the black book o f wyeth yerst and monitoring ......provided as an educational service by...

Provided as an Educational Service by

WYETH-AYERSTLABORATORIES

The Black Book o fPsy c h o tropic Dosing

and Monitoring

2016

Alan F. Schatzberg, MDCharles DeBattista, MD

A Supplement to

GradWORKSPo cket Handbook Se ri e s

GradWORKSPo cket Handbook Se ri e s

2 PS YC HOT ROP IC DO S I NG & MON I TOR I NG GU I DE L I N E S PS YC HOT ROP IC DO S I NG & MON I TOR I NG GU I DE L I N E S 3

A d a p t e d f r o m

D r. Schatzberg is chairman and Kenneth T. Norris, Jr. professor in theDe p a rtment of Ps yc h i a t ry and Behavioral Sciences at the St a n f o rdUn i versity School of Medicine in California.

Dr. DeBattista is assistant professor of psychiatry and director of thePs ychopharmacology Clinic in the De p a rtment of Ps yc h i a t ry andBehavioral Sciences at the Stanford University School of Medicine inCalifornia.

We would like to extend our sincere gratitude to C. Lindsay DeVane,PharmD, for his expert re v i ew of this edition of the “Black Book.” Dr.De Va n e’s contribution to the completion of this project was inva l u a b l e .He is professor of psychiatry and behavioral sciences at the MedicalUniversity of South Carolina in Charleston.

The editors are indebted to the original authors, L a r ry Ere s h e f s ky, P h a r m D, F C C P,BCCP, and Gerald P. Overman, PharmD, BCCP, for their contributions to the 1998 BlackBook of Psychotropic Dosing and Monitoring.

The Black Book o fPsy c h o tropic Dosing

and Monitoring

2016Alan F. Schatzberg, MDCharles DeBattista, MD

2016

DISCLAIMER

This pocket re f e rence is provided as a service to medicine by Wye t h -A yerst Laboratories. Sponsorship of this re v i ew does not imply thes p o n s o r’s agreement with the views expressed here i n .

Although eve ry effort has been made to ensure that drug doses and otherinformation are presented accurately in this publication, the ultimateresponsibility rests with the prescribing physician. Neither the publisher,the sponsor, nor the authors can be held responsible for errors or for anyconsequences arising from the use of information contained here i n .Readers are strongly urged to consult any re l e vant primary literature. Noclaims or endorsements are made for any drug or compound curre n t l yunder clinical inve s t i g a t i o n .

In an effort to allow for the widest distribution of these guidelines, theauthors have modified the originally printed material to more closelyconform to the limitations of product labeling. For many of the dru g sdiscussed herein, initiation at lower doses may increase tolerability ande f f i c a c y.

Copyright ©2016, Me d Wo rks Media In c .Printed in the USA. All rights re s e rved, including the right ofre p roduction, in whole or in part, in any form. The “Black Book ofPs yc h o t ropic Dosing and Mo n i t o r i n g” is a re g i s t e red trademark ofMe d Wo rks Media In c .

DeBattista C, Schatzberg AF. Universal Psychotropic Dosing andMonitoring Guidelines. TEN;3:60-70.

Introduction 6Dosing and Monitoring GuidelinesTable 1 10Psychotropic Drug Dosage Ranges

AntidepressantsTable 2 12Mood Disorders: AntidepressantsTable 3 14Pharmacokinetic Comparisonof Selected AntidepressantsTable 4 14CNS Neurotransmitters: SelectedAntidepressant EffectsTable 5 16Substrates, Inhibitors, and Inducers of Some Im p o rtant CYP P450 Is o f o r m sTable 6 20Examples of Drugs That Might Interact With an AntidepressantTable 7 20Examples of Drug Interactions

Mood StabilizersTable 8 24Mood StabilizersTable 9 26Baseline and Routine MonitoringParameters for Mood Stabilizers

Anxiolytics/HypnoticsTable 10 28Benzodiazepine AnxiolyticsTable 11 28Nonbenzodiazepine AnxiolyticsTable 12 30Benzodiazepine Drug Interactions

Table 13 30Hypnotic Agents

AntipsychoticsTable 14 32Typical Antipsychotic Dosages and Adverse EffectsTable 15 34Atypical Antipsychotic Dosages and Adverse EffectsTable 16 34Pharmacokinetic Parameters and Dosing of Depot AntipsychoticsTable 17 36Antiparkinsonian AgentsTable 18 36Antipsychotic Drug InteractionsTable 19 38Acute Neurologic Side Effectsof Antipsychotic MedicationsTable 20 40Pharmacokinetic Parameters ofSelected Oral Antipsychotics

Anorexiants/Psychostimulants and Cholinesterase InhibitorsTable 21 42AnorexiantsTable 22 42PsychostimulantsTable 23 42Drugs for Alzheimer’s DiseaseTable 24 42Ad verse Effects of Cholinesterase In h i b i t o r s

REFERENCES 44


C o n t e n t s

CU R R E N T PS YC HOT ROP ICDO S I NG A N D MON I TOR I NG

GU I DE L I N E S�By Alan F. Schatzberg, MD,

Charles DeBattista, MD, and

During the past 10 years, psychotropic agents havebecome some of the most common and lucrative drugs in all of medical practice. This has beenthe result of and a precipitant for larger research anddevelopment budgets for psychopharmacologic agents.The new developments have come in several forms, fromnovel drugs to new indications for older agents. New for-mulations of previously released drugs may now allow formore convenient dosing and administration. Since the2000 edition of this update, a number of new agents havebeen released.

Reboxetine (Edronax, Pharmacia) has been approved inover 30 countries and has been available as an antidepres-sant in Europe for several years. Reboxetine’s approval inthe United States (US) was delayed by the Food and DrugAdministration (FDA). A probable flaw in the researchdesign of the American trials resulted in an inability toseparate reboxetine from placebo on a primary outcomem e a s u re. New studies have now been completed.However, it is unclear if reboxetine will now, or ever, beapproved in the US.

Ziprasidone (Geodon, Pfizer), an atypical antipsychot-ic, was recently approved by the FDA. However, whileziprasidone skirted any serious “black box” cardiovascularwarning, a review of the agent prompted the FDA to takea closer look at the cardiac conduction effects of antipsy-c h o t i c s . Some agents that have been used for decades now includea black box warning about QTc prolongation. Among the

typical antipsychotics that have received this warning ist h i o r i d a z i n e (Mellaril, Novartis), which has been in common use forthe treatment of psychosis for almost 40 years.1 It is likelythat several other typical and atypical agents will ultimate-ly show the same propensity for QTc effects.

The distinguishing feature of ziprasidone may be its lackof a propensity to cause weight gain.2

Weight gain has been a significant problem with atypicalantipsychotics as well as with classic low potency agents,such as chlorpromazine (Thorazine, GlaxoSmithKline). Aswith other atypicals, ziprasidone may possess mood-elevating or stabilizingproperties.3 Another distinction of ziprasidone is that itwill be the only atypical antipsychotic available as an intramuscular (IM) injection. In the next 2years, it is likely that other atypical agents will be availablein IM or depot forms, including risperidone (Risperdal,Janssen) and olanzapine (Zyprexa, Eli Lilly). Olanzapinerecently became available as an orally disintegrating tabletthat dissolves in the mouth before being absorbed(Zyprexa ZYDIS, Eli Lilly).

Anticonvulsants, including gabapentin (Ne u ro n t i n ,P f i zer), lamotrigine (Lamictal, Gl a xo SmithKline), andtopiramate (Topamax, Ortho-McNeil), continue to beinvestigated in the treatment of mood and anxiety disor-ders. A newly introduced anticonvulsant, oxcarbazepine(Trileptal, Novartis), is likely to be quickly employed inthe treatment of bipolar disorder. Oxcarbazepine has beenstudied in the treatment of bipolar disorder for many yearsand appears to be effective.4,5 It is chemically related to car-bamazepine (Tegretol, Novartis), but lacks many of carba-mazepine’s drug interactions and some of the side effects.6

One significant disadvantage is cost; oxcarbazepine ismany times more expensive than generic carbamazepine.

Divalproex sodium (Depakote, Abbott) is now availablein a once-per-day extended-release formulation for the FDA indication of migraine


I n t ro d u c t i o n

prophylaxis. This preparation of divalproex will be furtherstudied in the treatment of mania, although a preliminarystudy failed to show efficacy. In addition, divalproexreceived a black box warning in 2000 regarding the risk ofpancreatitis, even though divalproex-induced pancreatitisappears to be idiosyncratic and extremely unusual. Thereport of rare, associated pancreatitis has not substantially impacted the widespread use of divalproex in the treat-ment of bipolar disorder.

A new acetylcholinesterase inhibitor, riva s t i g m i n e(Exelon, Novartis), was introduced in 2000 for the treat-ment of mild-to-moderate Alzheimer’s disease.Rivastigmine is thought to be selective in primarily tar-geting the hippocampal and cerebral cortical regions ofthe brain.7 The drug has already been approved in over 70countries and has been proven effective in improvingdementia-related declines in cognition and activities ofdaily living.8

Like other acetylcholinesterase inhibitors, riva s t i g-mine’s primary side effects are dose-related nausea, sweat-ing, dizziness, myalgia, and urinary incontinence. Mostpatients seem to be able to tolerate rivastigmine; at least10% of patients discontinue the medication at higherdoses secondary to side effects. There may be patientswho function better on rivastigmine than donepez i l(Aricept, Pfizer), but head-to-head trials are lacking.Likewise, galantamine (Reminyl, Janssen) is a recentlyapproved acetylcholinesterase inhibitor that also appearsto improve day-to-day functioning, behavior, and memo-ry in Alzheimer’s patients. It has a similar side-effect pro-file to the other cholinesterase inhibitors.9

New preparations of established drugs, especially sus-t a i n e d - release formulations, are expected. Fl u oxe t i n e(Prozac, Eli Lilly) was approved in 2001 as a once-per-week formulation. This may have appeal to those patientswho have trouble complying with a daily medication.However, missing a weekly dose may prove more prob-lematic than missing a daily dose. An orally-disintegrating

tablet form of mirtazapine (Remeron SolTab, Organon)was also recently introduced. For the patient who has trou-ble swallowing pills, this orange-flavored, rapidly-disinte-grating tablet may be advantageous.

New indications for established antidepressants havealso been secured. These include the first indication for pre m e n s t rual dysphoric disord e r —fluoxetine, under the trade name Sarafem (Eli Lilly)—andsertraline (Zoloft, Pfizer) for posttraumatic stress disorder.In addition, venlafaxine ER (Effexor XR, Wyeth-Ayerst)was the first antidepressant indicated for the treatment ofg e n e r a l i z e d anxiety disorder (GAD). Pa roxetine (Pa x i l ,GlaxoSmithKline) was also approved for the treatment ofGAD.

As with previous editions, the 2002 edition of this monograph is aimed at providing the clinician with anup-to-date set of tables and the framework for applying anever-expanding list of psychotropic agents in clinical prac-tice. �


D o s age Range sDosage

Brand R a n g e *G e n e r i c N a m e ( m g / d ay )Mirtazapine Remeron 15–45 Molindone Moban 15–225Nefazodone Serzone 200–600Nortriptyline Aventyl, Pamelor 75–150Olanzapine Zyprexa 5–20Oxazepam Serax 30–120Oxcarbazepine Trileptal 600–1,200Paroxetine†† Paxil 20–60Perphenazine Trilafon 12–64Phenelzine Nardil 15–90Pimozide Orap 1–10Prazepam Centrax 30–60Protriptyline Vivactil 15–60Quazepam Doral 7.5–15Quetiapine Seroquel 50–750Risperidone Risperdal 2–16Rivastigmine Exelon 6–12Sertraline Zoloft 50–200Temazepam Restoril 15–30Thioridazine Mellaril 20–800Thiothixene Navane 6–60Tiagabine Gabitril 4–32Topiramate Topamax 50–400Tranylcypromine Parnate 30–60Trazodone Desyrel 150–600Triazolam Halcion 0.125–0.5Trifluoperazine Stelazine 2–40Trimipramine Surmontil 50–300Valproic Acid/ Depakene, 750–4,200Divalproex DepakoteVenlafaxine‡‡ Effexor, 75–375

Effexor XR*** 75–225Zaleplon Sonata 5–20Ziprasidone Geodon 40–160Zolpidem Ambien 5–10* Recommended dosages may va ry by indication. Dosage ranges include starting doses that may not

re p resent effective dosages. Some drugs may be contraindicated or may re q u i re lower doses in pedi-atric, geriatric, or debilitated patients. Consult the prescribing information of individual drugs form o re detailed information.

† Zyban is indicated as an aid to smoking cessation.‡ Although carbamazepine is not approved by the FDA for psychiatric indications, the

authors view it as one of the most important agents available for the treatment of bipolardisorder. This view is supported in the medical literature.

§ For alcohol detoxification and withdrawal, doses of up to 300 mg of chlordiazepoxide and 90 mg of clorazepate may be warranted.

ll Labeling suggests that higher doses in severe cases may be appropriate, up to 2,000 mg/day,but little therapeutic gain is achieved by >1,000 mg/day for extended periods. Intramuscu-lar doses may be necessary.

** Starting dosage of clonazepam should not be >1.5 mg/day for PD but doses up to 20mg/day are approved for seizure disorders.

†† Dosage range for paroxetine adjusted for OCD and PD.‡‡ Recommended starting dose is 75 mg/day.***37.5 mg/day for 4–7 days is an initial dosing option.

Dosage Brand R a n g e*

G e n e r i c N a m e ( m g / d ay )A l p r a z o l a m X a n a x 0 . 7 5 – 1 0A m i t r i p t y l i n e E l av i l , E n d e p, E n ov i l 5 0 – 3 0 0A m ox ap i n e A s e n d i n 5 0 – 6 0 0B u p ro p i o n We l l b u t r i n , 2 0 0 – 4 5 0

Wellbutrin SR, 1 5 0 – 4 0 0Z y b a n† 1 5 0 – 3 0 0

B u s p i ro n e B u S p a r 1 5 – 6 0C a r b a m a z e p i n e‡ E p i t o l ,Te g re t o l 4 0 0 – 1 , 6 0 0Chloral Hydrate N o c t e c, 5 0 0 – 2 , 0 0 0

A q u a c h l o r a l - S u p p re t t e sC h l o rd i a z e p ox i d e§ L i b r i u m , 1 5 – 1 0 0

L i b r i t a b s ,M i t r a nC h l o r p ro m a z i n ell O r m a z i n e,Thorazine 3 0 – 8 0 0C i t a l o p r a m C e l e x a 2 0 – 6 0C l o m i p r a m i n e A n a f r a n i l 2 5 – 2 5 0C l o n a z e p a m* * K l o n o p i n 0 . 5 0 – 4C l o r a z e p a t e§ C l o r a z e C ap s , 1 5 – 6 0

C l o r a z e Ta b s ,G e n - X E N E ,Tr a n xe n e

C l o z ap i n e C l o z a r i l 1 2 . 5 – 9 0 0D e s i p r a m i n e N o r p r a m i n , Pe rtofrane 2 5 – 3 0 0D i a z e p a m Va l i u m ,Va l re l e a s e, 4 – 4 0

Zetran D oxe p i n A d ap i n , S i n e q u a n 2 5 – 3 0 0D ro p e r i d o l I n ap s i n e 2 . 5 – 1 5E s t a z o l a m P ro S o m 1 – 2F l u oxe t i n e P ro z a c,S a r a fe m 2 0 – 8 0F l u p h e n a z i n e Pe r m i t i l , P ro l i x i n 1 – 4 0F l u r a z e p a m D a l m a n e 1 5 – 3 0F l u vox a m i n e L u vox 5 0 – 3 0 0G a b ap e n t i n N e u ro n t i n 3 0 0 – 3 , 6 0 0G a l a n t a m i n e R e m i ny l 1 6 – 3 2H a l a z e p a m P a x i p a m 6 0 – 1 6 0H a l o p e r i d o l H a l d o l 1 – 1 0 0I m i p r a m i n e J a n i m i n e,To f r a n i l 5 0 – 3 0 0I s o c a r b ox a z i d M a r p l a n 2 0 – 6 0Lamotrigine Lamictal 25–400Lithium Cibalith-S, Eskalith, 6 0 0 – 1 , 8 0 0

Lithane, Lithobid,Lithonate, Lithotabs

Lorazepam Ativan 1–10Loxapine Loxitane 20–250Maprotiline Ludiomil 25–225Mesoridazine Serentil 30–400Methylphenidate HCl Concerta 18–54

Ritalin, Ritalin-SR 10–60

Ta ble 1: P S Y C H OT RO P I C D RUG DOSAGE RANGES9 - 1 7


A n t i d e p re s s a n t sTa ble 2: MOOD DISORDERS: A N T I D E P R E S S A N T S1 0 - 1 3 , 1 5 , 1 6 , 1 8 - 2 4

Typical Typical P roposed S t a rting Dosage Range* F DA T h e r apeutic Plasma

D r u g Dosage (mg) ( m g / d ay ) I n d i c a t i o n ( s ) Concentration (ng/mL)Amitriptyline 25 TID or 5 0 – 3 0 0 D e p re s s i o n 1 2 0 – 2 5 0†

( E l av i l , E n d e p, E n ov i l ) 50 QHSA m ox apine 50 BID/TID 5 0 – 6 0 0 D e p re s s i o n , —( A s e n d i n ) psychotic depre s s i o nB u p ropion (We l l b u t r i n ) 100 BID 2 0 0 – 4 5 0‡ D e p re s s i o n < 1 0 0†

B u p ropion SR (Wellbutrin SR) 150 QAM 1 5 0 – 4 0 0‡ D e p re s s i o nB u p ropion SR (Zyban) 150 QD 1 5 0 – 3 0 0‡ Smoking cessationCitalopram ( C e l e x a ) 2 0 2 0 – 6 0 D e p re s s i o n —Clomipramine (Anafranil) 25–100 QD in 2 5 – 2 5 0 O C D 1 0 0 – 2 5 0

divided doses within first 2 we e k s

Desipramine 25 T I D 1 0 0 – 3 0 0 D e p re s s i o n 1 1 5 – 1 8 0§

( N o r p r a m i n , Pe rt o f r a n e )D oxepin (Sinequan) 25 T I D 7 5 – 3 0 0 D e p re s s i o n , a n x i e t y, psychotic 7 0 – 2 5 0†

d e p re s s i ve disorders with associated anxietyF l u oxetine 20 QD 2 0 – 8 0 D e p re s s i o n , O C D, —( P ro z a c, S a r a fe m ) bulimia nervo s a , P M D DF l u voxamine (Luvox ) 50 QD 5 0 – 3 0 0 O C D —Imipramine 25 T I D 7 5 – 3 0 0 D e p re s s i o n , 2 0 0 – 2 5 0† ,§

( J a n i m i n e,Tofranil) childhood enu re s i sM ap rotiline (Ludiomil) 25 T I D 7 5 – 2 2 5 D e p re s s i o n —I s o c a r b oxazid (Marplan) 1 0 2 0 – 6 0 D e p re s s i o n —M i rt a z apine (Remero n ) 15 QHS 1 5 – 4 5 D e p re s s i o n —Nefazodone (Serzone) 100 BID 2 0 0 – 6 0 0 D e p re s s i o n —N o rtriptyline (Ave n t y l , P a m e l o r ) 25 T I D / Q D 7 5 – 1 5 0 D e p re s s i o n 5 0 – 1 5 0§

P a roxetine (Paxil)* * 20 QAM 1 0 – 6 0 D e p re s s i o n , O C D, —P D, social anxiety disord e r, G A D

Phenelzine 15 T I D 1 5 – 9 0 D e p re s s i o n , —( N a rd i l ) atypical depre s s i o nP rotriptyline (Vivactil) 5 T I D 1 5 – 6 0 D e p re s s i o n 7 0 – 2 5 0S e rtraline (Zoloft) 50 QAM 5 0 – 2 0 0 D e p re s s i o n , O C D, P D, P T S D —Tr a ny l c y p romine I n d i v i d u a l i z e d 3 0 – 6 0 D e p re s s i o n , — ( P a r n a t e ) d e p ression without melancholiaTrazodone (Desyre l ) 50 T I D 1 5 0 – 6 0 0 D e p re s s i o n —Trimipramine (Surmontil) 25 T I D 5 0 – 3 0 0 D e p re s s i o n —Venlafaxine (Effe x o r ) 37.5 BID 7 5 – 3 7 5 D e p re s s i o n —Venlafaxine ER (Effexor XR)† † 37.5–75 QD 7 5 – 2 2 5 D e p re s s i o n ,G A D —


* In geriatric patients, the appropriate dosage is widely variable, but in general it is one half the young adult dosage range for TCAs andfor compounds with significant cardiovascular toxicity.

† Parent and metabolite.‡ Not >150 mg/dose. Zyban is indicated as an aid to smoking cessation.§ Therapeutic drug monitoring is well established

** Dosage range for paroxetine adjusted for OCD and PD.†† 37.5 mg/day for 4–7 days is an initial dosing option.

FDA=Food and Drug Administration; OCD=obsessive-compulsive disorder;PMDD=premenstrual dysphoric disorder; PD=panic disorder; GAD=generalizedanxiety disorder; PTSD=posttraumatic stress disorder.

Ta ble 3: P H A R M ACOKINETIC COMPARISON OFSELECTED A N T I D E P R E S S A N T S2 5 , 2 6

S e rt r a l i n e F l u oxe t i n e P a roxe t i n e N e f a z o d o n e F l u vox a m i n eH a l f - l i fe (hours) 2 6 4 8 – 7 2 21 (mean) 2 – 4 1 5 . 6Metabolite activity 20–30% activity E q u a l I n a c t i ve 3 variably active Questionable M e t a b o l i t e 6 2 – 1 0 4 9 6 – 3 8 4 — 1 . 5 – 1 8 1 4 – 1 6h a l f - l i fe (hours)Steady state (day s ) 7 – 1 0 2 8 – 3 5 ~ 1 0 4 – 5 7D o s e - p ro p o rt i o n a l Ye s N o N o N o N oplasma leve l sP rotein binding (%) 9 8 9 4 . 5 9 3 – 9 5 9 9 8 0Dose reduction in elderly N o Ye s Ye s Ye s Ye s

C i t a l o p r a m Ve n l a f a x i n e C l o m i p r a m i n e A m i t r i p t y l i n e B u p ro p i o n M i rt a z ap i n eH a l f - l i fe (hours) 3 5 3 – 7 1 9 – 3 7 9 – 4 6 1 4 2 0 – 4 0Metabolite activity I n a c t i ve E q u a l E q u a l E q u a l 4 variably active 10% activityMetabolite half-life (hours) — 9 – 1 3 5 4 – 7 7 1 6 – 8 8 8 – 2 4 2 0 – 4 0Steady state (day s ) 7 3 7 – 1 4 4 – 1 0 Va r i a b l e 3 – 4D o s e - p ro p o rt i o n a l Ye s Ye s N o Ye s Ye s Ye splasma leve l sP rotein binding (%) 8 0 2 7 – 3 0 9 7 9 0 – 9 7 8 0 8 5Dose reduction in elderly N o N o Ye s Ye s Ye s N o

Ta ble 4: CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS: SELECTEDANTIDEPRESSANT EFFECTS25,27

S e ro t o n i n N o re p i n e p h r i n e D o p a m i n eA m i t r i p t y l i n e + + + + + + + + 0A m ox ap i n e + + + + + + 0B u p ro p i o n 0 / + + + +C i t a l o p r a m + + + + 0 0D e s i p r a m i n e + + + + + 0 / +D oxe p i n + + + + 0F l u oxe t i n e + + + + 0 0 / +F l u vox a m i n e + + + + 0 0 / +I m i p r a m i n e + + + + + 0 / +

L i t h i u m 0 / + +§ 0 0++++=high; +++=moderate; ++=low; +=very low; 0=none.

S e ro t o n i n N o re p i n e p h r i n e D o p a m i n eM ap ro t i l i n e 0 + + + + 0

M i rt a z ap i n e + + +* + +† 0

N e f a z o d o n e + + +‡ 0 / + 0N o rt r i p t y l i n e + + + + + 0P a roxe t i n e + + + + 0 / + 0 / +P ro t r i p t y l i n e + + + + + 0S e rt r a l i n e + + + + 0 0 / +

Tr a z o d o n e + +‡ 0 0Tr i m i p r a m i n e + + + + 0Ve n l a f a x i n e + + + + + + + 0 / +* 5-HT2 and 5-HT3 antagonist.† α2 presynaptic antagonist.‡ 5-HT2 antagonist. § Acutely increases; chronically stabilizes.


Inhibitors Inducers

† Clinically significant human polymorphism reported.CYP 450=cytochrome P450; TCAs=tricyclic antidepressants; NSAIDS=nonsteroidal anti-inflammatory drugs.

CYP% of all CYP*

CYP2E17

CYP2D6†2

CYP2C19†20 ( for all 2C)

C Y P 2 C 920 ( for all 2C)

CYP1A213

Substrates

Ta ble 5: S U B S T R AT E S , I N H I B I TO R S , AND INDUCERSOF SOME IMPORTANT CYTO C H ROME P450(CYP) ISOFORMS2 8 - 3 2


3° amine TCAs (N-demethylation)

AcetaminophenCaffeineClozapine (major)Methadone

OlanzapinePhenacetinPropranololTacrineTheophylline

CelecoxibFluvastatinGlipizideIrbesartanLosartan

NSAIDsPhenytoin (major)RosiglitazoneS-warfarinTolbutamide


Citalopram (partly)Diazepam (partly) (N-demethylation)

HexobarbitalIndomethacinLansoprazole

MephobarbitalMoclobemideNelfinavirOmeprazole (5-hydroxylation)

Phenytoin (minor)R-warfarinS-mephenytoin

2° and 3° amine TCAs( 2 , 8 , 1 0 - hy d rox y l a t i o n )

AlprenololAmphetamineBeta blockersCarvedilolClozapine (minor)Codeine (hydroxylation,O-demethylation)

D-fenfluramineDesipramineDextromethorphan(O-demethylation)

Donezepil (partly)Fluoxetine (partly)FluphenazineHaloperidol(reduction)

HydrocodoneMexiletineMirtazepine (partly)NortriptylineOxycodoneParoxetinePerphenazinePropafenone (IC antiarrhythmics)

RisperidoneTamoxifenThioridazineTimololTramdolTrazodone

AcetaminophenChlorzoxazoneEthanolHalothane

IsofluraneMethoxyfluraneSevoflurane

CimetidineFluoroquinolines(ciprofloxacin,norfloxacin)

Fluvoxamine

Mibefradil MoclobemideNaringenin Ticlopidine

AmiodaroneD-propoxypheneDisulfiramFluconazoleFluvastatin

FluvoxamineMiconazolePhenylbutazoneSulphaphenazoleZafirlukast

CimetidineFelbamateFluoxetineFluvoxamineImipramine

KetoconazoleMoclobemideOmeprazolePhenytoinTranylcypromine

AmiodaroneBupropionCelecoxibCimetidineFluoxetineFluphenazineFluvoxamine(weak)

Haloperidol

H y d rox y b u p ro p i o nMethadoneMoclobemideParoxetinePerphenazineQuinidineRitonavirSertraline (weak)Thioridazine

Diethyldithio-carbamate(Disulfirammetabolite)

Char-grilledmeat

OmeprazoleTobacco

PhenytoinRifampinSecobarbital

Rifampin

EthanolIsoniazid

Inhibitors Inducers

Ta ble 5: S U B S T R AT E S , I N H I B I TO R S , AND INDUCERSOF SOME IMPORTANT CYTO C H ROME P450(CYP) ISOFORMS (C O N T ’ D)2 8 - 3 2

Substrates

CYP% of all CYP*

CYP=cytochrome P450; TCAs=tricyclic antidepressants.



AcetaminophenAlfentanilAlprazolamAmiodaroneAndrogensAtorvastatinBuspironeCarbamazepineCerivastatinCitalopram (partly)Codeine (demethylation)

CyclophosphamideCyclosporineDexamethasoneDiazepam (partly)(hydroxylation and N-demethylation)

DiltiazemDisopyramideDonepezil (partly)Erythromycin(macrolides)

Estrogens (steroids)EthosuximideFelodipineFentanylIfosfamide

LidocaineLoratadineLovastatinMidazolamMirtazapine (partly)NefazodoneNifedipineNimodipineNisoldipineNitrendipineOmeprazole (sulfonation)

PropafenoneProtease inhibitors(HMG-CoA reductase inhibitors)

QuetiapineQuinidineSertralineSildenafilSimvastatinSufentanilTacrolimusTamoxifenTiagabineTriazolamVerapamilVinblastineVincristineZiprasidone

AmiodaroneCimetidineClarithromycinDexamethasoneDiltiazemErythromycinFluconazoleFluoxetineFluvoxamineGestodeneIndinavir (proteaseinhibitors)

Itraconazole

Ketoconazole(azole antifungals)

MibefradilNaringenin (grapefruit)

NefazodoneNelfinavirRitonavirSaquinavirSertraline (weak)Troleandomycin(macrolides)

Verapamil

BarbituratesCarbamazepineDexamethasonePhenobarbitalPhenytoinPioglitazoneRifampinSt. John’s wort

CYP3A430 ( for all 3A)

Ta ble 6: EXAMPLES OF DRU G S*T H AT MIGHT I N T E R ACT WITH AN A N T I D E P R E S S A N T3 1

CYP 1A2 CYP 2C19 CYP 2C9 CYP 2D6 CYP 3A4A c e t a m i n o p h e n B a r b i t u r a t e s D i c l o fe n a c A m p h e t a m i n e s A n d ro g e n sC a f fe i n e C i t a l o p r a m I b u p ro fe n C h l o r p h e n i r a m i n e B e n z o d i a z e p i n e sC l o z ap i n e D i a z e p a m N ap roxe n C o d e i n e / hy d ro c o d o n e ( a l p r a z o l a m , t r i a z o l a m , c l o n a z e p a m,H a l o p e r i d o l M e p h e ny t o i n O m e p r a z o l e D e s i p r a m i n e d i a z e p a m )O l a n z ap i n e M o c l o b e m i d e P h e ny t o i n other 2° T CA s Calcium channel blocke r sP h e n a c e t i n P ro p r a n o l o l P i rox i c a m D e x t ro m e t h o r p h a n C a r b a m a z e p i n eP h e n o t h i a z i n e s 3° T CA s S - Wa r f a r i n F l e c a i n i d e / e n c a i n i d e C o rt i c o s t e ro i d sR-warfarin (minor) To l b u t a m i d e Haloperidol (minor) C y c l o s p o r i n eTacrine P h e n o t h i a z i n e s D ap s o n e3° T CA s P ro p r a n o l o l , t i m o l o l , E s t ro g e n sT h e o p hy l l i n e m e t o p ro l o l HMG-CoA reductase inhibitorsT h i o t h i xe n e Reduced haloperidol Ke t o c o n a z o l e, i t r a c o n a z o l e

R i s p e r i d o n e M a c rolide antibioticsQ u i n i d i n e† Nonsedating antihistamines† †Tr a m a d o l P a c l i t a xe l

Q u i n i d i n eTa m ox i fe nZ o l p i d e m

* Drug can be a substrate and/or an inhibitor of a given enzyme system.†Inhibitor at 2D6, not a substrate.† †Loratadine not contraindicated.

C Y P = c y t o c h rome P450; TC A = t r i c yclic antidepre s s a n t .


Ta ble 7: EXAMPLES OF DRUG INTERAC T I O N S2 8 , 3 1 - 3 7

D r u g I n t e r a c t i o n M e c h a n i s mT CA Interactions A l c o h o l � s e d a t i o n , a t a x i a CNS depression synergismCalcium channel blocke r s � T CA leve l s Inhibit oxidation of T CA sC a r b a m a z e p i n e � T CA leve l s Hepatic enzyme inductionC i m e t i d i n e � T CA leve l s Inhibit T CA metabolismC l o n i d i n e A n t a gonize antihy p e rt e n s i ve effe c t s N o repinephrine re u p t a keE s t ro g e n � T CA leve l s Inhibit oxidation of T CA sG u a n e t h i d i n e R everse antihy p e rt e n s i ve effe c t s Block norepinephrine re u p t a keH a l o p e r i d o l / p h e n o t h i a z i n e s � antipsychotic leve l s CYP 2D6 inhibitionM e t h a d o n e � T CA leve l s Inhibit T CA metabolism

TC A = t r i c yclic antidepressant; � = i n c reased; CNS=central nervous system; � = d e c re a s e d ;C Y P = c y t o c h rome P450; MAO Is=monoamine oxidase inhibitors.

M AO I s S e rotonin syndrome S e rotonin synergism D r u g I n t e r a c t i o n M e c h a n i s mQ u i n i d i n e � T CA leve l s , a rr hy t h m i a Inhibit CYP 2D6S S R I s � T CA leve l s Inhibit various CYP systemsS t i mu l a n t s � T CA leve l s Inhibit T CA metabolismSSRI InteractionsC y p ro h e p t a d i n e R everse antidepressant effe c t S e rotonin antago n i s mD e x t ro m e t h o r p h a n S e rotonin syndro m e S e rotonin synergismH a l l u c i n o g e n s � LSD flashbacks 5 - H T2 a go n i s mM AO I s S e rotonin syndro m e S e rotonin synergismT CA s T CA tox i c i t y Inhibit various CYP systemsTry p t o p h a n S e rotonin syndro m e S e rotonin synergismT h e o p hy l l i n e T h e o p hylline tox i c i t y Inhibit theophylline metabolism (fluvox a m i n e )Wa r f a r i n � warfarin leve l s Inhibit CYP 2CM AOI InteractionsB a r b i t u r a t e s � s e d a t i o n Inhibit barbiturate metabolismH y p o g ly c e m i c s � e f fects of hy p o g ly c e m i c s M AOIs lower blood sugarM e p e r i d i n e S e rotonin syndro m e S e rotonin synergism S S R I s S e rotonin syndro m e S e rotonin synergism S u c c i ny l c h o l i n e P rolonged apnea in surgery D e c reased cholinesterase leve l sS y m p a t h o m i m e t i c s H y p e rt e n s i ve crisis I n d i rect pressor effe c tT CA s S e rotonin syndro m e S e rotonin synergism Tyramine (dietary ) H y p e rt e n s i ve crisis I n d i rect pressor effe c t sVenlafaxine InteractionsC i m e t i d i n e � venlafaxine leve l s CYP P450 inhibitionH a l o p e r i d o l � haloperidol leve l s U n k n ow n

Haloperidol elimination half-l i fe unchanged

M AO I s S e rotonin syndro m e S e rotonin synergismS S R I s Potential � venlafaxine leve l s 2D6 inhibition

S e rotonin syndro m e S e rotonin synergismNefazodone InteractionsG l u c o c o rt i c o i d s � s t e ro i d Inhibit 3A4 �=incr eased; TCAs=tricyclic antidepressants; CYP=cytochrome P450; SSRIs=selective serotonin reuptake inhibitors; LSD=lysergic acid diethylamide;MAOIs=monoamine oxidase inhibitors.


Ta ble 7: EXAMPLES OF DRUG INTERACTIONS (C O N T ’ D)2 8 , 3 1 - 3 7

Ta ble 8: MOOD STA B I L I Z E R S2 9 , 3 8 - 4 3

Serum plasma l eve l sUsual adult d a i ly dosageOnset of actionP rotein b i n d i n g

t1 / 2

M e t a b o l i cp a t h w ay ( s )

Route(s) ofe l i m i n a t i o nCommon drug i n t e r a c t i o n s

Common adverse e f fe c t s

I n d i c a t i o n ( s )

L i t h i u m*

( C i b a l i t h - S , E s k a l i t h , L i t h a n e,L i t h o b i d , L i t h o n a t e,L i t h o t a b s )0.6–1.2 mEq/L ( a c u t e )600–1,800 mg

5–14 day sNot bound to plasma pro t e i n s

24 hours (ave r a g e )� with age and/or with d e c reased renal functionNot metabolized, p r i m a r i ly excreted unchanged in urine

R e n a l

� lithium serum concentrations ( f l u oxe t i n e,† AC E i n h i b i t o r s , d i u re t i c s ,N S A I D s )

� lithium serum concentrations ( a c e t a z o l a m i d e,osmotic diure t i c s ,t h e o p hy l l i n e,u r i n a ry alkalinizers)

Antipsychotics may increase lithium n e u ro t ox i c i t yN a u s e a , vo m i t i n g , d i a rr h e a , p o ly u r i a ,p o ly d i p s i a , t re m o r, hy p o t hy roidism

Manic episodes of bipolar disord e r,bipolar disorder maintenance

Mood Stabilize r sVa l p roic A c i d*

( D e p a ke n e,D e p a ko t e )

50–100 µg / m L

750–4,200 mg

5–15 day s90% concentration dependent � with high concentration(variable due to saturation)6–16 hours (ave r a g e )� with age and/or decre a s e dhepatic functionHepatic (glucuro n i d a t i o n ,mitochondrial b ox i d a t i o n ,m i c rosomal ox i d a t i o n )G l u c u ro n i d a t i o n , renal

Interacts with drugs that areh e p a t i c a l ly metabolized;enzyme inducers can decre a s econcentrations of valproic acid;v a l p roic acid can increase phenobarbital by impairment of nonrenal clearance( s eve re CNS depre s s i o n )

GI distress, diplopia,sedation, tremor, edema,weight gain, alopecia, and thrombocytopeniaBipolar disord e r, acute mania(and seizure disord e r s )


C a r b a m a z e p i n e * ,‡

( C a r b i t ro l ,Te g re t o l )

4–12 µg / m L

400–1,600 mg

3–15 day s76%

Initial range 26–65 hours;with repeated dosing,12–17 hoursH e p a t i c : CYP 3A,2 D 6

Renal (72%), fecal (28%)

Induces metabolism of CYP 3A4-dependent drugs;d e c reases phe-n o b a r b i t a l ,p h e ny t o i n ,s e xs t e ro i d s ,h a l o p e r i d o l ,v a l p roic acid,calcium channel blocke r s ,e t c.(see Table 6).Va l p roate incre a s e s1 0 ,11 epoxide metabolite of c a r b a m a z e p i n e.

D i z z i n e s s , d row s i n e s s , a t a x i a ,and weight gain

P a rtial complex seizure s

�=decr eased; �=incr eased; CYP=cytochrome P450;ACE=angiotensin-converting enzyme; NSAIDs=nonsteroidal anti-inflammatory drugs; CNS=central nervous system;GI=gastrointestinal.

*Women taking a mood stabilizing agent should be given a pregnancytest at baseline and then as clinically indicated.

†Both increases and decreases have been reported and lithium levels should be moni-tored when used together.

‡Carbamazepine may decrease the efficacy of oral contraceptives through enzymeinduction.

Ta ble 9: BASELINE AND ROUTINE MONITO R I N GPARAMETERS FOR MOOD STA B I L I Z E R S3 3 , 4 2 , 4 3

L a b o r a t o ry Parameters L i t h i u m * C a r b a m a z e p i n e * ,†,‡ Va l p roic A c i d *

Serum plasma We e k ly x 4 we e k s , 2 weeks after 2 weeks after c o n c e n t r a t i o n s then monthly x 3 months, i n i t i a t i o n , then eve ry i n i t i a t i o n , then eve ry

then eve ry 3 months or as 3 months or as 3 months or asc l i n i c a l ly indicated c l i n i c a l ly indicated c l i n i c a l ly indicated

Complete B a s e l i n e,m o n t h ly B a s e l i n e, then monthly B a s e l i n e,then blood count x 3 months, x 3 months, then m o n t h ly x 6 months,

then as clinically indicated as clinically indicated then eve ry 6 months or as clinically indicated (include diffe rential and platelets)

Blood B a s e l i n e, then eve ry B a s e l i n e, then annu a l ly B a s e l i n e,m o n t h ly then x c h e m i s t r i e s 12 months or as clinically as indicated 6 months, then

indicated (eg, serum eve ry 6 months or as c re a t i n i n e,renal function, c l i n i c a l ly indicatedand electro ly t e s ) ( e g , hepatic and renal function)

ECG (in patients B a s e l i n e, then eve ry B a s e l i n e, then B a s e l i n e,t h e n� 45 years or with 12 months or as eve ry 12 months as clinically indicatedp reexisting cardiac disease) c l i n i c a l ly indicatedU r i n a ly s i s B a s e l i n e, then as clinically B a s e l i n e, then B a s e l i n e,then eve ry

i n d i c a t e d as clinically indicated 6 months or as c l i n i c a l ly indicated

P T / P T T — — B a s e l i n e,then eve ry 6 months or as clinically indicated

T hy roid function tests B a s e l i n e, then eve ry B a s e l i n e, then —( T 3 ,T 4 ,T S H ,F T I ) 12 months eve ry 12 months

*Women taking a mood stabilizing agent should be given a pregnancy test at baseline and then as clinically indicated.

†Although carbamazepine is not approved by the FDA for psychiatric indications, the authors view it as one of the most important agents availablefor the treatment of bipolar disorder. This view is supported in the medical literature.

‡Carbamazepine may decrease the efficacy of oral contraceptives through enzyme induction.

ECG=electrocardiogram; PT/PTT=prthrombin time; TSH=thyroid stimulaing hormone; FTI=free thyroid index; FDA=Food and Drug Administration.


Ta ble 10: BENZODIAZEPINE A N X I O LY T I C S*10,11,44

A n x i o ly t i c s / H y p n o t i c sA p p roved Oral Adult A p p rox i m a t e Pe a k H a l f - l i feDosage E q u i v a l e n t H a l f - l i fe P l a s m a for Major P regnancy R a n g e D o s a g e s of Pare n t L eve l A c t i ve Metabolic R i s k( m g / d ay ) ( m g / d ay ) Drug (hrs) tmax ( h r s ) M e t a b o l i t e s ( h r s ) P a t h w ay C a t e go ry

A l p r a z o l a m† , ‡ G e n e r a l : 0.5 6.3–26.9 1–2 N o n e O x i d a t i o n D( X a n a x ) 0 . 7 5 – 4 . 0

P a n i cd i s o rd e r:

1 – 1 0C h l o rd i a z e p ox i d e† ,l l 1 5 – 1 0 0 10 24–48 S everal D e s m e t hy l - N - d e a l k y - D( L i b r i u m , L i b r i t a b s , h o u r s c h l o rd i a z e p oxide l a t i o n (not FDAM i t r a n ) ( 1 8 ) s p e c i f i e d )

D e m oxepam (14–95)D e s m e t hy l d i a z e p a m( 3 0 – 2 0 0 )Oxazepam (3–21)

C l o n a z e p a m† , ‡ 1.5–20 0.25 18–50 1–2 N o n e R e d u c t i o n , D ( K l o n o p i n ) hy d rox y l a t i o n , (not FDA

ox i d a t i o n specified) C l o r a z e p a t e† ,l l 15–60 7.5 P ro d r u g 1–2 Oxazepam (3–21) O x i d a t i o n , D ( C l o r a z e C ap s , D e s m e t hy l d i a z e p a m hy d rox y - (not FDAC l o r a z e Ta b s , ( 3 0 – 2 0 0 ) l a t i o n , specified) G e n - X E N E , c o n j u g a t i o nTr a n xe n e )D i a z e p a m† 4 – 4 0 5 2 0 – 8 0 0 . 5 – 2 D e s m e t hy l d i a z e p a m O x i d a t i o n , D ( Va l i u m , ( 3 0 – 2 0 0 ) hy d rox y - (not FDA Va l re l e a s e, 3 - H y d roxydiazepam l a t i o n , s p e c i f i e d )Z e t r a n ) ( 5 – 2 0 ) d e m e t hy l -

Oxazepam (3–21) a t i o nH a l a z e p a m† 2 0 – 1 6 0 2 0 1 4 1 – 3 D e s m e t hy l - O x i d a t i o n D( P a x i p a m ) diazepam (30–200)L o r a z e p a m† 1 – 1 0 1 12 2 N o n e C o n j u g a t i o n D( A t i v a n )O x a z e p a m† 3 0 – 1 2 0 15 5.7–10.9 3 N o n e C o n j u g a t i o n D (not FDA ( S e r a x ) s p e c i f i e d )P r a z e p a m† 2 0 – 6 0 1 0 P ro d r u g 6 — O x i d a t i o n D (not FDA( C e n t r a x ) s p e c i f i e d )*Ad verse events commonly seen with the benzo d i a zepines include d rowsiness, ataxia, confusion, fatigue, anterograde amnesia, light-headedness, and dizziness.

†Single doses provide sedation and calming; chronic dosing reduces symptoms of generalized anxiety disorder.

‡C l o n a zepam and alprazolam are FDA approved for PD.

l l For alcohol detoxification and withdrawal, doses of up to 300 mg of chlordiazepoxide and 90 mg of clorazepate may be warranted.

D=relatively contraindicated; F D A = Food and Drug Administration; PD=panic disord e r.


Ta ble 11: NONBENZODIAZEPINE A N X I O LY T I C S4 5 - 4 7

D r u g Brand Name Dosage (mg) I n d i c a t i o n sB u s p i ro n e * B u S p a r 5–20 mg T I D GAD

or 15–30 mg BID

H y d rox y z i n e† V i s t a r i l , A t a r a x 50–100 mg QD A n x i e t y, t e n s i o n* Adverse events commonly seen with buspirone include dizziness, nausea, GAD=generalized anxiety disorder.

headache, nervousness, lightheadedness, and excitement. † Second-agent

D r u g I n t e r a c t i o n M e c h a n i s mA n t a c i d s � absorption and benzodiazepine leve l s � gastric pHC a r b a m a z e p i n e � benzodiazepine leve l s CYP inductionC i m e t i d i n e � benzodiazepine leve l s CYP inhibitionD i gox i n � d i goxin leve l s U n k n ow nE ry t h ro my c i n � alprazolam leve l s 3A4 inhibitionE t h a n o l � s e d a t i o n / re s p i r a t o ry depre s s i o n CNS depression synergismN e f a z o d o n e � a l p r a z o l a m , triazolam leve l s 3A4 inhibitionO p i o i d s � s e d a t i o n , re s p i r a t o ry depre s s i o n CNS add i t i veS S R I s � d i a z e p a m , alprazolam leve l s 2D6 and 3A4 inhibitionVa l p roic acid � benzodiazepine leve l s � metabolism � =decreased; CYP=cytochrome P450; � =increased; CNS=central nervous system; SSRIs=selective serotonin reuptake inhibitors.

Ta ble 12: BENZODIAZEPINE DRUG INTERAC T I O N S3 1 , 3 2

Ta ble 13: H Y P N OTIC AG E N T S1 0 - 1 3

Pharmacokinetic Parameters D a i ly Adult Dosage Time to Peak M e t a b o l i c A c t i ve P rotein

( m g / d ay ) Plasma Level t1 / 2 ( h o u r s ) P a t h w ay M e t a b o l i t e s Binding (%)B e n z o d i a z e p i n e s ( h o u r s )A m o b a r b i t a l* 65–200 T I D 1 1 6 – 4 0 Hepatic N o n e I n c reases with ( A my t a l ) g l u c u ro n i d a t i o n lipid solubilityE s t a z o l a m 0 . 5 – 2 0 . 5 – 6 1 0 – 2 4 O x i d a t i o n N o n e 9 3( P ro S o m )F l u r a z e p a m 15–30 0 . 5 – 1 2 . 3 O x i d a t i o n , N - d e s a l k y l f l u r a z e p a m , 9 7( D a l m a n e ) 4 . 7 – 1 0 0† 3 6 – 1 2 0† N - d e a l k y l a t i o n hy d rox ye t hy l f l u r a z e p a m ,

flurazepam aldehy d eQ u a z e p a m 7.5–15 2 3 9 O x i d a t i o n N - d e s a l k y l f l u r a z e p a m , > 9 5( D o r a l ) 7 3† 3 6 – 1 2 0† 2 - ox o q u a z e p a mTe m a z e p a m 7 . 5 – 3 0 1 . 2 – 1 . 6 3 . 5 – 1 8 . 4 C o n j u g a t i o n N o n e 9 6( R e s t o r i l )Tr i a z o l a m 0.125–0.5 2 1 . 5 – 5 . 5 C o n j u g a t i o n N o n e 8 9( H a l c i o n )N o n b e n z o d i a z e p i n e s

Chloral hy d r a t e 5 0 0 – 2 , 0 0 0 0 . 5 – 1 2† 8 – 1 1† O x i d a t i o n , Tr i c h l o ro e t h a n o l 3 5 – 4 1†( N o c t e c, Aquachloral Suppre t t e s ) re d u c t i o nZ a l e p l o n 5 – 2 0 1 1 O x i d a t i o n 5 - ox o - z a l e p l o n 9 2( S o n a t a )Z o l p i d e m 5–10 1 . 6 2 . 6 O x i d a t i o n , N o n e 9 2 . 5( A m b i e n ) 1 . 4 – 4 . 5 hy d rox y l a t i o n*Quitken FM. Current Psychotherapeutic Drugs. 2nd ed. Washington, DC: American Psychiatric Press; 1998.†Values given for active metabolite.


D o s a g e * Usual Maximum Usual DosageR a n g e Dosage for for Patients

Tr a d i t i o n a l ( m g / d ay ) Organic Mental >65 Years of C l a s s E q u i v a l e n t s P O S y n d rome (mg/day ) Age (mg/day ) *

C h l o r p ro m a z i n e† Aliphatic 1 0 0 3 0 – 8 0 0 4 0 0 4 0 0(O r m a z i n e,T h o r a z i n e ) p h e n o t h i a z i n eThioridazine Piperidine 1 0 0 2 0 – 8 0 0 2 0 0 2 0 0( M e l l a r i l ) p h e n o t h i a z i n eMesoridazine P i p e r i d i n e 5 0 3 0 – 4 0 0 — —( S e re n t i l ) p h e n o t h i a z i n eF l u p h e n a z i n e P i p e r a z i n e 2 1 – 4 0 1 0 1 0( Pe r m i t i l , P ro l i x i n ) p h e n o t h i a z i n ePe r p h e n a z i n e P i p e r a z i n e 8 1 2 – 6 4 1 6 1 6( Tr i l a fo n ) p h e n o t h i a z i n eTrifluoperazine P i p e r a z i n e 5 2 – 4 0 2 0 2 0( S t e l a z i n e ) p h e n o t h i a z i n eT h i o t h i xene ( N av a n e ) T h i ox a n t h e n e 4 6 – 6 0 1 5 1 5Haloperidol ( H a l d o l ) B u t y ro p h e n o n e 2 1 – 1 0 0 1 5 1 5L ox apine ( L ox i t a n e ) D i b e n z ox a z e p i n e 1 0 2 0 – 2 5 0 6 0 6 0Molindone ( M o b a n ) D i hy d ro i n d o l o n e 1 0 1 5 – 2 2 5 5 5 5 5Pimozide ( O r ap ) P i p e r i d i n e — 1 – 1 0 — —D ro p e r i d o l ( I n ap s i n e ) B u t y ro p h e n o n e — 2 . 5 – 1 5 — —

A d verse Effe c t s‡ A d verse Effe c t s‡

E x t r apy r a m i d a l S e d a t i o n A n t i c h o l i n e r g i c O rthostatic HypotensionC h l o r p ro m a z i n e + + + + + + + + + + +T h i o r i d a z i n e + + + + + + + + + + +Mesoridazine + + + + + + + + + +F l u p h e n a z i n e + + + + + + + + + +Pe r p h e n a z i n e + + + + + + + + +Tr i f l u o p e r a z i n e + + + + + + + + +T h i o t h i xe n e + + + + + + + + +H a l o p e r i d o l + + + + + + +L ox ap i n e + + + + + + + + +Molindone + + + + + + + + +P i m o z i d e + + + + + +D ro p e r i d o l + + + + + + + + + +* In elderly patients, doses should be lowered and tailored to the patient.† Labeling suggests higher doses may be appropriate, noting intramuscular

doses up to 2,000 mg (using >1,000 mg only in severe cases).‡ Severity: ++++=extremely high; +++=high; ++=moderate; +=low.

A n t i p s y c h o t i c sTa ble 14: T Y P I CAL A N T I P S Y C H OTIC DOSAG E S

AND A DVERSE EFFECTS1 0 , 1 1 , 1 4


*In elderly patients, doses should be lowered and tailored to the patient. †Severity: ++++=extremely high; +++=high; ++=moderate; +=low; 0=none.‡Tolerance develops; slow dose titration is necessary. §Dose-dependent extrapyramidal effects.N/A=not available.

Usual Maximum Usual Dosage for Patients Tr a d i t i o n a l Dosage* Range (mg/day ) Dosage for Organic Mental >65 Years ofE q u i v a l e n t s P O S y n d rome (mg/day ) Age (mg/day ) *

C l o z apine (Clozaril) 5 0 1 2 . 5 – 9 0 0 2 0 0 3 0 0Risperidone (Risperd a l ) N / A 2 – 1 6 2 0.5 to startO l a n z apine (Zypre x a ) N / A 5 – 2 0 — 5 to startQ u e t i apine (Sero q u e l ) N / A 5 0 – 7 5 0 — S l ower rate of dose titration,

l ower target doseZiprasidone (Geodon) N / A 4 0 – 1 6 0 U n k n ow n S l ow rate of dose titration,

l ower target dose

A d verse Effe c t s† A d verse Effe c t s†

E x t r apy r a m i d a l S e d a t i o n Weight Gain A n t i c h o l i n e r g i c O rthostatic Hypotension

C l o z ap i n e 0 + + + + + + + + + + + + + + +‡

Risperidone 0 / + + +§ + + + + + +‡

O l a n z ap i n e 0 / + + + + + + + + +Q u e t i apine 0 / + + + / + + + + + + + + +Z i p r a s i d o n e + + + + + / 0 + + +

Ta ble 15: AT Y P I CAL A N T I P S Y C H OTIC DOSAG E SAND A DVERSE EFFECTS1 7 , 4 8 - 5 1

Ta ble 16: P H A R M ACOKINETIC PARAMETERS AND DOSING OF DEPOT A N T I P S Y C H OT I C S *5 2 , 5 3

t1/2 t1/2 Time to S t a rting Maintenance tm a x Single Dose Multiple Dose Steady State

D r u g D o s a g e D o s a g e ( d ay s ) ( d ays) ( d ay s ) ( we e k s )H a l o p e r i d o l 20 x oral haloperidol 10–15 x oral haloperidol 4 – 1 1 2 1 2 1 1 2d e c a n o a t e 100–450 mg/28 day s 50–300 mg/28 day sF l u p h e n a z i n e 1.2 x oral fluphenazine Based on starting dose 0 . 3 – 2 6 – 1 0 1 4 4 – 8d e c a n o a t e 12.5–75 mg/7–14 day s and clinical re s p o n s eF l u p h e n a z i n e 12.5–100 mg/7–21 day s Based on starting dose 2 – 3 3 . 5 – 4 N / A 3e n a n t h a t e and clinical re s p o n s e*Patients maintained for 1 year or longer demonstrated a very long time to wash out drug (terminal observed half-life exceeding 60 days).

N/A=not available.


Ta ble 17: A N T I PARKINSONIAN AG E N T S1 2 , 5 4 - 5 6

Ta ble 18: A N T I P S Y C H OTIC DRUG INTERAC T I O N S3 1 , 4 9

Interacting Medication M e c h a n i s m Clinical Effe c tDrug interactions assessed to have major seve r i t yA n t i c h o l i n e r g i c s Pharmacodynamic effe c t s D e c reased antipsychotic effe c t

A dd i t i ve anticholinergic effe c tB a r b i t u r a t e s Phenobarbital induces antipsychotic D e c reased antipsychotic

metabolism c o n c e n t r a t i o n sB e t a - b l o c ke r s Synergistic pharmacologic effe ct; S eve re hy p o t e n s i o n

antipsychotic inhibits metabolism of pro p r a n o l o l ; antipsychotic i n c reases plasma concentrations

C a r b a m a z e p i n e Induces antipsychotic metabolism Up to 50% reduction in antipsychotic concentrationsC h a rc o a l Reduces GI absorption of antipsychotic M ay reduce antipsychotic effect or cause toxicity when used

and absorbs drug during entero h e p a t i c during ove rdose or for GI disturbancesc i rc u l a t i o n

C i g a rette smoking Induction of microsomal enzymes Reduced plasma concentrations of antipsychotic agentsE p i n e p h r i n e, Antipsychotic antagonizes pressor effect H y p o t e n s i o nn o re p i n e p h r i n eE t h a n o l A dd i t i ve CNS depre s s i o n I m p a i red psychomotor skillsF l u vox a m i n e F l u voxamine inhibits metabolism I n c reased concentrations of

of haloperidol and clozap i n e haloperidol and clozap i n eG u a n e t h i d i n e Antipsychotic antagonizes I m p a i red antihy p e rt e n s i ve effect

guanethidine neuronal uptakeL i t h i u m U n k n ow n R a re re p o rts of neuro t ox i c i t yM e p e r i d i n e A dd i t i ve CNS depre s s i o n Hypotension and sedationGI=gastrointestinal; CNS=central nervous system.


A p p roximate Dose D r u g Equivalent (mg) Dosage Range (mg/day ) Dose Fo r m sA n t i mu s c a r i n i c s

B e n z t ropine (Cogentin) 1 1 – 8 T, IBiperiden (Akineton) 2 2 – 8 T, IE t h o p ropazine (Parsidol) 5 0 5 0 – 6 0 0 TOrphenadrine (Va r i o u s ) 5 0 5 0 – 2 5 0 TP rocyclidine (Ke m a d r i n ) 2 7 . 5 – 2 0 TTrihexyphenidyl (Art a n e ) 2 2 – 1 5 T,C - S R , L

A n t i h i s t a m i n i cD i p h e n hydramine (Va r i o u s ) 5 0 5 0 – 4 0 0 C,T, L , I

Dopamine A go n i s t sAmantadine (Symadine,S y m m e t re l ) N / A 1 0 0 – 4 0 0 C,LR o p i n i role (Requip) N / A 0 . 7 5 – 2 4 * TPramipexole (Mirap e x ) N / A 1 . 5 – 4 . 5 * T

*Maintenance dose for Parkinson’s disease.T=tablet; I=injection; C=capsule; SR=sustained release; L=liquid solution, elixir, or suspension; N/A=not available.

Interacting Medication M e c h a n i s m Clinical Effe c tDrug interactions assessed to have minor or moderate seve r i t yA m p h e t a m i n e s , D e c rease pharmacologic effect of Diminished weight-loss effe ct;a n o re x i a n t s a m p h e t a m i n e ; drug-disease state amphetamines may exacerbate psychosis;

i n t e r a c t i o n t re a t m e n t - re f r a c t o ry patients may improveACE inhibitors A dd i t i ve hy p o t e n s i ve effe c t H y p o t e n s i o n ,postural intolerance Antacids containing Insoluble complex in GI tract fo r m e d Possible reduced antipsychotic effe c ta l u m i nu mA n t i d e p ressants D e c reases metabolism of antidepressant I n c reased antidepressant concentration( a n t i d e p re s s a n t ,n o n s p e c i f i c ) t h rough competitive inhibitionB e n z o d i a z e p i n e s I n c reases pharmacologic effect of R e s p i r a t o ry depre s s i o n ,s t u p o r,hy p o t e n s i o n

b e n z o d i a z e p i n eB ro m o c r i p t i n e Antipsychotic antagonizes dopamine I n c reased pro l a c t i n

receptor stimu l a t i o nC a f feinated Form precipitate with antipsychotic Possible diminished antipsychotic effe c tb eve r a g e s s o l u t i o n sC i m e t i d i n e Reduces antipsychotic absorption I n c reased or decreased antipsychotic effect

and inhibits clearanceC l o n i d i n e Antipsychotic potentiates H y p o t e n s i o n

α- 2 - a d renergic hy p o t e n s i ve effe c tD i s u l f i r a m Impairs antipsychotic metabolism I n c reased antipsychotic concentrationsM e t hy l d o p a U n k n ow n Blood pre s s u re elev a t i o n sP h e ny t o i n Induction of antipsychotic metabolism; D e c reased antipsychotic concentrations;

i n c reases phenytoin metabolism d e c reased phenytoin leve l sS S R I s Impair antipsychotic metabolism; S u dden onset of extrapyramidal symptoms

pharmacodynamic interactionVa l p roic acid Antipsychotic inhibits valproic I n c reased valproic acid half-life and leve l s

acid metabolismACE=angiotensin-converting enzyme; GI=gastrointestinal; SSRIs=selectiveserotonin reuptake inhibitors.

Ta ble 19: ACUTE NEUROLOGIC SIDE EFFECTS OF A N T I P S Y C H OTIC MEDICAT I O N S4 9 , 5 6 , 5 7

A p p rox i m a t eR e a c t i o n Clinical Fe a t u re s Onset Tre a t m e n tAcute dystonia Spasm of tongue, t h ro a t , <1 we e k Injectable benztropine or diphenhy d r a m i n e,

f a c e,j aw,eye s , n e c k , or fo l l owed by oral anticholinergics orback mu s c l e s b e n z o d i a z e p i n e s

A k a t h i s i a Motor re s t l e s s n e s s , <1 we e k – If possible,reduce dose of antipsychotic;inability to stay still 2 we e k s a dd beta-blocke r s ,b e n z o d i a z e p i n e s ,

or anticholinergicsP s e u d o p a r k i n s o n i s m B r a d y k i n e s i a , r i g i d i t y, resting ~1 we e k A dd anticholinergics or

t re m o r, rabbit syndro m e, a m a n t a d i n e ;s i a l o rr h e a , flat affe c t d i p h e n hydramine and

lorazepam may also be effe c t i ve


Ta ble 18: AN T I P S Y C H OTIC DRUG INTERAC T I O N S ( C O N T ’ D )3 1 , 4 9 , 5 6

Ta ble 20: P H A R M ACOKINETIC PARAMETERS OF SELECTED ORAL A N T I P S Y C H OT I C S1 0 , 1 1 , 4 9 , 5 4 , 5 7 , 5 8

T h e r apeutic P ro t e i n Plasma B i n d i n g V d Plasma t1/2 A c t i ve C o n c e n t r a t i o n

B i o availability (%) ( % ) ( L / k g )* ( h o u r s ) M e t a b o l i t e s ( n g / m L )

C h l o r p ro m a z i n e 1 0 – 3 3 9 0 – 9 5 7 – 2 0 8 – 3 5 7 - hy d rox y 1 0 0 – 3 0 0†C l o z ap i n e — 9 5 4 – 6 6 4 – 6 6 D e s m e t hy l � 3 5 0H a l o p e r i d o l 4 0 – 7 0 9 2 1 0 – 3 5 1 2 – 3 6 R e d u c e d 3 . 0 – 3 0

h a l o p e r i d o l 5 – 1 2‡F l u p h e n a z i n e 1 0 – 5 0 9 0 – 9 5 — 1 4 – 2 4 H y d rox y 0 . 2 – 3

O l a n z ap i n e ˜6 0 9 3 1 0 – 2 0 2 1 – 5 4 — 9 – 2 0†Pe r p h e n a z i n e 2 5 — 1 0 – 3 5 8 – 2 1 None know n —Q u e t i ap i n e 1 0 0 8 3 6 – 1 4 ˜6 7 - hy d rox y —

7 - hy d rox y - N - d e a l k y l a t e dR i s p e r i d o n e 7 0 9 0 — 3 – 2 0 9 - hy d rox y —

T h i o r i d a z i n e 2 5 – 3 3 9 9 — 9 – 3 0 M e s o r i d a z i n e, 2 0 0 – 8 0 0†s u l p h o r i d a z i n e

T h i o t h i xe n e 5 0 9 0 – 9 5 — 3 4 None know n 1.0–5.0 * ,§10–30 * , * *

*Range given includes mean +/- standard deviation.†Data inconclusive regarding therapeutic range for these drugs.‡Optimal concentration for response not emcompassing neuroleptic threshold (3–5 ng/mL). §Trough concentration, predose.**Peak concentration 2–3 hours postdose.


S y m p t o m D o n e p e z i l G a l a n t a m i n e R i v a s t i g m i n e Ta c r i n eG IN a u s e a , + + + + + + + + + +vo m i t i n gWe i g h t + + ++ +l o s s (dose dependent)LFTs rise - - - + + +S y m p t o m D o n e p e z i l G a l a n t a m i n e R i v a s t i g m i n e Ta c r i n eC N SI n s o m n i a + / - + + / - +F a t i g u e + / - + + / - + / -D e p re s s i o n + / - + + / - + / -

S y m p t o m D o n e p e z i l G a l a n t a m i n e R i v a s t i g m i n e Ta c r i n eM i s c e l l a n e o u sS y n c o p e + / - + + + / -I n c reased + / - + + / - + / -u r i n a t i o nR h i n i t i s + / - + - -

A n o rex i a n t s / Cholinesterase P s y c h o s t i mu l a n t s I n h i b i t o r sTa ble 21: A N O R E X I A N T S5 9 - 6 1

Peak E l i m i n a t i o n Steady P rotein D r u g Dosage Plasma H a l f - l i fe State B i n d i n g M e t a b o l i s mDonepezil (Aricept) 5–10 mg/day 3–4 hours 70 hours 15 day s 9 6 % 2 D 6 , 3 A 3 / 4Galantamine (Reminy l ) 16–32 mg/day 1 hour 7 hours – 1 8 % 2 D 6 , 3 A 4Rivastigmine (Exe l o n ) 6–12 mg/day 1.4–2.6 hours 1.5–3 hours 24–48 day s 4 0 % Not CYP

d e p e n d e n tTacrine (Cognex) 40–160 mg/day 1–2 hours 2–4 hours 24–36 hours 5 5 % 1 A 2CYP=cytochrome P450.

A g e n t Dosage Range (mg/day ) I n d i c a t i o nAmphetamine (Biphetamine) 5 – 4 0 O b e s i t yMazindol (Mazanor, S a n o re x ) 1 – 3 O b e s i t yMethamphetamine (Desox y n ) 1 0 – 1 5 O b e s i t yOrlistat (Xenical) 120 TID with meals O b e s i t yPhendimetrazine (various) 7 0 – 1 0 5 O b e s i t yPhentermine (Adipex-P, v a r i o u s ) 1 8 . 7 5 – 3 7 . 5 O b e s i t ySibutramine (Meridia) 1 0 – 1 5 O b e s i t y

A g e n t Dosage Range (mg/day ) I n d i c a t i o nD e x t roamphetamine (Dexe d r i n e ) 5 – 4 0 A D H D

5 – 6 0 N a rc o l e p s yD e x t roamphetamine + amphetamine (Add e r a l l ) 5 – 4 0 A D H D

5 – 6 0 N a rc o l e p s yMethamphetamine (Desox y n ) 5 – 2 5* A D H DM e t hylphenidate (Ritalin) 1 0 – 4 0 A D H D

1 0 – 6 0 N a rc o l e p s yM e t hylphenidate HCI (Concert a ) 1 8 – 5 4 A D H DModafinil (Prov i g i l ) 2 0 0 – 4 0 0 N a rc o l e p s y, idiopathic

hy p e r s o m n i aPemoline (Cylert ) 3 7 . 5 – 1 1 2 . 5 A D H DADHD=attention-deficit/hyperactivity disorder. *20–25 mg is effective dosage range; can be titrated up from 5 mg.

Ta ble 22: P S Y C H O S T I M U L A N T S1 0 - 1 3 , 4 8 , 6 2

Ta ble 23: D RUGS FOR ALZHEIMER’S DISEASE9 , 1 0 , 6 3 - 6 7

(Cholinesterase Inhibitors)

Ta ble 24: A DVERSE EFFECTS OF CHOLINESTERASE INHIBITO R S7 , 9 , 6 3 - 6 6 , 6 8 , 6 9

++++=high; +++=moderate; ++=low; +=very low; -=none.GI=gastrointestinal; LFTs=liver function tests; CNS=central nervoussystem.


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