors, 376, 381, 395Protein binding, and drug toxicity, 12,

14Proton pump inhibitors, 37, 131Protriptyline, 19, 26, 220–221Pruritus, 407, 415Psoriasis, 408, 413–414, 419

Psychiatric disorders and psychiatric symptoms. See also Adverse effects; Anxiety and anxiety disorders; Bipolar disorder; Comorbidity; Depression; Differential diagnosis; Mania; Obsessive-compulsive disorder; Panic disorder; Posttraumatic stress disorder; Psychosis; Schizophrenia

cancer patients and, 237, 239–244diabetes mellitus and, 306–309endocrine and metabolic disorders,

305, 306HIV/AIDS patients and, 385–391interferon-alpha and preexisting, 123obstetric and gynecological disorders

and, 341–342 renal disease and, 150–152respiratory disorders and, 214

Psychodermatological disorders, 405–406

Psychogenic polydipsia (PPD), 151–152, 164

Psychomotor retardation, and organ transplantation, 476

Psychopharmacology. See Administration; Adverse effects; Bioavailability; Dose and dosages; Drug–drug interactions; Drug reactions; Medical conditions; Pharmacodynamics; Pharmacokinetics

Psychosis. See also SchizophreniaAlzheimer’s disease and, 273–274corticosteroids and, 322, 323drug–drug interactions and, 292,

293epilepsy and, 285


Psychosis (continued)HIV/AIDS patients and, 389–390Huntington’s disease and, 283hyperthyroidism and, 310hypothyroidism and, 309multiple sclerosis and, 279Parkinson’s disease and, 281–282renal disease and, 150–151traumatic brain injury and, 277–278

Psychostimulantsbreastfeeding and, 354cancer patients and, 241–242cardiac effects of, 197–198drug–drug interactions and, 26, 37,


125hepatic insufficiency and, 121HIV/AIDS patients and, 386interferon-alpha and, 123nonoral preparations of, 85, 94organ transplantation and, 479pregnancy and, 347, 352 renal insufficiency and, 157respiratory disorders and, 224

Psychotherapy, combined with medication

for chronic daily headache, 508for HIV/AIDS patients, 386

Psychotropic-induced metabolic syndrome, 316–317

Pulmonary disease, and metabolism, 18Pulmonary embolus, 215Pyrimidine analogs, 249

QTc prolongationanticancer drugs and, 259–260antipsychotics and, 50, 52, 53, 194,

446

dermatological medication interactions and, 411

immunosuppressant drug interactions and, 489

methadone and, 545neurological drug interactions and,

294, 295obstetrics/gynecology drug

interactions and, 359oncology drug interactions and, 252,

253pain medication interactions and,

523pimozide and, 409respiratory drug interactions and,

228substance abuse drugs and, 551

Quetiapinecardiac effects of, 193delirium in hospitalized patients

and, 444drug–drug interactions and

gastrointestinal medications, 135neurological agents, 295obstetric/gynecology drugs, 360oncology drugs, 252, 254organ transplantation drugs, 489pharmacokinetics of, 34renal and urological drugs, 170,

173gastric bypass surgery and, 113hematological reactions and, 66hepatic insufficiency and, 119hyperprolactinemia and, 319pain management and, 513,

520–521Parkinson’s disease and, 281–282renal insufficiency and, 155systemic clearance of, 19

Index 599

Quinidine, 11, 30, 136, 202Quinolones, 375

Radiotherapy, 247Raltegravir, 34Ramelteon, 119, 155Ramosetron, 134, 136Randomized controlled trials (RCTs),

240Ranitidine, 36, 131Ranolazine, 30Rasagiline, 33, 54, 292Recombinant human growth hormone,

321, 327Rectal administration

of antidepressants, 90of antipsychotics, 92of anxiolytics and sedative-

hypnotics, 88of mood stabilizers, 93properties of, 81, 86

Rejection, of transplanted organ, 471–472, 473

Renal disease. See also Kidneys; Renal insufficiency

adverse effects of psychotropic drugs and, 164–166

antidepressants and, 153, 157, 159

antipsychotics and, 159


Respiratory disorders (continued)psychiatric symptoms associated

with, 214psychotropic medications used in,

220–225Restless legs syndrome (RLS), 151, 345Retinoic acid compounds, 249, 250,

420–421Rhabdomyolysis, 68, 70–71Rheumatoid arthritis, 13, 432Rheumatological disorders

adverse effects of psychotropic medications on, 434–435

drug–drug interactions and, 435, 436

prevalence of neuropsychiatric disorders in patients with, 431

psychiatric side effects of medications for, 433, 434

treatment of psychiatric disorders in patients with, 432–433

Rifabutin, 32, 378Rifampin, 21–22, 32, 375, 378Risk factors

for cancer in patients with schizophrenia, 244

for cardiac effects of antipsychotics, 194, 195, 196

for central nervous system drug reactions, 41–43

for diabetic ketoacidosis in patients receiving antipsychotics, 69

for drug-induced hyperprolactinemia, 319

for lithium-induced hypothyroidism, 314

for neuroleptic malignant syndrome, 40, 41

for renal drug reactions, 60–61

Risperidoneanemia and, 66cancer risk and, 245delirium in hospitalized patients

and, 443, 445drug–drug interactions and, 133,

136, 173, 202, 253, 360gastric bypass surgery and, 113hepatic insufficiency and, 119HIV/AIDS patients and, 389, 390hyperprolactinemia and, 319mortality associated with

antipsychotics in elderly patients with dementia-related psychosis and, 47

nonoral preparations of, 83pain management and, 513pharmacokinetics of, 34renal insufficiency and, 155smoking and, 20systemic clearance of, 19urinary effects of, 166

Ritonavir, 34, 376, 382, 395 Rituximab, 252, 485, 486Rivastigmine

adverse psychiatric effects of, 290drug–drug interactions and, 26, 292hepatic insufficiency and, 120nonoral preparations of, 85, 86, 94renal disease and, 156, 160

Rizatriptan, 19, 33, 523Ropinirole, 19, 290, 293, 295Rosiglitazone, 325Roux-en-Y procedures, 111, 112Roxithromycin, 32

St. John’s wortdermatological disorders and, 415,

421

Index 601


HIV/AIDS patients and, 387oncology drugs and, 259organ transplantation and, 488, 490pharmacokinetics of, 38respiratory medications and, 229

Salmeterol, 217Saquinavir, 34, 376Scalp dysesthesia, 412Schizoaffective disorder, 307Schizophrenia

pregnancy and, 342premenstrual dysphoric disorder

and, 340psychogenic polydipsia and, 151rate of diabetes in patients with, 69,

307risk factors for cancer and, 244

Screener and Opioid Assessment for Patients in Pain (SOAPP), 511

Seborrheic dermatitis, 419Sedative-hypnotics.

See also Benzodiazepines; Hypnotics

breastfeeding and, 353cardiovascular disorders and, 187–

188drug–drug interactions and, 26,

34–35, 455, 456, 459gastrointestinal adverse effects of, 124hepatic insufficiency and, 119–120nonoral preparations of, 87–89pregnancy and, 344–345renal disease and, 155, 159–160respiratory disorders and, 221–222

Seizures. See also Epilepsyalcohol withdrawal syndrome and,

540

bupropion and, 478central nervous system reactions to

psychotropic medications and, 43, 48–49, 288


Selective serotonin reuptake inhibitors (SSRIs)

Alzheimer’s disease and, 272–273cancer patients and, 240–241cardiac adverse effects of, 187, 189,

200–201, 205coadministration with

antipsychotics and neuroleptic malignant syndrome, 40

discontinuation of prior to surgery, 448

drug–drug interactions andantibiotics, 380cardiac medications, 205neurological medications, 292,

294obstetrics/gynecology drugs, 359oncology medications, 254pain medications, 523pharmacokinetics of, 26

endocrinological adverse effects of, 313

epilepsy and, 284, 285frontotemporal dementia and, 275gastrointestinal adverse effects of,

124, 126gastroparesis and, 109hematological reactions and, 66hepatic insufficiency and, 118HIV/AIDS patients and, 385, 387Huntington’s disease and, 282–283hypoglycemic effects of, 307interferon-alpha and, 122–123


Selective serotonin reuptake inhibitors (SSRIs) (continued)

irritable bowel syndrome and, 114neurological adverse effects of, 287,

294organ transplantation and, 476–477pain management and, 512, 517Parkinson’s disease and, 281pathological laughter and crying,

285pregnancy and, 346, 348, 349premenstrual dysphoric disorder

and, 342renal insufficiency and, 154renal and urological adverse effects

of, 165rheumatological disorders and, 433seizures and, 49serotonin syndrome and, 46, 254,

292, 395, 523sexual side effects of, 166, 355syndrome of inappropriate

antidiuretic hormone secretion and, 63

Selegilineadverse psychiatric effects of, 290drug–drug interactions and, 33,

292, 479hepatic insufficiency and, 118hypertensive crisis and, 54nonoral preparations of, 83, 86, 89organ transplantation and, 479renal insufficiency and, 154sublingual form of, 81

Self-induced dermatoses, 412–413Sepsis, and plasma levels of albumin, 13Serotonin–norepinephrine reuptake

inhibitors (SNRIs)cardiac adverse effects of, 187, 205

coadministration with antipsychotics and neuroleptic malignant syndrome, 40

drug–drug interactions andantibiotics, 380cardiac medications, 205, 206neurological agents, 292, 294obstetric/gynecology drugs, 359oncology drugs, 254pain medications, 523


gastrointestinal adverse effects of, 124neurological adverse effects of, 287,

294organ transplantation and, 478pain management and, 512, 516–517pregnancy and, 346premenstrual dysphoric disorder

and, 342renal insufficiency and, 154renal and urological adverse effects

of, 165, 166rheumatological disorders and, 433serotonin syndrome and, 254, 292,

395sexual dysfunction and, 355

Serotonin syndromediagnostic criteria for, 47drug–drug interactions and, 254,

292, 380, 523dysphagia and, 105linezolid coadministered with SSRIs

and SNRIs, 395psychotropic drugs implicated in,

42, 46triptans in combination with

serotonergic antidepressants and, 293, 296

Index 603

Sertralineanemia and, 66burning mouth syndrome and, 104cancer patients and, 241cardiac effects of, 190, 192diabetic patients and, 308drug–drug interactions and, 26, 31,

325, 381, 382, 477gastric bypass surgery and, 113multiple sclerosis and, 278–279organ transplantation and, 477pregnancy and, 349rheumatological disorders and,


Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), 189–190

Sevoflurane, 453, 455Sexual disinhibition, and central

nervous system disorders, 286Sexual dysfunction, as side effect of

psychotropic drugs, 166, 319, 326,355

Shingles, and neuropathic pain, 505Sickle cell anemia, 509Side effects. See Adverse effectsSildenafil

cardiovascular side effects of, 171, 395


drug-induced sexual dysfunction and, 166, 355

Simvastatin, 31, 203Sinus node dysfunction, and heart

transplant, 472Sirolimus, 36, 485, 486, 488

Sleep disorders. See also Insomnia; Obstructive sleep apnea

dermatological disorders and, 413HIV/AIDS patients and, 391pain and sleep deprivation, 504postoperative delirium in elderly

patients and, 442–443renal disease and, 151respiratory disorders and, 215

Small-for-size syndrome (SFSS), and liver transplants, 474

Smoking cessation. See also Nicotine dependence; Nicotine replacement therapy

bupropion and, 193, 478drug–drug interactions and, 38, 227pharmacodynamics and

pharmacokinetics, 219–220risperidone and, 20varenicline and, 198–199

Solifenacin, 163, 169, 172Somatic pain, 509Somatization disorder, 502Somatostatin, 321, 324Sorafenib, 33, 255Spinal cord injury, and neuropathic

pain, 505–506Spironolactone, 168Statins, 201, 204Status epilepticus, and benzodiazepines,

87Steroids. See also Corticosteroids

drug–drug interactions and, 37HIV/AIDS patients and, 387posttransplant organ rejection and,

471psychiatric adverse effects of, 321

Stevens-Johnson syndrome (SJS), 417


Stimulants. See also Psychostimulantscardiac adverse effects of, 187drug–drug interactions and, 380seizures and, 288

Stress. See also Posttraumatic stress disorder

dermatological disease and, 407surgical and critical care patients

and, 451–452Stroke

neuropsychiatric disturbances in 275–276

plasma levels of alpha-1 acid glycoprotein and, 13

Sublingual administrationof antidepressants, 90–91of antipsychotics, 92of anxiolytics and sedative-

hypnotics, 88–89properties of, 81

Substance use disorders. See also Alcohol and alcohol use disorders

chronic pain and, 502–503, 507drug–drug interactions and, 547,

550–551drug intoxications and, 538–539incidence of, 537–538medications for treatment of,

539–547organ transplantation and

medications for treatment of, 483–484

psychiatric adverse effects of drugs used in, 547, 548–549

Substrate drugs, and drug–drug interactions, 22

Succinylcholine, 453, 454, 455, 459Sucralfate, 133

Sudden death. See also Mortalityantipsychotics and, 49, 50, 52,

194–195, 196pimozide and, 409

Suicide and suicidal ideationcorticosteroids and, 322dermatological disorders and, 407,

408interferon-alpha therapy and, 122multiple sclerosis and rate of, 278pain comorbid with depression and

risk of, 503substance use disorders and, 538

Sulfamethoxazole, 375, 384Sulfaphenazole, 32Sulfasalazine, 131, 434, 436Sulfinpyrazone, 36Sulfonamides, 32, 375Sulfonylureas, 321Sumatriptan, 19, 33, 523Sunitinib, 33Supportive therapy, for HIV/AIDS

patients, 386Surgery and critical care

acute and posttraumatic stress, 451–452

alcohol use disorders and, 539delirium and, 440–447difficulty of psychopharmacological

treatment and, 439drug–drug interactions and, 454–460menopause and, 357neuropsychiatric effects of drugs for,

453–454plasma levels of albumin and alpha-1

acid glycoprotein and, 13preoperative anxiety and, 449–451psychotropic drugs in perioperative

period and, 447–449

Index 605

Suxamethonium, 455, 459Sweating, anticholinergic-induced

inhibition of, 67Swedish National Birth Register, 349Sympathomimetic agents

drug–drug interactions and, 254,380, 455, 456, 459–460

psychiatric adverse effects of, 453,454

Symptom Checklist–90, 191, 240Syndrome of inappropriate antidiuretic

hormone secretion (SIDH), 60,62–64, 164, 205, 206

Syphilis, 373Systemic lupus erythematosus, and

plasma levels of alpha-1 acid glycoprotein, 13

Systemic viral infections, 392

Tacrine, 36Tacrolimus


metabolic systems and, 488neuropsychiatric adverse effects of,

434, 485–486pharmacokinetics of, 36

Tactile hallucinations, 406Tadalafil, 169, 172, 173Taenia solium, 393Talinolol, 35Tamoxifen

cognitive effects of, 250drug–drug interactions and, 252,

254, 255, 258, 359, 360pharmacokinetics of, 33, 258,

259Tamsulosin, 162, 163, 171, 172, 173,

174

Tardive dyskinesiadiscontinuation of antipsychotics

and, 286, 288dysphagia and, 105–106respiratory disorders and, 223

Tegafur, 33Tegaserod, 133Telithromycin, 379Temazepam

drug–drug interactions and, 35, 135hepatic insufficiency and, 119nonoral preparations of, 82phase II metabolism of, 16systemic clearance of, 19

Teniposide, 33, 258Tennessee, and data on sudden deaths in

antipsychotic drug users, 195Teratogenicity, of psychiatric

medications, 344–345, 346–347,348–352

Terazosin, 173Terbinafine, 411Terbutaline, 356, 359, 423Testosterone

drug–drug interactions and, 37HIV/AIDS patients and, 386–387hypogonadism and replacement

therapy, 312–313menopause and, 358psychiatric adverse effects of, 321,

323–324Tetracyclines, 375Theophylline


neuropsychiatric adverse effects of, 217, 218

pharmacokinetics of, 35Thiabendazole, 377


Thiamine hydrochloride, 541Thiazide diuretics. See also Diuretics

drug–drug interactions and, 168,171, 203, 205, 206

pharmacokinetics and, 167, 186psychiatric adverse effects of, 163

Thiazolidinediones, 321Thioridazine

cardiovascular reactions to, 52drug–drug interactions and, 34, 295HIV/AIDS patients and, 390lithium toxicity and, 46

ThioTEPA, 254, 255Thiothixene, 84Thrombocytopenia, 65, 66Thyroid disorders, 309–311.

See also Hyperparathyroidism; Hyperthyroidism; Hypothyroidism

Thyroid hormone, and drug–drug interactions, 325

Tiagabine, 30, 519Ticlopidine, 30Timolol, 35Tipranavir, 34, 376, 383Tocolytics, 357, 360Tolbutamide, 37, 325Tolcapone, 290, 294Tolerance, and long-term opioid

administration, 515Tolterodine, 163, 169Tolvaptan, 162, 172, 173, 174Topical administration, of drugs, 86Topiramate

adverse psychiatric effects of, 289, 290, 291

alcohol dependence and, 199drug–drug interactions and, 292hepatic insufficiency and, 120

nonoral preparations of, 84, 93organ transplantation and, 483pain management and, 512, 519pregnancy and, 351renal insufficiency and, 156, 158systemic clearance of, 19

Topotecan, 33Torsade de pointes

antipsychotics and, 50, 194, 446drugs implicated in, 53QTc prolongation as predictor of, 52risk factors for, 195

Toxic epidermal necrolysis (TEN), 417, 418, 418

Toxicity. See also Hepatotoxicity; Nephrotoxicity; Neurotoxicity; Teratogenicity

immunosuppressant drugs and, 489,490

lithium in infants and, 354liver injury and, 127oncology medications and, 274protein binding and, 12, 14theophylline and, 218

Tramadolanticonvulsants and, 520drug–drug interactions and, 252,

253, 489, 523fibromyalgia and, 509pharmacokinetics of, 36

Transaminases, and hepatotoxicity, 57Transdermal patch

amitriptyline and, 90continuous drug delivery by, 86haloperidol and, 92psychostimulants and, 94selegiline and, 89testosterone replacement therapy

and, 312

Index 607

Tranylcypromine, 31, 294Trauma, and plasma levels of albumin,

13.See also Posttraumatic stress disorder

Traumatic brain injury (TBI), 276–278Trazodone

cardiac adverse effects of, 187, 192, 205

drug–drug interactions andantibiotics, 381, 382cardiac medications, 205gastrointestinal medications, 133neurological drugs, 292pharmacokinetics of, 26, 31

hepatic insufficiency and, 118nonoral preparations of, 83organ transplantation and, 478pain management and, 518renal insufficiency and, 154respiratory effects of, 226, 227systemic clearance of, 19

Tretinoin, 249, 250, 252Triamcinolone, 37Triazolam


hepatic insufficiency and, 119nonoral preparations of, 82systemic clearance of, 19

Trichlormethiazide, 163Trichotillomania, 407, 412Tricyclic antidepressants

cardiac effects of, 52–53, 187, 189, 192, 205

colonic toxicity of, 130diabetes patients and, 307, 308discontinuation of prior to surgery,

448

drug–drug interactions andantibiotics and, 380cardiac medications, 202, 205endocrine drugs, 325gastrointestinal medications,

133, 135, 136inhalational anesthetics, 458neurological medications and,

292, 293, 294obstetric/gynecology drugs, 360oncology medications and, 253,

254pain medications and, 523pharmacokinetics of, 26renal and urological drugs, 168,

173respiratory agents, 228



globus hystericus and, 106hepatic insufficiency and, 118irritable bowel syndrome and, 114neurological adverse effects of, 287,

294neuropathic pain and, 505organ transplantation and, 479pain management and, 512,

515–516peptic ulcer disease and, 108pheochromocytoma and, 311pregnancy and, 346, 348–349renal insufficiency and, 155, 157,

159renal and urological adverse effects

of, 165, 173respiratory disorders and, 221, 226,

227


Tricyclic antidepressants (continued)rheumatological disorders and, 432,

433seizures and, 48–49serotonin syndrome and, 254surgery and critical care, 458

Trifluoperazine, 34Trigeminal neuralgia, 506Trihexyphenidyl

drug–drug interactions and, 26gastrointestinal adverse effects of, 124neurological adverse effects of, 287renal and urological adverse effects

of, 165Trimethobenzamide, 131, 134Trimethoprim, 375Trimipramine, 26Triptans

central nervous system reactions to, 42drug–drug interactions and, 293, 294migraine and, 508serotonin syndrome and, 293

Trofosfamide, 259Troleandomycin, 32, 379Tropisetron, 136, 137Trospium, 163Tuberculosis, 214, 374Tubocurarine, 455Tyramine, and MAOIs, 21, 38, 53

UGT2B7, 17Ulcerative colitis, 112U.S. National Library of Medicine, 344,

353Upper gastrointestinal bleeding, 126Uremia

cognitive dysfunction and, 151plasma levels of alpha-1 acid

glycoprotein and, 13, 14

Uridine 5′-diphosphate glucuronosyltransferase (UGT) enzyme system, 11, 17, 21–22

Urine. See also Uremia; Urological disorders

drug–drug interactions and changes in pH of, 23, 171

psychotropic drugs and retention of, 166

Urological disordersadverse effects of psychotropic drugs

and, 164–166drug–drug interactions and,

166–171, 172–174psychiatric adverse effects of

medications for, 161–162, 163psychiatric symptoms of, 149

Urticaria, 408, 414, 416

Valacyclovir, 377Valinomycin, 32Valproate

cancer risk and, 246drug–drug interactions and, 30,


125hematological reactions and, 66hepatic insufficiency and, 120HIV/AIDS patients and, 388intravenous administration of, 81lamotrigine and, 21–22liver injury and, 127neurological adverse effects of, 287,

290, 292nonoral preparations of, 84, 93pain management and, 512, 518,

522polycystic ovarian syndrome and, 355

Index 609

pregnancy and, 350renal insufficiency and, 156, 158systemic clearance of, 19

Valproic acidbreastfeeding and, 354cardiac effects of, 196drug–drug interactions and, 294endocrinological adverse effects of,

313gastrointestinal reactions and, 56,

57, 58HIV/AIDS patients and, 388–389intravenous administration of, 93organ transplantation and, 482pain management and, 518pancreatitis and, 129pregnancy and, 347, 350, 351

Vardenafil, 169, 171, 172, 173Varenicline

black box warning on preexisting psychiatric illness and, 547

neuropsychiatric adverse effects of, 549

nicotine dependence and, 198–199, 484, 546–547

Vascular dementia, 151, 275Vasculitis, 417Vasoconstriction, and psychostimulants,

295Vasodilator hypotensive agents, 453,

454, 457, 460Vasomotor symptoms, of menopause,

343Vasopressin


nephrogenic diabetes insipidus and, 62

Vasopressin antagonists, 162, 163, 170,172

Venlafaxinecardiac effects of, 191drug–drug interactions and, 26, 31,


124hepatic insufficiency and, 118menopause and, 343organ transplantation and, 478pain management and, 512, 516renal insufficiency and, 154, 159respiratory effects of, 226systemic clearance of, 19

Ventricular arrhythmias, 49, 50, 52Verapamil, 203, 351, 521Veterans Affairs health care system, 69Viloxazine, 83Vinblastine, 33Vinca alkaloids, 251Vincristine, 33Vinorelbine, 33Viral encephalitis, 392Viral infections

herpes encephalitis (HSE) and, 392–393

HIV/AIDS and, 374, 377, 385–391metabolic effects of hepatitis, 18

Visceral pain, 509Visual hallucinations, and Parkinson’s

disease, 281Vitamin B supplements, 541Vocal cord dysfunction (VCD), 214,

215Volume of distribution, 11–12Von Willebrand disease, 66Vulvodynia, 412


Warfarin, 14, 30, 201, 204Water deprivation test, for nephrogenic

diabetes insipidus, 316Weight gain, and antipsychotics, 223,

317Wernicke-Korsakoff syndrome, 541White blood cells, and hematological

toxicity, 64Withdrawal.

See also Alcohol withdrawal syndrome; Discontinuation

corticosteroids and, 323opioids and, 545–546

Women’s Health Initiative (WHI), 358World Health Organization, and

Adverse Drug Reactions database, 245

Xerostomia, 104–105

Yasmin, 342Yaz-24, 342Young Mania Rating Scale, 389

Zafirlukast, 219, 228Zaleplon

drug–drug interactions and, 26hepatic insufficiency and, 120renal insufficiency and, 155systemic clearance of, 19

Ziconotide, 521Zidovudine, 34, 376Ziprasidone

carbamazepine and, 25cardiovascular reactions to, 52, 194drug–drug interactions and

gastrointestinal medications, 135, 136

immunosuppressants, 489neurological agents, 295obstetrics/gynecology drugs, 360oncology drugs, 252, 253pharmacokinetics of, 34renal and urological drugs, 170,

173gastric bypass surgery and, 113hepatic insufficiency and, 119nonoral preparations of, 83pain management and, 513renal insufficiency and, 155

Zolmitriptan, 19, 33, 523Zolpidem



hepatic insufficiency and, 120HIV/AIDS patients and, 391menopause and, 343nonoral preparations of, 82, 89pregnancy and, 345renal insufficiency and, 155respiratory disorders and, 222sublingual form of, 81systemic clearance of, 19

Zonisamide, 519Zopiclone



hepatic insufficiency and, 120HIV/AIDS patients and, 391renal insufficiency and, 155

Zuclopenthixol, 84

psycho pharmacology for the mentally ill

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