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73Primary Psychiatry

The Use of Psychotropic Drugs in Patients with Impaired Renal FunctionRoger S. McIntyre, RS, MD, FRCPC, Nour T. Baghdady, Suman Banik, and Shari A. Swartz

ABSTRACTThis article provides a pragmatic and clinically accessible approach

to the selection and dosing of psychotropics for individuals with

suboptimal renal function (SRF). The authors conducted a PubMed

search of all English-language articles published between 1977

and 2007. The key search terms selected were “renal,” “kidney,”

“renal failure,” “kidney failure,” “pharmacokinetics,” “renal

impairment,” and “renal insufficiency.” Each term was cross-

referenced with the non-proprietary names of constituent antide-

pressants, antipsychotics, lithium, anticonvulsants, anxiolytics,

hypnotics, and psychostimulants. Article reference lists were also

reviewed. Due to heterogeneity in manuscript quality and scientific

methodology as well as a dearth of available adequately powered

controlled studies, an inclusive approach was taken. SRF is asso-

ciated with clinically significant alterations in all dimensions of

pharmacokinetics. Taken together, SRF predictably affects renal

excretion of psychotropic agents with more variable effects on

absorption, distribution, and metabolism. The adjudication of the

safe and effective dose for any psychotropic needs to be individu-

alized for each such agent. Strong pronouncements regarding con-

traindication of use for any psychotropic extends beyond available

data. Nevertheless, psychotropics that depend on normal kidney

function for disposal require dosing alteration and in many cases

should be avoided. Specific tactics and strategies regarding the

use of psychotropics in this patient population are provided.

Needs Assessment: This article facilitates knowledge as it relates to the safe and judi-cious use of psychotropics in individuals with deteriorating kidney function. Also provided are tactics and strategies to the selection, sequencing, and dosing of psychotropics across disparate patient populations which share in common kidney failure.

Learning Objectives:• Describe the effect of renal failure on psychotropic pharmacokenetics.• Describe the effect of psychotropic drugs on kidney function in indivduals with renal failure.• Discuss tactics and strategies for prescribing psychotropic drugs in renal failure.Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the plan-ning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclo-sure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 5, 2007.

Dr. Hollander reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Sussman is a consultant to and on the advisory boards of GlaxoSmithKline and Wyeth; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth.

To receive credit for this activity: Read this article and the two CME-des-ignated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation found on page 96. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by January 1, 2010 to be eligible for credit. Release date: Jaunary 1, 2008. Termination date: January 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

CLINICAL FOCUSPrimary Psychiatry. 2008;15(1):73-88

3CME

January 2008

Dr. McIntyre is associate professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit at the University Health Network at the University of Toronto in Ontario, Canada. Ms. Baghdady is a PharmD candidate at King Abdul-Aziz University in Jeddah, Saudi Arabia. Mr. Banik is a medical student at the Royal College of Surgeons in Ireland in Dublin. Ms. Swartz is a medical student at the University of Ottawa in Ontario, Canada.

Disclosure: Dr. McIntyre is on the advisory boards of AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly, the France Foundation, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Pfizer, Shire, and Solvay/Wyeth; is on the speaker’s bureaus of AstraZeneca, Biovail, Eli Lilly, Janssen-Ortho, and Lundbeck; receives grant support from Eli Lilly, the National Alliance for Research on Schizophrenia and Depression, and Stanley Medical Research Institute; and receives honoraria from AstraZeneca, Bristol-Myers Squibb, the France Foundation, i3CME, Physician’s Postgraduate Press, and Solvay/Wyeth. Ms. Baghdady, Mr. Banik, and Ms. Swartz report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Roger S. McIntyre, RS, MD, FRCPC, Head, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8; Tel: 416-603-5279; Fax: 416-603-5368; E-mail: [email protected].

R.S. McIntyre, N.T. Baghdady, S. Banik, S.A. Swartz

74Primary Psychiatry January 2008

INTRODUCTIONSeveral definitions and operational criteria have been pro-

posed for renal disease. There are two commonly employed definitions. First, the British National Formulary has divided suboptimal renal function (SRF) into three subcategories based on glomerular filtration rate (GFR), including mild (20–50 mL/minute), moderate (10–20 mL/minute), and severe (0–10 mL/minute).1 Second, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) divided SRF into five groups, three of which were defined solely on the basis of diminished GFR; these groups include moderate (30–59 mL/minute/1.73 m2), severe (15–29 mL/minute/1.73 m2), and kidney failure (<15 mL/minute/1.73 m2; Table 1).2

Clinical studies indicate that individuals with renal disease are differentially affected by mental disorders.3 The co-occur-rence of mental and renal disorders invites the need for famil-iarity with the safety, pharmacokinetic profile, and efficacy of psychotropics in individuals with SRF. Hitherto, the eviden-tiary base which informs the selection, dosing, monitoring, and sequencing of psychotropics in SRF is woefully inadequate.

This article provides a clinically accessible and pragmatic review of the effect of SRF on the handling of psychotropics. The article also includes responses to commonly encountered clinical scenarios.

THE EFFECT OF SUBOPTIMAL RENAL FUNCTION ON PHARMACOKINETICS

The term “pharmacokinetics” refers to the physiologic handling of pharmacologic agents and has been convention-ally categorized into absorption (ie, bioavailability), distribu-tion, metabolism, and excretion of the parent drug and its respective metabolites.4 Patients with renal failure may evince

alterations in any of these pharmacokinetic parameters.5 Consequently, the risk for treatment-emergent adverse events is significantly increased (Table 2).6

BioavailabilityBioavailability denotes the extent to which a dose of drug

enters the systemic circulation. An oral dose is first absorbed from the gastrointestinal tract subsequently passing through the liver wherein metabolism and biliary excretion may occur.4,7 In SRF, a decrease in bioavailability for some agents occurs at the level of drug absorption from the gastrointesti-nal tract. It is hypothesized that gastric alkalinity, resulting from uremia (due to excessive urea generation by the internal urea-ammonia cycle), and changes in gastrin levels mediate the decreased absorption.4,6,8 The concurrent use of alumin-ium- or calcium-containing antacids, commonly prescribed

TABLE 2

PHARMACOKINETICS IN RENAL FAILUREAbsorption:

• Decreased absorption due to: – Gastric alkalinity due to uremia – Chelation due to concurrent use of medication (eg, antacids) – Changes in gastrin level – Nausea and vomiting – Delayed gastric emptying due to gastroparesis – Altered drug partitioning due to bowel edema and vitamin D deficiency

Bioavailability:

• Decreased due to decreased absorption. • Increased due to decreased intestinal elimination as a result of: – Decreased intestinal CYP – Decreased in drug extrusion by Pgp and MDR2

Distribution:

1. Volume of distribution: • Increased in edema leading to drug dilution • Decreased in muscle wasting, cachexia, and dehydration, leading to drug

concentration

2. Decreased protein binding due to: • Hypoalbuminemia • Altered albumin conformation • Competitive inhibition of plasma proteins by retained endogenous-bind-

ing inhibitor

Elimination:

1. Metabolism • Decreased kidney metabolic activity • Altered hepatic metabolic activity (increased, decreased, or unchanged)

2. Excretion • Most psychotropic drugs are excreted through the bile and are not dialyzable

CYP=cytochrome P450; Pgp=P-glycoprotein; MDR2=multi-drug resistance-related pro-tein type 2.

McIntyre RS, Baghdady NT, Banik S, Swartz SA. Primary Psychiatry. Vol 15, No 1. 2008.

TABLE 1

STAGES OF SUBOPTIMAL RENAL FUNCTION2

Stage DescriptionGFR

(mL/minute/1.73 m2)

1. Kidney damage with normal or ↑ GFR ≥90

2. Kidney damage with mild ↓ GFR 60–89

3. Moderate ↓ GFR 30–59

4. Severe ↓ GFR 15–29

5. Kidney failure <15 (or dialysis)

Suboptimal renal function is defined as either kidney damage or GFR <60 mL/minute/1.73 m2 for ≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage including abnormalities in blood or urine tests or imaging studies.GFR=glomerular filtration rate.


The Use of Psychotropic Drugs in Patients with Impaired Renal Function


in renal failure, may form non-absorbable complexes with psychotropic drugs that hinder their absorption.4,8

Rival mechanisms affecting absorption in individuals with renal failure relate to nausea and vomiting as well as increased gastric emptying time (ie, due to gastroparesis).5,9 Vitamin D deficiency and bowel edema may result in altered drug parti-tioning across the gastrointestinal tract membrane with a con-sequent decrease in the overall amount of drug absorbed.6

Alternatively, SRF (ie, uremia) may be associated with an increase in drug bioavailability. A hypothesized mechanism involves reduced functional capacity of gut cytochrome P450 (CYP) enzymes, and decreased expression and function of the two main efflux protein transporters, P-glycoprotein (Pgp) and multi-drug resistance-related protein type 2 (MDR2).9,10

DistributionFollowing absorption, a drug is distributed across body

fluids, tissues, and compartments. The two overarching fac-tors influencing distribution are the volume of distribution and protein binding. Changes in these factors would be predicted to alter distribution of any drug administered.

Mechanisms mediating altered volume of distribution in states of SRF are edema, which is related to hypoalbumin-emia and consequent fluid retention, and muscle wasting. Edema alters the apparent volume of distribution of drugs, particularly those of high hydrophilicity, by expanding the extracellular fluid volume. This effect is predicted to result in dilution of the drug and hypothetically requiring an increase in dose. Alternatively, muscle wasting, dehydration, and cachexia, all of which are commonly encountered in SRF, are predicted to decrease the apparent volume of distribution, possibly inviting the need for dose reduction.

The importance of fully understanding the effect of renal failure on protein binding is underscored by the fact that most psychotropics are highly protein bound.4 The principle plasma protein responsible for binding to acidic drugs is albumin, while α1-acid glycoprotein is the primary binding protein for alkaline drugs.11 Renal failure is characterized by proteinuria and hypo-albuminemia with the consequent accumulation of endogenous binding inhibitors (eg, organic acids and uremic toxins).6 Binding inhibitors compete with drugs for the carrier protein-binding site. Moreover, in states of SRF, albumin undergoes conformational changes with hypothesized changes in binding properties.5 Taken together, SRF results in diminished protein binding and an increase in the bioactive free fraction of acidic drugs in plasma.

Alternatively, for SRF patients undergoing renal transplant or hemodialysis, the circulating concentration of α1-acid glycoprotein may increase. As a result, there would be a dec-rement in the unbound circulating fraction and diminished biologic activity of the drug.12

Changes in total drug concentrations reflect both bound and unbound fractions. In most jurisdictions, laboratory evaluation

does not parse out and separately evaluate the unbound and biologically active fraction. In the context of SRF, evidence indicates that alterations in free fraction may be observed.11,13

Elimination

MetabolismAs the glomerular filtration rate (GFR) declines, the rate

of renal metabolism by the renal brush border is predicted to decrease.5 Along with these changes, emerging evidence indicates that metabolism by the liver is variably altered in SRF.6,14,15 For example, the expression and function of CYP 2C9 and CYP 3A4 were decreased in severe end-stage renal disease (ESRD).15 Preclinical studies have documented a 25% to 70% decrease in the metabolism of hepatically cleared agents in some individuals with SRF. Again, like other aspects of pharmacokinetics, an opposite effect may be observed, as some studies have documented a normal or increased activity of drug hepatic biotransformation proteins.6

Taken together, in conditions of SRF there is a decrease in hydrolysis and chemical reduction with no apparent effect on glucouridation, sulfate conjugation, and microsomal oxidation.4

ExcretionDrugs are excreted through the gastrointestinal tract by

three exclusive pathways, including inabsorption, active secretion into the gastrointestinal lumen, and excretion via the biliary system.

Renal drug excretion also involves three distinct mechanisms, including glomerular filtration, active tubular secretion, and passive tubular reabsorption.7 In renal failure, all three processes are differentially affected.6 Most psychotropics are metabolized by the liver and excreted through the bile; however, some are excreted unchanged from the kidney (eg, lithium) and others are converted to active metabolites that pass through the kidney.4,6,8

THE EFFECT OF SUBOPTIMAL RENAL FUNCTION ON PHARMACODYNAMICS

Several studies indicate that in states of SRF, the overall burden of treatment-emergent adverse events is increased. It is hypothesized that the mechanism mediating this obser-vation relates to increased translocation of drugs from the systemic circulation across the blood-brain barrier as well as accumulation of uremic toxins.11,16-18

PRESCRIBING PSYCHOTROPICS IN INDIVIDUALS WITH SUBOPTIMAL RENAL FUNCTION

Table 3 provides a guide to prescribing psychotropics in individuals with SRF.6,8,9,15,18-50



TABLE 3

PSYCHOTROPIC DRUG PHARMACOKINETICS FOR PATIENTS WITH RENAL FAILURE6,8,9,15,18-50

Agent Absorption Distribution Metabolism Excretion DDIs Dosage Half-life (h)Drug Dialyzability

Isocarboxazid (MAOI)

ND, C, HP, P

Phenelzine (MAOI) No dosage adjustment for SRF

ND, C, HP, P

Tranylcypromine (MAOI)

Not studied ND, C, HP, P

Moclobemide (RIMA)

Absolute oral bio-activity (healthy and SRF) 55% ↑ absorption time for SRF

Vd: 84 L (healthy and SRF) Protein binding: 50% (with ↓ SRF)

Active metabo-lites excreted via kidney (6%–10%)Primarily hepatic

<1% renal clearance Systemic clear-ance (40 L/h)

1.6 (healthy and SRF)

Selegiline (RIMA) AUC (ngxh/mL) ↑ 4 and 6X in SRF*: selegiline (2.81 vs 16.7) l-amphet-amine ↑ SRF (287 vs 413), l-methamphet-amine ↑ 2X (572 vs 957), desmeth-ylselegiline ↑ (101.5 vs 141.0; compared to con-trols)

Metabolites Desmethyl- selegiline, l-meth-amphetamine, l-amphetamine

↑ t½: Desmethyl- selegiline (5.1 vs 8.4) l-methamphet-amine (14.0 vs 28.2)* l-amphetamine (18.5 vs 41.9; compared to control group)

ND, C, HP, P

Bupropion (Misc.) AUC: hydroxybu-propion to bupro-pion ratio ↓ 66%; hydrobupropion to bupropion ratio ↓ 69%

Protein binding: 82%–88%

Metabolites (active): Hydroxy-bupropion, erthyrohydro-bupropion and threohydrobu-propion

No dosage adjustment for SRF

t½ ↑: Bupropion (34.2 vs 14)Hydroxybupro-pion (24 vs 34 [single dose], 38 [multiple dose])

ND, C, HP, P

Maprotiline (Misc.)

Metabolites: Desmethyl-maprotiline, maprotiline-N-oxide

Contradicting dosage recommenda-tions (SRF)

48–51 (healthy) No, CND, HPU, P

Reboxetine†

(Misc.)AUC (ngxh/mL): 4,140 (mild SRF), 4,462 (moder-ate SRF), 5,923 (severe SRF), 2,106 (healthy)*

Protein binding: 97% (healthy), 96% (mild SRF), 96% (moderate SRF), 96% (severe SRF)*

Mainly hepatic 10% renal clearance (drug unchanged)

8–10 mg/day (healthy), ↓ dose recom-mended 4 mg/day for SRF

13 (normal), 24 (mild SRF), 26 (severe SRF)*

Mirtazapine (Misc.)

Bioavailability: 50% (healthy)

Protein binding: 85%↑ free fraction plasma for SRF

Oral clearance: 50% ↓ for severe SRF, 33% ↓ for moderate SRF

Dose adjust-ment for SRF

t½ ↑ 39% for SRF (44.0 vs 31.6)

U, C, PND, HP

Nefazodone (Serotonin Agonist)


Protein binding: 99%

Primary metabolites: p-hydroxy-nefazo-done, m-CPP, hydroxynefazo-done, triazole-done

25 mg BID (healthy) No dosage adjustment for SRF

Moderate SRF and healthy t½ are the same

U, C, PND, HP

(Cont. on next page)



Trazodone (Triazolopyridine Antidepressant; Serotonin Agonist)

Absolute bioavailability: 80% (healthy)


Major metabo-lite: m-CPP

Parent drug t1/2 does not increase in hemodialysis patients

U, C, ND, HP, P

Duloxetine (SNRI) AUC: ↑ 2X (duloxetine), ↑ 7–9X (glucuronide metabolites) for SRF

Protein binding: >90%

25 metabolites (glucuronide conjugates)

70% excreted via urine, 20% excreted via faeces

Relative con-traindication (severe SRF); CrCl ≥30 mL/min no adjust-ment (40–60 mg/day)

8–17 (healthy) U, C, HP, P

Milnacipran (SNRI)†

Primarily renal 12 (healthy), ↑ 3X for SRF

Venlafaxine (SNRI)


Metabolites (active): N, O-desmethyl-venlafaxine

87% excreted via kidneys

37.5 mg QD (venlafaxine XR), 25 mg BID (venlafax-ine IR)75% dose (mild SRF), 50% dose (moderate/severe SRF)

4 (healthy), 6–11 (SRF)

No, CND, HPU, P

Tianeptine (SSRE)†

Bioavailability: 99% (healthy)AUC: ↑ for SRF (1.1 vs 0.5 mg/Lxh)

Vd: 0.5–0.8 L/Kg (healthy)

Major metabo-lite: pentanoic acid-MC5

<3% excreted unchanged in urine, 20% to 25% excreted via urine as conjugate0.2 L/h tianep-tine clearance, 1.1 L/h MC5 clearance

Salicyclic acidProtein binding ↓ in tianeptine dose if taken with salicyclic acid

12.5 mg TID (healthy)25 mg/day in 2, 12.5 mg/day in 2, 12.5 mg/day (SRF)

t½: ↑ for SRF (4.9 vs 14.2)

Citalopram (SSRI) High bioavail-ability with oral administration

Metabolite: didemethyl-citalopram, citalopram-N-oxide

20%–23% excreted via urineClearance ↓ by >40% (SRF)Clearance 1–53 (SRF) vs 66 mL/min (healthy)

20–60 Q24 (healthy) 10–60 mg/day (SRF)

35% ↑ (SRF) No, C, HPU, P

Escitalopram (SSRI)


Major metabolite: S-didemethyl-citalopram

10 mg/day (healthy and SRF)

t½: ↑ 35% (SRF), 27–32 (healthy), S-didemeth-ylcitalopram: 50–54 (healthy)

ND, C, HP, P

Fluoxetine (SSRI) AUC: ↑ SRF Protein binding: 95%

Major metabo-lite (active): Norfluoxetine

20 mg/day (healthy)No dose adjustment

1–4 days (healthy), 1.8 days (SRF)Norfluoxetine 7–15 days (healthy)

No, C, PND, HP

TABLE 3 (cont. from page 76)






Paroxetine (SSRI) Protein binding: 95%

10–30 mg/day (SRF)No dose adjustment for mild SRF, 50%–75% dose (moder-ate SRF), 50% dose (severe SRF)

17–25 (healthy) vs 11–55 (SRF)

No, CND, HPNo, P

Sertraline (SSRI) Protein binding: 98%

Metabolite (active): desmethylser-traline



No, CND, HPU, P

Amitriptyline (TCA)

Metabolites (active): nortriptyline, hydroxy-amitriptyline, hydroxynotrip-tyline

25 mg Q8H (healthy)No dosage adjustment for SRF

32–40 (healthy and SRF)

No, C, PND, HP

Amoxapine (TCA) Vd: 85% Metabolites (active): 8-hydroxy-amoxapine, 7-hydroxy-amoxapine

100 mg/day–100 mg Q8HNo dosage adjustment for SRF

10–21 (healthy) U, C, PND, HP

Clomipramine (TCA)


Metabolites (active): des-methylclomip-ramine

24%–32% via urine, 51%–60% via feces

Not studied Not studied U, C, PND, HP

Doxepin (TCA) Protein binding: 80% to 85%

Metabolites (active): des-methyldoxepin

60% via urine (rats), 50% via urine (dogs)*

25 mg Q8H (healthy and SRF)


No, C, PND, HP

Imipramine (TCA) Metabolites (active): des-methyldoxepin

25 mg Q8H (healthy and SRF)

No, C, PND, HP

Nortriptyline (TCA)

Plasma values (ng/ml) ↓ 29.8%74.5% for SRFProtein binding: 93%

Metabolites (active): (10-hydroxyno-triptyline, Z-10-hydroxyno-triptyline)

25 mg Q6–8H (healthy and SRF)

18-93 (healthy) vs 15-66 (SRF)

No, C, PND, HP

Protriptyline (TCA) No dosage adjustment for SRF

No, C, PND, HP

Trimipramine (TCA)


U, C, PND, HP

Fluvoxamine • AUC: ≠ for CKD 860 �g h/L (healthy) vs 1338 �g h/L (CKD)

• Protein bind-ing: 77%

• No dose adjustment

• t½: ≠, 2–8 h (healthy) vs 13.3–42.3 h (CKD)

• U=C• No=HP• U=P







Lithium (Mood Stablizer)

Bioavailability: 80%–100% (healthy)

Vd: 0.7–1.0 L/kg Protein binding: 0%

Not metabolized

Primarily via kidneys Clearance: 10–40 mL/min

Diuretics (thia-zide diuretics) ↓ clearance 40%–68%NSAIAs

Relative con-traindication (severe SRF) GFR >50 mL/min (no dose adjustment), GFR 10–50 mL/min (↓ dose 50%–75%), GFR <10 mL/min (↓ dose 25% –50%)

Terminal β-t½: 18-36 (healthy)

Yes, C, HP, P

Alprazolam (Benzo– diazepine)

AUC (hxng/mL): 441.2 (healthy), 349.9 (C and HP), 592.1 (CAPD) for 2 mg* AUC (hxng/mL): 124.9 (healthy),102.8 (C and HP), 197.0 (CAPD), for 0.5 mg* >90% absorbed (healthy)

Vd (L/kg): 1.09 (healthy), 1.26 (C and HP) for 2 mg* Vd (L/kg):1.14 (C and HP), 1.05 (CAPD) for 0.5 mg* Protein binding: 80%

Metabolites: alphahydroxy-alprazolam, 4-hydroxyal-prazolam

15% alpha-hydroxyalpra-zolam excreted via urine, <1% 4-hydroxyalpra-zolam excreted via urine

0.25–5.0 mg TID (healthy and SRF) No dosage adjustment for SRF

9–19 (healthy)11.22 (C and HP), 18.43 (CAPD) for 2 mg

No, CND, HPU, P

Buspirone (Benzo– diazepine)

Absolute bio-availability: 4% (healthy) AUC: 2X (SRF) for 20 mg AUC (ng/Lxh): 2.89 (healthy), 6.63 (mild SRF), 4.64 (moderate SRF), 4.09 (severe SRF)*

Vd: 5.3 L/kg (healthy) Protein binding: >95%

Metabolite: 1-pyrimidinyl-piperazine or [1-PP]

Systemic clear-ance: 1.7 L/h/kg (healthy) <1% unchanged drug excreted (healthy)

2, 15 mg/day (healthy) No dosage adjustment for SRF

2.25 (healthy)*3.18 (healthy), 12.61 (mild SRF), 4.34 (moderate SRF), 2.74 (severe SRF)*

No, CND, HP, P

Chlordiazepoxide (Benzo– diazepine)

Protein binding: 90%–98%

7.5–50 mg/day (dose adjusted) No adjustment (mild-moderate SRF), 50% dose (severe SRF)


Clonazepam (Benzo– diazepine)


No active metabolites

0.5 mg TID No dosage adjustment for SRF


Diazepam (Benzo– diazepine)


Metabolites (active): desmethyl-diazepam, oxazepam

5–40 mg/day No dosage adjustment for SRF

Parent drug 92, desmeth-yldiazepam 57.3 (healthy), parent drug 37, desmethyldi-azepam 36.1 (SRF)

No, CND, HPU, P







Lorazepam (Benzo– diazepine)



1–2 mg BID or TID (healthy), contradicting dosing recom-mendations (SRF)


No, CND, HPU, P

Midazolam (Benzo– diazepine)

Protein binding: 94% to 97% Free fraction ↑ in SRF (6.5% vs 3.9%)

Metabolite: α1-hydroxymi-dazolam

Clearance*: α1-hydroxymi-dazolam (186 mL/min), midazolam (198 mL/min; healthy)α1-hydroxymi-dazolam (14 mL/min), mid-azolam (132 mL/min) (SRF)

Drug moniter-ing suggested No dosage adjustment (mild-moder-ate SRF), 50% dose (severe SRF)

α1-hydroxymi-dazolam: 0.8–1 (healthy)

No, CND, HPU, P

Nitrazepam (Benzo– diazepine)

Vd: 228 L (3.61 L/kg) (healthy), 283 L (4.16 L/kg) (SRF)* Protein binding: ↓ for SRF

Primarily hepatic

Clearance: 111 mL/min (healthy), 281 mL/min (SRF)*


24.5 (healthy) vs 31.5 (SRF)

Oxazepam (Benzo– diazepine)

Protein binding: 86% to 99% (varies)


30–120 mg/day (healthy and SRF)No dose adjusment (SRF)


No, CND, HPU, P

Temazepam (Benzo– diazepine)



15–30 mg HS No dosage adjustment for SRF


Triazolam (Benzo– diazepine)


Metabolite: α-hydroxytri-azolam

0.125–0.5 mg/dayNo dosage adjustment for SRF

2–4 (healthy) vs 2.3 (SRF)

No, CND, HPU, P

Zaleplon (Non-benzo– diazepine)

Systemic bioavail-ability: 30% (healthy)

Vd: 275 L for 10 mg (healthy) Protein binding: 60%

No active metabolites Primarily hepatic

<1% excreted via urine

5–10 mg HS Dose adjusted for SRF Adjustment (severe SRF), no adjustment (mild-moder-ate SRF)

1 (healthy) ND, C, HP, P

Zolpidem (Non-benzo– diazepine)


Vd: 66 L for 10 mg Protein binding: 92% ↑ free fraction for SRF

No active metabolites Primarily hepatic

≤1% excreted via urineMetabolites excreted via urine (48% to 67%)

10 mg/day (healthy) Dosage adjustment for SRF (↓50%)


No, CND, HPU, P







Zopiclone (Non-benzo– diazepine)


Protein binding: 45% to 80%

Metabolites (active): N-oxide; (inactive): N-desmethyl-metabolite

50% excreted via lungs, 30% (initial) excret-ed via urine (metabolites)

Erythro-mycin 5 (healthy)

Amisulpride (Typical Antipsychotic)

AUC (ngxh/mL): 404 (healthy), 754 (mild SRF), 1,709 (moderate SRF), 4,606 (severe SRF)*

Excreted unchanged in feces and urine

CsA inhibits P-glycoprotein

11.2 (healthy), 14.0 (mild SRF), 14.4 (moderate SRF), 25.8 (severe SRF)*

Chlorpromazine (Typical Antipsychotic)

Metabolites (active): CPZ-N-oxide, CPZ-sulfoxide, 7-hydroxy-CPZ, nor1-CPZ, nor2-CPZ sulfoxide, 3-hydroxy-CPZ

50–400 mg/day (healthy) No dosage adjustment for SRF


No, C, PND, HP

Haloperidol (Typical Antipsychotic)


Metabolite (active): hydroxy-halo-peridol

<1% excreted via urine

1–2 mg Q8–12HNo dosage adjustment for SRF


No, C, PND, HP

Perphenazine (Typical Antipsychotic)

4–16 mg BID–QID (healthy) Dosage adjustment not studied

9.5 (healthy) U, C, PND, HP

Sulpiride (Typical Antipsychotic)

AUC (mgxh/L): 8.27 (intrave-nous), 2.41 (oral) (healthy)* Absolute bioavail-ability: 35% (healthy)

Vd: 1.19 L/kg (intravenous), 2.05 L/kg (oral)*

36.9% excreted via urine

6.63 (IV), 6.73 (oral; healthy)

Thioridazine (Typical Antipsychotic)

Metabolites (active): mesoridazine, sulforidazine

50–800 mg/day (healthy) Dosage adjustment not studied

21–24 (healthy) U, C, PND, HPU, P

Trifluoperazine (Typical Antipsychotic)

No, C, PND, HP

Aripiprazole (Atypical Antipsychotic)

Bioavailability: 87% (healthy) AUC: ↑ 7% (dehy-dro-aripiprazole), ↓ 15% (aripip-razole)

Vd: 404 L (4.9 L/kg; healthy) Protein binding: 99%

Primarily hepaticMetabolites (active): dehy-dro-aripipra-zole

3.3–4.0 L/h (healthy) 25% excreted via urine (<1% unchanged), 55% excreted via fae-ces (18% unchanged)

10–30 mg/day (healthy) Dosage adjustment for SRF

47–146 (healthy)

U, C, HP, P










Clozapine (Atypical Antipsychotic)

Vd: 2–7 L/kg (healthy) Protein binding: 95%

Primarily hepatic Metabolites (active): N-desmethylclo-zapine

27%–50% excreted unchanged (systemic clearance)

9–17 (healthy)

Olanzapine (Atypical Antipsychotic)

85% of oral olan-zapine absorbed

Protein binding: 93% Oral bioavailabil-ity: 60%

Metabolites (active): N-desmethy-lolanzapine, olanzapine, 10-N-glucuro-nide 40% inac-tivated via hepatic metabolism

Total urine recovery (56.2%), fecal recovery (30%)Clearance via urine: N-des-methylolan-zapine (0.8%), 10-N-glucuro-nideolanzapine (28.6%), olan-zapine (17.7%)

5–20 mg (healthy and SRF) No dosage adjustment for SRF


No, C, PND, HP

Quetiapine (Atypical Antipsychotic)

AUC (ngxh/mL): 366 (healthy), 553 (SRF) AUC: ↑ 42% for SRF

Vd: 593 L (healthy), 310 L (SRF)* Vd: ↓ 48% for SRF Protein binding: 83%

Metabolites (active): 7-hydroxy-quetiapine, N-dealkylated quetiapine Contains sulfoxide metabolite

<1% excreted unchanged via urineOral clearance: 26% lower than healthy volunteers (insignificant)

150–750 mg/day BID or TID No dosage adjustment for SRF

5–6 (healthy) vs 4.1 (SRF)

Risperidone (Atypical Antipsychotic)


Metabolites (active): 9-hydroxyrisperi-done

Clearance: 10% renal, 40% of metab-olite cleared via urine

1–3 mg BID (healthy), 0.5–1.5 mg BID (SRF)

3–30 (healthy), 19 (9-hydroxy-risperidone; healthy)25 (9-hydroxy-risperidone; SRF)

ND, C, HP, P

Ziprasidone (Atypical Antipsychotic)

AUC (ngxh/mL): 272 (healthy), 370 (mild SRF), 250 (moderate SRF), 297 (severe SRF)*


Inactive metabolites

20–80 mg BID (SRF)

5–7 (healthy), 6.4 (mild SRF), 4.9 (moder-ate SRF), 4.2 (severe SRF)

No, CND, HPU, P

Carbamazepine (Antiepileptic)

Vd: 0.8 kg Protein binding: 75%

Clearance: 1% via renal, 99% via liver

10–25 kg/day (healthy) Low GFR=No dose adjust-ment for SRF

9–15 (healthy) No C, PYes, HP

Divalproex (Antiepileptic)


Primarily via liver

Clearance: 1%–3% excreted unchanged via urine


No, C, PYes, HP







Gabapentin (Antiepileptic)

Bioavailability ↓ when dose ↑ (300 mg=57%, 1,600 mg=35%)

Vd: 0.7 kg

Protein binding: 0%

Primarily renal excretion

Clearance: 80% via urine

Dosage adjustment for SRF

400–600 mg/day (healthy), 200–300 mg BID (mild-moderate SRF), 100–150 mg/day (severe SRF)

5–7 (healthy) Yes, C

L, HP

ND, P

Lamotrigine (Antiepileptic)

Bioavailability: 98%

Vd: 0.5–0.7 kg (healthy and SRF)


Clearance: 10% renal, 90% liver

1,000–3,000 mg/day (healthy)

Dose adjust-ment for SRF may be neces-sary, but ↓ may be more effective

12–62 (healthy)

No, C

ND, HP

U, P

Oxcarbazepine (Antiepileptic)

Almost completely absorbed


Primarily hepatic

Clearance: 50% excreted via urine

300–600 mg/day BID (healthy)

Contradicting dosing recom-mendations (SRF)

8–10 (healthy) ND, C, HP, P

Pregabalin (Antiepileptic)

AUC (ngxh/mL): 15.9 (healthy), 28.2 (mild SRF), 52.3 (moderate SRF), 101 (severe SRF)*

Vd (oral): 42.1 L (healthy), 42.4 L (mild SRF), 35.7 L (moderate SRF), 34.9 L (severe SRF)*

Protein binding: 0%

>90% of drug eliminated unchanged via urine

150–600 mg/day BID or TID (healthy), 75–300 mg/day BID or TID (mild SRF), 25–150 mg/day BID or TID (moderate SRF), 25–75 mg/day QD (severe SRF)*

↑ as SRF ↑, 9.11 (healthy), 16.7 (mild SRF), 25.0 (moderate SRF), 48.7 (severe SRF)

Yes, C

L, HP

ND, P

Topiramate (Antiepileptic)

Protein binding: 15% to 20%

Excreted unchanged via urine

100–200 mg BID (healthy), 50–100 mg (mild-severe CDK)

Yes, C

L, HP

ND, P

Dexamphetamine (Psycho- stimulant)

2.5 QD initial (healthy)

12 (healthy) ND, C, HP, P

Methylphenidate (Psycho- stimulant)

AUC (ngxh/mL) for 20 mg: 70.48*

50% excreted via bile


5.07 (healthy) for multilayer-release drug

U, C, P




COMMONLY-ENCOUNTERED CLINICAL SCENARIOS

How is End-Stage Renal Disease Defined?SRF can be defined as either kidney damage or GFR <60

mL/minutes/1.73 m2 that is present for ≥3 months.2 The kidney disease staging system is based on GFR (Table 1).2 The presence of SRF should be established based on the occurrence of kidney damage or the level of kidney function (ie, GFR), regardless of the specific diagnosis. Disease stage should be assigned based on the level of kidney function regardless of the principal cause of SRF.2

ESRD is defined as either a level of GFR <15 mL/min-ute/1.73 m2 (ie, Stage 5), which is accompanied in most cases by signs and symptoms of uremia, or as a need for initiation of kidney replacement therapy (dialysis or transplantation) for treatment of complications from decreased GFR which would otherwise increase the risk of morbidity and mortal-ity.2 Some patients may need dialysis or transplantation at GFR ≥15 mL/minute/1.73 m2 because of symptoms of ure-mia. ESRD almost always follows SRF, which may exist for 10–20 years or longer before progressing to become ESRD, when kidney function is <10% of normal.51 At this point, the compromised kidney function is associated with multiple complications requiring dialysis or kidney transplantation.

What Determines Drug Dialyzability?Patients receiving dialysis treatment require special atten-

tion with regard to dosing regimens and the potential need

for supplemental dosing following dialysis. The need for supplemental dosing is determined by the extent to which a drug is removed by dialysis (ie, drug dialyzability). A marked lowering of blood levels will occur upon dialysis in patients receiving medication that is dialyzable (of the psychotropics, namely, lithium, gabapentin, and pregabalin). Practitioners prescribing psychotropics should obtain post-dialysis blood levels and use the information obtained to determine how much of that agent needs to be given after the dialysis run (See Table 3 for drug dialyzabilities).52

Drug dialyzability is determined primarily by several physi-cal and chemical characteristics of the drug. These include molecular size, protein binding, water solubility, volume of distribution, and plasma clearance (ie, the sum of renal and non-renal clearance). In addition, technical aspects of the dialysis procedure (eg, dialysis membrane and flow rates) may also determine drug dialyzability. Overall, peritoneal dialysis is much less efficient at removing drugs than hemodialysis. In general, if a drug is not removed by hemodialysis, it cannot be removed by peritoneal dialysis.53

Lithium and Nephrotoxicity: At What Glomerular Filtration Rate Should Lithium Be Discontinued?

The predominant form of chronic renal disease associ-ated with lithium therapy is a chronic tubulointerstitial nephropathy (CTIN). This condition is often heralded by the insidious development of renal insufficiency, with little or no proteinuria, often in the setting of chronic neph-rogenic diabetes insipidus. It is unequivocally established

Modafinil (Psycho- stimulant)

40% to 65% absorption (oral)

AUC (mgxh/L): 56.9 (healthy) on 200 mg*, AUC ↑ with SRF

Vd: 0.8 L/kg (healthy)*


Primarily hepatic

<10% of oral dose excreted unchanged

100 QD (ini-tial) (healthy)

11.7 (healthy) on 200 mg

↑ with SRF (12–15)

ND, C, HP, P

* Data was obtained from a study.

† The drug is not available in the United States.DDIs=drug-drug interactions; MAOI=monoamine oxidase inhibitor; ND=no data available; C=conventional hemodialysis; HP=high permeability hemodialysis; P=peritoneal dialysis; SRF=suboptimal renal failure; RIMA=reversible inhibitor of monoamine oxidase type A; AUC=area under the curve; Vd=volume of distribution; h=hour; vs=versus; t1/2=half-life; misc.=miscellaneous; No=dialysis has no effect on plasma clearance; U=significant drug removal unlikely (based on pharmacokinetic drug qualities); NaSSA=noradrenergic and specific serotonergic antidepressant; m-CPP=meta-chlorophenylpiperazine; SNRI=serotonin norepinephrine reuptake inhibitor; CrCl=creatine clearance; XR=extended release; IR=immediate release; NSAIA=non-steroidal anti-inflammatory agent; GFR=glomerular filtration rate; min=minute; CAPD=continuous ambulatory peritoneal dialysis; CPZ=chlorpromazine; CSA=cyclosporine A; Yes=dialysis increases plasma clearance by ≥30% dosing to supplement might be needed or dosing after dialysis is recommended; L=no published data exists; extrapolated information from studies using conventional hemodialysis techniques indicates significant drug removal is likely.







that long-term lithium administration may induce CTIN leading to renal failure (ESRD).54 A review of lithium neph-rotoxicity, including data from 14 separate studies, found that the prevalence of reduced GFR associated with chronic lithium therapy was 15%.54 An even smaller number of lith-ium-treated patients go on to develop renal insufficiency, ultimately leading to dialysis (ESRD).55,56

Taken together, studies indicate that a small number of patients treated with lithium develop progressive renal damage (associated with CTIN). Despite withdrawal of lithium, several patients have been reported to develop ESRD after long-term lithium exposure (ie, >20 years) requiring dialysis therapy. Nonetheless, in patients with mild-to-moderate chronic renal insufficiency from lithium, withdrawal of lithium may be associ-ated with gradual improvement in GFR.57

Recently, an increasing number of publications have published on the hazardous effects of progressive increases in creatinine levels (“creeping creatinines”) and renal insuf-ficiency as a result of long-term lithium therapy. Lithium was first approved for the acute treatment of mania by the United States Food and Drug Administration in 1970, which implies that there is a significant number of indi-viduals who have received lithium therapy for >15 years.58 Uninterrupted lithium exposure decreases the kidney’s endogenous ability for cellular regeneration. With further progression of renal insufficiency, there is the appearance of renal fibrosis which may progress, despite elimination of the offending agent (ie, lithium), to ESRD.54 A consensus does not exist as to when lithium treatment should be dis-continued in the context of diminishing kidney function. For example, it has been suggested that repeat serum cre-atinine concentrations exceeding 140 mmol/L (1.6 mg/dl) should invite the need for expert consultation.56

Prognosticating which individuals will progress to ESRD has substantial clinical importance. A single report docu-mented that serum creatinine levels could serve as a useful biomarker in categorizing individuals at risk for progres-sion. More specifically, after long-term lithium cessation, an initial serum creatinine of >2.5 mg/dl identified an at-risk group with a high probability of progression while individuals with a serum creatinine <2.5 mg/dl were significantly less likely to progress to ESRD requiring dialysis.59 Another study using the biomarker of estimated creatinine clearance (CrCl) (via the Cockcroft-Gault for-mula) identified an at-risk group; individuals with a CrCl ≤40 mL/minute had a high likelihood of continued renal deterioration at lithium discontinuation than those with CrCl >40 mL/minute.54

In addition to its predictive value for the irreversible onset of kidney failure, the GFR level is also strongly associated with the risk of complications from SRF. Based on evidence-based guidelines,2 the prevalence of complica-tions from SRF increases at GFR levels of <60 mL/min-ute/1.73 m2. Complications include hypertension, mal-nutrition, anemia, bone disease, neuropathy, and reduced functioning and well being (eg, depression). Furthermore, the risk of progression to ESRD is considerably increased below this GFR level.

Moreover, as K/DOQI states, the risk for kidney pro-gression should be taken into consideration, such as the rate of GFR decline and non-modifiable and modifiable risk factors. Examples include diabetes, hypertension, family history of kidney failure, and ethnicity (ie, African Americans, American Indians, Hispanic Americans). In addition, specific risk factors for impaired renal function for patients on lithium have been documented, including previous lithium intoxication; concomitant medication (ie, thiazide diuretics, angiotensin converting enzyme inhibitors, some nonsteroidal anti-inflammatory drugs), which promotes renal lithium retention and thus lithium intoxication; chronic physical illness (eg, diabetes, hyper-tension); and increasing age.60 The foregoing factors do not contraindicate lithium treatment but should prompt increased vigilance on the part of the practitioner and most probably an earlier cutoff point.

Side by side with prognostication interventions, strate-gies for minimizing the renal effects of lithium should also be implemented. This includes diligently avoiding episodes of renal toxicity; monitoring serum lithium concentrations in order to achieve optimal efficacy at the lowest possible concentration (in view of the association of renal damage with lithium toxicity); and monitoring serum creatinine levels and estimated GFR on a yearly basis, referring for expert consultation when the serum creatinine level consis-tently rises >1.6 mg/dl.56

It should be noted that equations estimating GFR based on serum creatinine (eg, Cockcroft-Gault formula) are more accurate and precise than estimates of GFR from serum cre-atinine measurements alone.2 Therefore, in a clinical setting, serum creatinine levels should be examined in addition to reporting the estimated GFR. In addition, as these prognos-ticating cutoffs are putative, it should not be inferred from this data that a serum creatinine <2.5 mg/dl, a CrCl >40 mL/minute, or a GFR >60 mL/minute/1.73 m2 are necessar-ily safe and that the declining GFR may reverse if lithium is discontinued at this point.



Lithium and End-Stage Renal Disease: What is the Dosing Procedure for Hemodialysis?

Given concerns over renal safety and excretion, efforts should be made to substitute other drugs for lithium in patients with SRF. However, discontinuation of lithium in long-term lithium responders often exposes individuals to the risk of severe recur-rences of bipolar disorder or even an uncontrollable worsening in the course of the illness, and so the psychiatric risk also has to be taken into account despite availability of other mood stabilizers (ie, antipsychotics or anticonvulsants).58 Moreover, some bipolar patients with ESRD do not respond to the anti-convulsants or antipsychotics that are often used as alternatives to lithium. Additionally, some patients whose illness is well controlled by lithium therapy refuse to consider interruption and substitution (ie, psychological dependence). In light of the above, lithium’s use as an effective and non-toxic agent in patients with kidney failure is established.4 It can be used with caution in ESRD with careful monitoring of renal function by creatinine clearance over time, while maintaining the serum lithium level within the lower therapeutic range.4,57

In ESRD, the dosage of lithium must be reduced in order to prevent toxicity, so at low levels of renal function the dosage should be 25% to 50% of the usual dose and should be moni-tored carefully by blood levels (Table 3).4,53 Treatment involves administration of a single dose (usually 600 mg) after each dialy-sis run. A single dose will result in a steady serum level and, as a result, no supplemental lithium is required. At the next dialysis, which removes the lithium from the body, the same single dosing should be repeated.4,61 Serum lithium levels obtained before and after dialysis sessions are used to establish the proper dose. Ideally, lithium levels should be obtained immediately before dialysis and 2 hours after completion of dialysis; the level obtained immediately after dialysis will often be lower than that observed later due to a post-dialysis redistribution effect.62

Which Antidepressants are Preferred for Use in End-Stage Renal Disease?

Table 3 provides a guide to which antidepressants are pre-ferred for use in ESRD.

Effective treatment of depression in dialyzed patients with ESRD has been understudied. Only one small study was identified in a recent comprehensive Cochrane review63 of randomized clinical trials. The study compared 12 patients treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine with those given a placebo.64 The intervention did not find a difference between treatment groups, although it was certainly underpowered.65

There is some preliminary evidence that SSRIs have a role in the treatment of depression in patients with ESRD. Fluoxetine is the most studied medication in this class in ESRD. It appears to be both non-toxic and efficacious in SRF patients. A group of researchers in Korea found HAM-D scores to be significantly reduced in patients with ESRD treated with fluoxetine.34,65 Fluoxetine also has a very high therapeutic index, contributing to its non-toxic effects in ESRD. Further, the kinetic profile of single doses of fluox-etine is unchanged in anephric patients.62 Additional pre-liminary evidence has shown that depressive symptoms were markedly ameliorated in patients who completed a 12-week course of treatment with sertraline, bupropion, or nefazo-done, despite low rates of compliance overall.34,67

There are several non-SSRI antidepressants that should be used with caution with ESRD. Tricyclic antidepres-sants (TCAs), although considered as potential therapeutic options and prescribed in earlier studies, have not been employed in more recent studies due to concerns of safety and tolerability.62,67,68

Venlafaxine levels are markedly increased in patients with renal failure as clearance is reduced by >50% in patients undergoing dialysis.8,69 Accordingly, lower doses of this drug are indicated in this population; the initial dosage should be reduced and slowly titrated.8,69 Additionally, hypertension, a common comorbidity in ESRD, in theory could intensify with venlafaxine treatment.68

Bupropion and its active metabolites are almost com-pletely excreted through the kidney; these metabolites may accumulate in dialysis patients and predispose to seizures.62 Nefazodone should also be used conservatively until more is known concerning its pharmacokinetics in patients with chronically impaired renal function.68 It should not be used as first-line therapy due to potential for hepatotoxicity.8

Less is known about the use of tetracyclic antidepres-sants (ie, mirtazapine, trazodone, maprotiline, amoxapine) in ESRD than about the TCAs; thus, caution is advised. Moreover, trazodone can cause postural hypotension (which diabetic dialysis patients are even more prone to) and mapro-tiline can cause QTc prolongation.70

Individuals with ESRD receiving hemodialysis have increased plasma levels of duloxetine and particularly of its metabolites, as evidenced by single-dose studies. The area under the curve (AUC) value of duloxetine (ie, the total amount of drug absorbed by the body) was doubled in subjects with ESRD receiving hemodialysis compared to subjects with normal renal function, while the AUC values of the major circulating metabolites were 7–9 times greater.71



Additionally, the predominant route of excretion of these metabolites is through the kidneys. Taken together, dulox-etine is not recommended for patients with ESRD requiring dialysis; if administered, however, a lower starting dose with gradual titration should be used.

Patients with ESRD treated with kidney transplanta-tion are often co-administered immunosuppressive agents (eg, tacrolimus, cyclosporine). Several psychotropics are inhibiting agents (ie, increase immunosuppressant levels) of these agents, via inhibition of CYP 3A4 enzymes and Pgp. Specifically, there is potential for drug-drug interactions with fluvoxamine, fluoxetine, nefazodone, sertraline, and parox-etine (a weak inhibitor).62

CONCLUSIONTaken together, SRF predictability effects renal excretion

of psychotropics with more variable effects on absorption, distribution, and metabolism. The adjudication on the safe and effective dose for any psychotropic needs to be indi-vidualized for each psychotropic agent. Strong pronounce-ments regarding contraindication of use for any psychotropic extends beyond available data. Nevertheless, psychotropics that depend on normal renal function for disposal require dosing alteration, and in many cases should be avoided. PP

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Bipolar Depression: Best Practices for the Hospitalized Patient

By Paul E. Keck, Jr, MD Mark A. Frye, MD Michael E. Thase, MD

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Supported by an educational grant from AstraZeneca.

Now Available at www.primarypsychiatry.com An Expert Panel Review of Clinical Challenges in Psychiatry

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