Psychotropic drugs and renal failure: Translating the evidence for clinical practice

Adv Ther (2009) 26(4):404-424.DOI 10.1007/s12325-009-0021-x

REVIEW

Psychotropic Drugs and Renal Failure: Translating the Evidence for Clinical Practice

Nour T. Baghdady · Suman Banik · Shari A. Swartz · Roger S. McIntyre

Received: February 9, 2009 / Published online: May 4, 2009 / Printed: May 8, 2009 © Springer Healthcare Communications 2009

REVIEW

ABSTRACT

Introduction: The kidney is a primary route of drug elimination; abnormal kidney function is predicted to alter the pharmacokinetics of agents metabolized and/or excreted predomi-nantly through this route. The high preva-lence of mental disorders associated with psychotropic drug use in individuals with deteriorating renal function suggests there is a need to investigate the effects of renal failure on psychotropic pharmacokinetics. The aim

DOI

0021-x

Issue Number:

4of this review is to provide a clinically acces-sible overview of the effect of chronic renal failure on the pharmacokinetics for each of the major classes of prescribed psychotropic agents. Methods: All English language arti-cles published between 1977 and 2008 were searched through PubMed, using the fol-lowing keywords: “renal,” “kidney,” “phar-macokinetics,” “renal impairment,” “renal insufficiency,” and “renal failure.” Each of these search words was cross-referenced with the non-proprietary name of each psychotro-pic agent. The manufacturer’s product insert was also reviewed for some agents for updated dosing. Owing to the lack of adequately pow-ered studies, an inclusive manner was used. Results: Chronic renal failure variably affects the pharmacokinetic parameters of psycho-tropic drugs. A review of each psychotropic drug is provided, with an emphasis on the individual pharmacokinetic parameters and recommended dosing. Conclusions: The adju-dication of safe and effective doses for any psychotropic agent needs to be individual-ized. Tactics including dosage adjustment, slow titration, and careful monitoring for serious adverse events should be incorporated into practice.

Nour T. Baghdady King Abdul-Aziz University, Jeddah, Saudi Arabia, and Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada

Suman Banik Royal College of Surgeons in Ireland, Dublin, Ireland, and Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada

Shari A. Swartz University of Ottawa, Faculty of Medicine, Ottawa, Ontario, Canada, and Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada

Roger S. McIntyre ( ) Department of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada, and Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Email: [email protected]

Adv Ther (2009) 26(4):404-424. 405

Keywords: kidney failure; pharmacokinetics; psychotropic agents; renal disease

INTRODUCTION

The kidney is a primary route of drug elimi-nation; abnormal kidney function is predicted to alter the pharmacokinetics of agents metab-olized and/or excreted predominantly through this route.1 Mental and renal disorders co-occur together, particularly in end-stage renal disease (ESRD). One systematic review showed that the mean prevalence of mental disorders in patients undergoing dialysis was 44% (range 20%-83%) with the most common diagnosis being major depression.2 The co-occurrence of these disorders invites the need for familiar-ity with the safety, pharmacokinetic profile, and efficacy of psychotropic agents in indi-viduals with deteriorating kidney function. Herein, we provide a clinically accessible and pragmatic review of the effect of suboptimal renal function on the handling of the major classes of psychotropic agents with an empha-sis on antidepressants, antipsychotics, and anticonvulsants.

METHODS

All English language articles published between 1977 and 2008 were searched through PubMed using the following keywords: “renal,” “kidney,” “pharmacokinetics,” “renal impair-ment,” “renal insufficiency,” and “renal failure.” Each of these words was cross-referenced with the non-proprietary name of each psychotropic agent. The manufacturer’s product insert was also reviewed for some agents for updated dosing recommendations, ie, GlaxoSmithKline for par-oxetine, Eli-Lilly & Co. for duloxetine, Bristol-Myers Squibb Co. for aripiprazole, Sanofi-Aventis for zolpidem, and Wyeth Pharmaceuticals for

zaleplon. The articles selected for inclusion were decided after discussion amongst the authors.

PSYCHOTROPIC DRUG CLASSES

Antidepressants

Selective Serotonin Reuptake InhibitorsEscitalopram is the (S)-enantiomer of the race-

mic antidepressant citalopram. Although the pharmacokinetics of escitalopram have not been extensively studied in patients with compromised renal function, the pharmacokinetics of citalo-pram in diseased kidney states are known to be altered (Table 1; adapted with permission).3 The elimination half-life (t1/2) of citalopram in patients with mild to moderate renal insufficiency (creati-nine clearance [CrCl] 10-53 mL/min) increases by approximately 35%, while the renal clearance decreases by 40%.17 In keeping with these find-ings, patients with mild to moderate kidney dis-ease should initiate treatment at 10-20 mg/day with lower doses (ie, 5 mg) for more severe renal impairment.17,40,41

Fluoxetine is the most studied selective sero-tonin reuptake inhibitor (SSRI) among individ-uals with renal failure.10 Fluoxetine treatment administered to depressed individuals undergo-ing renal dialysis has been proven to be highly efficacious and well tolerated.42 The pharmacoki-netic parameters of fluoxetine and its primary active metabolite, norfluoxetine, were unaltered in patients with renal failure when compared with healthy controls (Table 1). Fluoxetine treat-ment in patients undergoing hemodialysis does not require a change in dose initiation or titra-tion when compared with individuals without kidney disease.8,42

A single study evaluating the effect of renal impairment on fluvoxamine (100 mg/day for 6 weeks) pharmacokinetics in individuals with renal impairment (CrCl <50 mL/min) did not

406 Adv Ther (2009) 26(4):404-424.

observe any significant differences in any kinetic parameter (Table 1).8

Several studies regarding the use of parox-etine in renal failure reported an increase in plasma concentration (Cmax) and t1/2. One study demonstrated a mean t1/2 of 29.7 hours (10.9-54.8 hours) in subjects with impaired renal function (CrCl <30 mL/min) versus a mean t1/2 of 17.3 hours (9.6-25.1 hours) in subjects with normal kidney function (CrCl >100 mL/min) (Table 1).8 Paroxetine should be initiated at a lower dose (ie, 10 mg of paroxetine or 12.5 mg of controlled-release formulations of parox-etine) in patients with severe renal impairment (CrCl <30 mL/min).8,10,43

Like most SSRIs, sertraline has not been extensively studied in individuals with renal fail-ure. A small case series of patients with anuria reported an increase in the t1/2 (ie, 42-92 hours vs. 24-36 hours in healthy controls).8 Interestingly, sertraline has been reported to prevent hypoten-sive reactions to hemodialysis, but the exact mechanism subserving this operation has not been elucidated.44

Tricyclic AntidepressantsThe serum concentration and mean t1/2 of

tricyclic antidepressant conjugated hydroxy-lated metabolites are markedly increased in subjects with renal failure; however, no con-siderable increase in unconjugated hydrox-ylated metabolites are reported.8,45 Dose adjustment is not necessary for commonly prescribed tricyclic antidepressants (ie, desip-ramine, imipramine, and nortriptyline); how-ever, caution is advised.8 Therapeutic drug monitoring can be beneficial but is not fre-quently performed as patients may exhibit toxicity despite normal laboratory values.45 Therefore, clinical signs of therapeutic and toxic effects are often used to guide appropri-ate dosing.45

Serotonin and Norepinephrine Reuptake Inhibitors

VenlafaxineVenlafaxine is metabolized in the liver to

O-desmethyl-venlafaxine.46 The major excretion pathway of both the parent drug and metabolite are via the kidney (87% of dose is recovered in the urine).46 Patients with moderate renal insuffi-ciency undergoing dialysis exhibit an increase in t1/2 of venlafaxine and O-desmethyl-venlafaxine; this is in contrast to the pharmacokinetics for venlafaxine in individuals with mild renal impairment, which remained unchanged (Table 1).8,45 In patients with mild renal impair-ment, no alteration of dose is required; further decrements in renal function invite the need for lower dose initiation and slower titration.45 The association between venlafaxine and elevations in blood pressure require increased vigilance for this vital sign in all patients with renal failure who were treated with venlafaxine.10,45,46

DuloxetineDuloxetine was only approved by the US

Food and Drug Administration (FDA) in 2004;13 thus, limited data on the safety of duloxetine in patients with renal failure are available. Duloxetine is highly protein bound (>90%), binding primarily to albumin and alfa1-acid gly-coprotein.13 The binding to plasma proteins does not appear to be significantly affected by renal failure. Duloxetine administered as a single dose results in a 100% increase in Cmax and the area under the concentration-time curve (AUC) in patients with ESRD receiving hemodialysis.47 The major metabolites of duloxetine, 4-hydroxy duloxetine glucuronide, and 5-hydroxy,6-meth-oxy duloxetine sulfate, all of which are primarily excreted via the kidneys, exhibit AUC values seven to nine times higher in patients with renal failure compared with subjects with normal renal function.47 Taken together, duloxetine is

Adv Ther (2009) 26(4):404-424. 407

best avoided in ESRD, patients requiring dialysis, or patients with severe renal impairment (CrCl <30 mL/min).47 Duloxetine seems to be a reason-able alternative in individuals with mild to mod-erate renal impairment (CrCl 30-80 mL/min) as no significant effects on pharmacokinetics are observed (Table 1).47

Serotonin Agonists/AntagonistsTrazodone and NefazodoneLimited data concerning the effect of renal

failure on the pharmacokinetic profile of tra-zodone are available. The t1/2 of the parent drug was reported to be unchanged in patients receiv-ing hemodialysis, although the effect on its metabolites was unknown.8 It has been reported that hemodialysis does not hasten the elimina-tion of trazodone.8 Renal impairment does not seem to considerably alter the pharmacokinetics of nefazodone (Table 1). However, nefazodone is problematic in the fact that it causes acute hepa-totoxicity; based on this, the drug was withdrawn from the Canadian and European markets.8,48

Noradrenergic and Specific Serotonergic Antidepressants

MirtazapineA single-dose study using 15 mg of mir-

tazapine demonstrated that the clearance in mild renal impairment was largely unaffected, whereas it decreased by 33% and 50% in mod-erate and severe renal insufficiency, respectively (Table 1). In addition, time to peak plasma concentration (tmax) and AUC were higher in moderate and severe renal impairment.8,12 The manufacturer (Schering-Plough, Kenilworth, NJ, USA) dosage should be adjusted in patients with renal failure.45,49

Monoamine Oxidase InhibitorsThe use of monoamine oxidase inhibitors

(MAOI) in patients with impaired renal function

is discouraged, due to the lack of efficacy data, as well as tolerability and safety issues in crit-ically ill patients.8 For example, orthostatic hypotension, a common side effect of MAOIs, may augment the drop in blood pressure associ-ated with dialysis therapy.8,50 The use of MAOIs are thus reserved for treatment-resistant and tertiary cases.8,51

Noradrenaline and Dopamine Reuptake Inhibitors

BupropionAlthough bupropion is eliminated almost

entirely by the liver, renal impairment may affect its disposition (Table 1). For example, the AUC ratios of hydroxybupropion:bupropion and hydrobupropion:bupropion were decreased by 66% and 69%, respectively, in patients with renal impairment.9 These changes most likely reflect a decrease in the metabolic clearance of bupro-pion rather than an alteration in protein bind-ing.9 Bupropion may accumulate in individuals with renal failure as the drug may build up and predispose seizure activity.10 Hence, dose adjust-ment should be considered; however, the exact dose recommendation is still not yet available.9

Antipsychotic Drugs

First-Generation AntipsychoticsHaloperidol appears to be safe in ESRD

based on its minimal excretion in urine (<1%).52 The electrolyte imbalances associated with renal failure may portend increased risk for cardiac dysrhythmias (QTc prolongation) when exposed to antipsychotic treatment.10 In this context, piperidine phenothiazines such as mesoridazine and thioridazine should be avoided.10 Furthermore, phenothiazine antipsychotics may intensify vulnerability to hypotension in patients with deteriorated renal function.53

408 Adv Ther (2009) 26(4):404-424.

Second-Generation AntipsychoticsOlanzapineOlanzapine is metabolized in the liver to

produce metabolites that are cleared via the kidney.10 Multiple-dose studies in renal fail-ure are not yet available; however, single-dose studies illustrate the safe use of olanzapine with no dose adjustment (Table 1). A notewor-thy adverse effect associated with olanzapine therapy is the exacerbation of glucoregula-tory disturbances, a common cause of chronic renal failure.10

QuetiapineA single-dose study evaluated low-dose que-

tiapine (ie, 25 mg) in a small case series of individuals with renal disease and a CrCl rang-ing from 8 to 33 mL/min per 1.73 m2 (n=8), and healthy volunteers (n=8).32 A 26% lower-ing in the mean apparent oral clearance and a corresponding 48% reduction in the appar-ent volume of distribution in participants with compromised kidney function were reported relative to the healthy volunteers. The AUC and the mean Cmax were also reported to be higher, with values of 42% and 52%, respec-tively. The mean t1/2 was similar in both groups (Table 1).32,54

Ziprasidone, Risperidone, and PaliperidoneA single study reported that ziprasidone’s

pharmacokinetics are unaltered in patients with impaired renal function.33 The associa-tion of ziprasidone and other antipsychot-ics with electrocardiographic changes requires vigilance for toxicity in individuals with electrolyte disturbances.10

The oral clearance of the primary metabolite of risperidone, 9-hydroxy-risperidone (ie, pali-peridone), was decreased by 50% in individuals with renal failure (Table 1).55 These observa-tions provide the impetus for lower initial

dosing and slower titration in subjects treated with risperidone.33,55

AripiprazoleAripiprazole (15 mg) treatment in patients

with severe renal failure (CrCl <30 mL/min) resulted in a higher Cmax for both aripiprazole and its main metabolite dehydro-aripiprazole by 36% and 53%, respectively.56 Moreover, the AUC of aripiprazole exhibited a 15% decrease, con-trary to dehydro-aripiprazole which increased by 7% (Table 1). Renal excretion for both the parent drug and the metabolite was <1%.56,57

Anxiolytics/Hypnotics

BenzodiazepinesBenzodiazepines (BZD) carry the advantage

of having a wide therapeutic window, allowing flexibility of dosing and the use of various routes of administration.8 They are also solely metab-olized by the liver; consequently, BZDs do not usually require dose adjustment in renal failure (Table 1).10 Selection of a BZD should be based on its pharmacokinetic profile, taking solubil-ity, absorption, and t1/2 into consideration (refer to Table 1 for details on pharmacokinetics). In keeping with this view, the clinician is often able to predict the onset and duration of anxiolytic effect and portend adverse effects.8

Non-BenzodiazepinesZolpidemZolpidem is a novel sedative-hypnotic that

is used for short-term treatment of insom-nia.58 Zolpidem (10 mg/day for 14 or 21 days) was evaluated in a small case series (n=11) in patients with ESRD.58 The results indi-cated that there were no significant changes in medication pharmacokinetics (Table 1). Moreover, this agent is not reliably removed by hemodialysis.58

Adv Ther (2009) 26(4):404-424. 409

ZaleplonZaleplon is a new non-benzodiazepine hyp-

notic agent also used for the short-term treatment of insomnia.10 The pharmacokinetics of zaleplon are unaltered in patients with mild to moderate renal impairment, as <1% of the dose is excreted unchanged in the urine (Table 1). As a result, dos-age adjustment is not necessary. As a cautionary note, however, zaleplon has not been adequately studied in individuals with severe renal failure or those undergoing hemodialysis.10,59

Mood Stabilizers

LithiumA known side effect of lithium is nephro-

toxicity. A review that included data from 14 separate studies reported that the prevalence of reduced glomerular filtration associated with chronic lithium therapy was approximately 15%.60 In patients with renal failure, lithium can be used cautiously where reliably manag-ing the psychiatric and renal condition can be assured.20

The renal clearance of lithium declines pro-portionally with the decline in renal function to a threshold of CrCl 30 mL/min.20 Treatment studies regarding the kinetics of lithium in ESRD are relatively limited. A dose reduction in patients with compromised renal function is of paramount importance in order to avoid toxicity as a result of lithium accumulation.20 Lithium is a small molecule that is largely removed by dialysis.20 Typically, a single supple-mentary dose given post-dialysis would be suffi-cient to maintain steady-state plasma levels.20

Antiepileptics

CarbamazepineCarbamazepine is almost entirely metabo-

lized by the cytochrome P450 enzyme system

in the liver.34 It is first metabolized to the active epoxide metabolite; further metabolism yields inactive metabolites that are excreted by the kidney.34 An insignificant amount of parent or active metabolite is excreted by the kidney.34 Therefore, dose adjustment is not necessary for carbamazepine in renal failure. Although 20%-50% of carbamazepine is extracted by dialysis, a post-dialysis supplement dose is not required.34

Carbamazepine has been associated with hyponatremia and possibly interstitial nephri-tis; however, the mechanisms subserving these adverse events are not well-characterized.34 In patients with severe renal impairment it is rec-ommended that serum sodium levels are mon-itored every 3 months after the initiation of carbamazepine therapy.34

OxcarbazepineOxcarbazepine was developed through

structural alteration of carbamazepine.34 Although similar in structure, both agents are different in their pharmacokinetic profiles.34 In contrast to carbamazepine, oxcarbazepine is excreted largely via the kidney (Table 1), as the parent compound or its metabolite (ie, mono-hydroxy derivatives [MHD]).34 The clearance of MHD is linearly correlated to CrCl.61

A single-dose study involving 20 patients with varying degrees of renal insufficiency com-pared with healthy volunteers was reported.62 All subjects were administered a single 300 mg oral dose of oxcarbazepine. A modest elevation in the plasma concentration of oxcarbazepine and MHD were reported. In keeping with these observations, dose reduction was not essential in patients with CrCl >30 mL/min; however, patients with a CrCl of 15-30 mL/min required a 50% dose reduction and a prolonged titra-tion of the drug.62 In patients with a CrCl <10 mL/min, there is an increased tendency

410 Adv Ther (2009) 26(4):404-424.

for the accumulation of the glucuronides of oxcarbazepine and MHD upon multiple dos-ing.62 The association between oxcarbazepine and hyponatremia warrant close attention to serum electrolyte levels in individuals with renal disease.34

Valproic AcidNo dose adjustment is required for val-

proic acid in patients with impaired renal function owing to its minimal renal excre-tion (1%-3%).34 Hemodialysis, using low effi-ciency dialyzers, removes approximately 20% of plasma valproic acid resulting in a short-term decline in plasma concentrations. A post-dialysis supplementary dose is not nec-essary as the decline in valproic acid levels is temporary and no significant change in mean t1/2 is noted. The use of high efficiency dia-lyzers in cases of valproic acid toxicity has been reported, and has been demonstrated to significantly increase its clearance. With chronic hemodialysis, the effect of high effi-ciency dialyzers on valproic acid clearance is unknown. Rare renal adverse events associated

with the use of valproic acid, including tub-ulointerstitial nephritis, Fanconi syndrome, and hyponatremia, have been reported in a few cases.34,63,64

GabapentinPharmacokinetic studies on gabapentin

have documented that this agent is absorbed by a saturable process; therefore, an increase in dose will lead to a decrease in bioavailabil-ity.34 They also confirmed that gabapentin is not hepatically metabolized and is eliminated entirely unchanged by the kidney.34 Renal fail-ure does not affect the extent of gabapentin absorption.65 On the other hand, the clearance of gabapentin was significantly altered, result-ing in an accumulation with a corresponding increase in t1/2 and the occurrence of dose-dependent toxicity (eg, somnolence, dizziness, ataxia, nystagmus, and tremor). Hemodialysis extracts 35% of gabapentin from the blood.36 As a result, a 200-300 mg dose is suggested after each session. The effect of peritoneal dialysis on the kinetics of gabapentin has not been investigated.34

Adv Ther (2009) 26(4):404-424. 411

Table 1. Psychotropic drug pharmacokinetics for patients with renal failure. (Adapted with permission.)3

Psychotropic drug Absorption Distribution Metabolism Excretion

Drug-drug interactions Dosage Half-life

Drug dialyzability References

Anti- depressants

MAOI

Isocarboxazid ND ND ND ND ND ND ND ND=C

ND=HP

ND=P

4

Phenelzine ND ND ND ND ND No dosage adjustment for CKD

ND ND=C

ND=HP

ND=P

4,5

Tranyl-cypromine

ND ND ND ND ND ND ND ND=C

ND=HP

ND=P

4,5

RIMA

Moclobemide Absolute oral bioavailability: 55% (healthy and CKD)

absorption time for CKD

Vd: 84 L (healthy and CKD)

Protein binding: 50% (altered, often , with CKD)

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

Primarily hepatic

<1% renal clearance

Systemic clearance (40 L/h)

ND ND 1.6 h (healthy and CKD)

ND 6

Selegiline *AUC 4 and 6× in CKD:

Selegiline (2.81 ng h/mL vs. 16.7 ng h/mL)

l-Amphetamine CKD

(287 ng h/mL vs. 413 ng h/mL)

l-Methamphet-amine 2× (572 ng h/mL vs. 957 ng h/mL)

Desmethylselegi-line (101.5 ng h/mL vs. 141.0 ng h/mL) (compared with control group)

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

ND ND ND ND * t½:

Desmethyl-selegiline (5.1 h vs. 8.4 h)

l-Metham-phetamine (14.0 h vs. 28.2 h)

l-Amphet-amine (18.5 h vs. 41.9 h) (compared with control group)

ND=C

ND=HP

ND=P

4,7

(continued on next page)

412 Adv Ther (2009) 26(4):404-424.

Table 1. (Continued)




Miscellaneous

Bupropion *AUC:

Hydroxy-bupropion to bupropion ratio

66%

Hydrobupropion to bupropion ratio 69%

Protein binding: 82%-88%

Metabolites (active): hydroxy-bupropion, erthyro-hydro-bupropion and threo-hydro-bupropion

ND ND Dosage adjustment for CKD should be considered; exact recom-mendation not available

*t½ :

Bupropion (34.2 h vs. 14 h)

Hydroxy-bupropion (24 h vs. 34 h, [single dose] 38 h [multiple dose])

No=C

No=HP

No=P

4,5,8,9

Maprotiline ND ND Metabolites: desmethyl-maprotiline, maprotiline-N-oxide

ND ND ND 48-51 h (healthy)

CKD: ND

No=C

ND=HP

U=P

5,10

Reboxetine† *AUC (ng h/mL): 4140 (mild CKD), 4462 (moderate CKD), 5923 (severe CKD), vs. 2106 (healthy)

*Protein binding:

97% (healthy)

~95% (mild CKD)

~95% (moderate CKD)

~95% (severe CKD)

ND Mainly hepatic <10% renal clearance (drug unchanged)

ND dose recom-mended:

2 mg b.i.d, (for CKD)

8-10 mg/day (healthy)

*t½:

13 h (healthy)

~24 h (mild CKD)

~23 h (moder-ate CKD)

~26 h (severe CKD)

ND 11

NaSSA

Mirtazapine Bioavailability:

50% (healthy)

CKD: ND

Protein binding: 85%

ND Oral clearance: 50% (severe CKD), 33 (moderate CKD)

ND Dose adjustment for CKD

t½: 39% for CKD (44.0 h vs. 31.6 h in healthy)

U=C

ND=HP

U=P

4,12

Serotonin agonists

Nefazodone Bioavailability:

20% (healthy)

CKD: ND


Primary metabo-lites: p-hydroxy-nefazodone, m-CPP, hydroxy-nefazodone, triazoledione

ND ND 25 mg b.i.d. (healthy)

No dosage adjustment for CKD

Moderate CKD and healthy t½ are the same

U=C

ND=HP

U=P

4,5,8

Trazodone Absolute bio-availability:

80% (healthy)

CKD: ND


Major me-tabolite: m-chlorophenyl-piperazine

ND ND ND Parent drug t½ does not in hemodialysis patients

U=C

ND=HP

U=P

4,8


Adv Ther (2009) 26(4):404-424. 413





SNRI

Duloxetine AUC:

2× (dulox-etine), 7 and 9× (glucu-ronide metabo-lites) for CKD

Protein binding: >90%

Major:

4-hydroxy dulox-etine glucuronide

5-hydroxy, 6-methoxy duloxetine sulfate

Minor:

25 metabolites (glucuronide conjugates)

70% excreted via urine, 20% excreted via feces

ND CrCl <30 mL/min (avoid )

CrCl ≥30 mL/min no adjustment (40-60 mg/day)

Consider lower starting dose and gradual titration

8-17 h (healthy)

U=C

U=HP

U=P

4,5,13

Milnacipran† ND ND ND Primarily renal ND ND 12 h (healthy),

3× (CKD)

ND 14

Venlafaxine ND Protein binding: <30%

Metabolites: O-desmethyl-venlafaxine (active); N,O-didesmethyl-venlxine (major); N-desmethylven-lafaxine (minor)

87% excreted via kidneys

ND Healthy:

Venlafaxine: 37.5-75 mg b.i.d.-t.i.d

Venlafaxine XR: 75-225 mg q.d.

CrCl <30 mL/min:

Dose of ~37.5-112.5 mg (venlafaxine XR)

4 -5 h (healthy)

6-11 h (CKD)

No=C

ND=HP

U=P

4,5,8,10,15

SSRE

Tianeptine† Bioavailability: 99% (healthy)

AUC: of MC5 for CKD (1.1 mg/L·h vs. 0.5 mg/L·h)

Vd: 0.5-0.8 L/kg (healthy)

PB: 95%

Major metabolite: pentanoic acid- MC5

Minor metabolite: propionic acid- MC3

<3% excreted unchanged in urine, 20%-25% excreted via urine as conjugate

0.2 L/h tianep-tine clearance, 1.1 L/h MC5 clearance

Salicylcic acid

Protein binding

in tianeptine dose if taken with salicy-clic acid

12.5 mg t.i.d. (healthy)

12.5 mg b.i.d (CKD)

t½: of MC5 for CKD (4.9 h vs. 14.2 h)

ND 16


414 Adv Ther (2009) 26(4):404-424.





SSRI

Citalopram High bio-availability with oral administration

ND Metabolite (active):

Desmethyl- citalopram,

Didesmethyl-citalopram, citalopram-N-oxide

20%-23% excreted via urine

Clearance by 40% (CKD), 10-53 mL/min clearance (CKD) vs. 66 mL/min (healthy)

ND 20-60 q 24 h (healthy) 10-60 mg/day (CKD)

35% (CKD) No=C

No=HP

U=P

4,5,8,17

Escitalopram ND Protein binding: 56%

Major metabo-lite: S-didem-ethyl-citalopram

Renal clearance: 0% (CKD)

Oral clearance:

15% (CKD)

ND Initial dose: 10 mg/day (healthy and mild to moderate CKD)

t½:

35% (CKD)

27-33 h (healthy)

S-didemethyl-citalopram: 50-54 h (healthy) (multiple doses)

ND=C

ND=HP

ND=P

4,8,17

Fluoxetine ND Protein binding: 95%

Major metabolite (active): norfluoxetine

ND ND 20 mg/day (healthy)

No dose adjustment (CKD)

1-4 days (healthy), 1.8 days (CKD)

Norfluoxetine: 7-15 days (healthy)

No=C

ND=HP

No=P

4,5,10

Fluvoxamine AUC:

860 µg/h/L (healthy)

CKD: ND


ND ND ND No dose adjusment

t½:

8-28 h (healthy)

CKD: ND

U=C

No=HP

U=P

4,5,8

Paroxetine ND Protein binding: 95%

ND ND ND 20-60 mg/day (healthy)

10-30 mg/day (CKD)

t½: 10-25 h (healthy) vs. 11-55 h (CKD)

No=C

ND=HP

No=P

4,5,8,10

Sertraline ND Protein binding: 98%

Metabolite (active): desmethyl-sertraline

ND ND 50-200 mg/day (healthy and CKD)

t½:

, 24-36 h (healthy)

42-92 h (CKD)

No=C

ND=HP

U=P

4,5,8


Adv Ther (2009) 26(4):404-424. 415





Tricyclic anti-depressants

Amitriptyline ND ND Metabolites (active): nortrip-tyline, hydroxy-amitriptyline, hydroxy-nortrip-tyline

ND ND 25 mg q 8 h (healthy)


t½: 32-40 h (healthy and CKD)

No=C

ND=HP

No=P

4,5,10

Amoxapine ND Vd: 85%


Metabolites (active): 8-hydroxy-amox-apine, 7-hydroxy-amoxapine

ND ND 5-200 mg/day (healthy)


t½:

8-30 h (healthy)

CKD: ND

U=C

ND=HP

U=P

4,5,10

Clomipramine ND Protein binding: 97%

Metabolite (ac-tive): desmethyl-clomipramine

24%-32% via urine, 51%-60% via faeces

ND ND ND U=C

ND=HP

U=P

4

Doxepin ND Protein binding: 80%-85%

Metabolites (active): desmethyl-doxepin

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

ND 25 mg q 8 h (healthy)


8-25 h (healthy)

10-30 h (CKD)

No=C

ND=HP

No=P

4,5,10,18

Imipramine ND ND Metabolites (active): desmethyl-doxepin

ND ND 25 mg q 8 h (healthy)


ND No=C

ND=HP

No=P

4,5,10

Nortriptyline ND Plasma values (ng/mL) 29.8%

74.5% for CKD


Metabolites (active): 10-hydroxy-notriptyline, Z-10-hydroxy-notriptyline

ND ND 25 mg q 6-8 h (healthy)


t½:

18-93 h (healthy)

15-66 h (CKD)

No=C

ND=HP

No=P

4,5,10,19

Protriptyline ND ND ND ND ND No dosage adjustment for CKD

ND No=C

ND=HP

No=P

4,5

Trimipramine ND ND ND ND ND No dosage adjustment for CKD

ND U=C

ND=HP

U=P

4,5

Mood stabilizers

Lithium Bioavailability:

80%-100% (healthy)

CKD: ND

Vd: 0.7-1.0 L/kg

Protein binding: 0%

Not metabolized

Primarily via kidneys

Clearance: 10-40 mL/min

Diuretics (thiazide diuretics) clearance 40%-68%

NSAIDs

Relative con-tra-indicated (severe CKD)

GFR >50 mL/min (no dose ad-justment), GFR 10-50 mL/min ( dose 50%-75%), GFR <10 mL/min ( dose 25%-50%)

t½:

18-36 h (healthy)

CKD: ND

Yes=C

Yes=HP

Yes=P

4,20


416 Adv Ther (2009) 26(4):404-424.





Anxiolytics/hypnotics

Benzo- diazepines

Alprazolam *AUC (h ng/mL): 441.2 (healthy), 349.9 (C and HP), 592.1 (CAPD) for 2 mg

*AUC (h ng/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): 1.28 (healthy), 1.14 (C and HP), 1.05 (CAPD) for 0.5 mg


Metabolites: α-hydroxy-alprazolam, 4-hydroxy-alprazolam

15% α-hydroxy-alprazolam excreted via urine, <1% 4-hydroxy-alprazolam excreted via urine

ND 0.25-5 mg t.i.d. (healthy)

No dosage adjust-ment for CKD

t½:

9-19 (healthy)

11.22 h (C and HP)

18.43 h (CAPD) for 2 mg

No=C

ND=HP

U=P

4,10,21

Buspirone Absolute bio-availability: 4% (healthy)

AUC: 2× (CKD) for 20 mg (single dose)

*AUC (µg/L h): 2.89 (healthy), 6.63 (mild CKD), 4.64 (moderate CKD), 4.09 (severe CKD)

Vd: 5.3 L/kg (healthy)


Metabolite: 1-pyrimid-inyl-piper-azine (or 1-PP)

Systemic clearance: 1.7 L/h/kg (healthy)

<1% unchanged drug excreted (healthy)

ND 15 mg/day (healthy)

No dosage adjust-ment for CKD

*t½: 2.5 h (healthy)

*t½:

3.18 h (healthy)

12.61 h (mild CKD)

4.34 h (mod-erate CKD)

2.74 h (severe CKD)

No=C

ND=HP

ND=P

4,5,22

Chlor-diazepoxide

ND Protein binding: 90%-98%

ND ND ND 15-100 mg/day (healthy)

No adjustment (mild-moderate CKD)

50% dose: 7.5-50 mg/day (severe CKD)

t½:

5-30 h (healthy)

CKD: ND

No=C

ND=HP

U=P

4,5,10

Clonazepam ND Protein binding: 85%

No active metabolites

ND ND 0.5 mg t.i.d.


t½:

18-80 h (healthy)

CKD: ND

No=C

ND=HP

U=P

4,10


Adv Ther (2009) 26(4):404-424. 417





Diazepam ND Protein binding: 98%

Metabolites (active): desmethyl- diazepam, oxazepam

ND ND 5-40 mg/day


t½:

Parent drug 92 h (desmethyl-diazepam 57.3 h) (healthy)

Parent drug 37 h (desmethyl-diazepam 36.1 h) (CKD)

No=C

ND=HP

U=P

4,10

Lorazepam ND Protein binding: 85%


ND ND 1-2 mg b.i.d. or t.i.d. (healthy), 0.5-2 mg b.i.d. (CKD)

t½:

9-16 h (healthy)

32-70 h (CKD)

No=C

ND=HP

U=P

4,5,10

Midazolam ND Protein binding: 94%-97%

Free fraction in CKD (6.5% vs. 3.9%)

Metabolite: α1-hydroxy-midazolam

*Clearance: α1-hydroxy mida-zolam (186 mL/min), midazolam (198 mL/min) (healthy)

α1-hydroxy-midazolam (14 mL/min), midazolam (132 mL/min) (CKD)

ND Drug monitor-ing suggested

No dosage adjustment (mild-moderate CKD), 50% dose (severe CKD)

t½ (α1-hydroxy-midazolam):

0.8-1 h (healthy)

CKD: ND

No=C

ND=HP

U=P

4,5,23

Nitrazepam ND *Vd: 228 L (3.61 L/kg) (healthy), 283 L (4.16 L/kg) (CKD)

*Protein binding: for CKD

Primarily hepatic

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

ND No dosage adjustment for CKD

t½:

24.5 (healthy)

31.5 (CKD)

ND 10,24

Oxazepam ND Protein binding: 86%-99% (varies)


ND ND 30-120 mg/day (healthy and CKD)

No dose adjustment (CKD)

t½:

6-25 h (healthy)

25-90 h (CKD)

No=C

ND=HP

U=P

4

Temazepam ND Protein binding: 96%


ND ND 15-30 mg h.s.


t½:

4-10 h (healthy)

CKD: ND

No=C

ND=HP

U=P

4,10

Triazolam ND Protein binding: 89%

Metabolite: α-hydroxy-triazolam

ND ND 0.125-0.5 mg/day


t½:

2-4 h (healthy)

2.3 h (CKD)

No=C

ND=HP

U=P

4,10


418 Adv Ther (2009) 26(4):404-424.





Non- benzodiazepines

Zaleplon Systemic bioavailability:

30% (healthy)

CKD: ND

Vd: 275 L for 10 mg (healthy)



Primarily hepatic

<1% excreted unchanged via urine

ND Healthy dose 5-20 mg h.s.

Dose adjusted for severe CKD

t½:

1 h (healthy)

CKD: ND

ND=C

ND=HP

ND=P

4,10,25

Zolpidem Bioavailability:

70% (healthy)

CKD: ND

Vd: 66 L for 10 mg


free fraction for CKD


Primarily hepatic

≤1% excreted via urine

Metabolites excreted via urine (48%-67%)

ND 10 mg/day (healthy)

Dosage adjustment for severe CKD ( 50%)

t½:

2-3 h (healthy)

4-6 h (CKD)

No=C

ND=HP

U=P

2,10,25,26

Zoplicone Bioavailability:

80% (healthy)

CKD: ND


Metabolites (active): N-oxide metabolite

Metabolites (inactive): N-desmethyl metabolite

Metabolites: 50% excreted via lungs, 30% (initial) excreted via urine

Erythro-mycin and cimetidine

ND t½:

5 h (healthy)

CKD: ND

ND 25,27

Antipsychotics

Typical

Amisulpiride *AUC (ng h/mL):

404 (healthy)

754 (mild CKD)

1709 (moderate CKD)

4606 (severe CKD)

ND ND Excreted unchanged in feces and urine

Cyclosporine A inhibits P-glycopro-tein

ND *t½:

11.2 h (healthy)

14.0 h (mild CKD)

14.4 h (moder-ate CKD)

25.8 h (severe CKD)

ND 4,28

Chlor-promazine

ND ND Metabolites (active):

CPZ-N-oxide

CPZ sulfoxide

7-hydroxy-CPZ

nor1-CPZ

nor2-CPZ

nor2-CPZ sulfoxide

3-hydroxy-CPZ


CKD: ND

t½: 11-42 (healthy and CKD)

No=C

ND=HP

No=P

4,5,10

Haloperidol ND Protein binding: 90%

Metabolite (active): hydroxy- haloperidol

<1% excreted via urine

ND 1-2 mg q 8-12 h



No=C

ND=HP

No=P

4,10


Adv Ther (2009) 26(4):404-424. 419





Perphenazine ND ND ND ND ND 4-16 mg b.i.d.-q.i.d. (healthy)

CKD: ND

t½: 9.5 h (healthy)

CKD: ND

U=C

ND=HP

U=P

10,28

Sulpiride *AUC (mg/h/L): 8.27 (i.v.), 2.41 (oral) (healthy)

*Absolute bioavailability (sulpiride sulfate):

35% (healthy)

CKD: ND

*Vd: 1.19 L/kg (i.v.), 2.05 L/kg (oral)

ND *36.9% excreted via urine

ND ND *t½:

6.63 h (i.v.)

6.73 h (oral) (healthy)

CKD: ND

ND 4,29

Thioridazine ND ND Metabolites (active): mesoridazine, sulforidazine


Dosage ad-justment not studied; use in CKD is best avoided

t½:

21-24 h (healthy)

CKD: ND

U=C

ND=HP

U=P

4,10

Triflu-operazine

ND ND ND ND ND ND ND No=C

ND=HP

No=P

4

Atypical

Aripiprazole Bioavailability: 87% (healthy)

AUC (ESRD): 15% (aripipra-

zole), 7% (dehydro-

aripiprazole), (aripiprazole)

Vd: 404 L (4.9 L/kg) (healthy)


Primarily hepatic

Metabolites (active): dehydro-aripip-razole

Oral clearance: 3.3-4.0 L/h (healthy)

Renal excre-tion: 25% (<1% unchanged), 55% excreted via feces (18% unchanged)

Significant drug inter-actions with drugs metabolized on enzyme 2D6 and 3A4



t½:

47-68 h (healthy)

CKD: ND

U=C

U=HP

U=P

10,30

Clozapine ND Vd: 2-7 L/kg (healthy)


Primarily hepatic

Metabolites (ac-tive): N-desm-ethyl-clozapine

27%-50% ex-creted unchanged (systemic clearance)

ND 12.5-450 mg (healthy)

CKD: ND (titrate to response)

t½:

9-17 h (healthy)

CKD: ND

ND 4,30

Olanzapine Bioavailabilty:

60% (healthy)

CKD: ND


Vd: 16±5 L

Metabolites (active): N-desmethyl olanzapine, olan-zapine 10-N-glucuronide

Total urine recov-ery (56.2%), fecal recovery (30%)

Clearance via urine: N-desmethyl olanzapine (0.8%), 10-N-glucuronide olanzapine (28.6%), olanzapine (17.7%)

ND 5-20 mg (healthy and CKD)



No=C

ND=HP

No=P

2,10,30,31


420 Adv Ther (2009) 26(4):404-424.





Quetiapine AUC: 42% for CKD than in healthy (533 vs. 366 ng h/mL)

Vd 48% for CKD than in healthy (593 vs. 310 L)


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

Quetiapine sulfoxide metabolite

<1% excreted unchanged via urine

Oral clearance: 53% (healthy), 64% (CKD)

ND 150-750 mg/day b.i.d. or t.i.d.


t½:

5-6 h (healthy)

4.1 h (CKD)

ND 4,31,32

Risperidone ND Protein binding: 90%

Metabolites (active): 9-hydroxy-risperidone

Clearance: 10% renal, 40% of 9-hydroxy risperidone

Oral clearance: 50% in CKD

ND 1-3 mg b.i.d. (healthy), 0.5-1.5 mg b.i.d. (CKD)

t½:

3-30 h (healthy)

19 h (9-hydroxy-risperidone) (healthy)

25 h (9-hydroxy-risperidone) (CKD)

ND=C

ND=HP

ND=P

4,10,33

Ziprasidone *AUC (ng h/mL):

272 (healthy)

370 (mild CKD)

250 (moderate CKD)

297 (severe CKD)


Inactive metabolites

ND ND 20-80 mg b.i.d. (CKD)

Dose adjustment not needed in mild and moder-ate CKD

*t½:

5-7 h (healthy)

6.4 h (mild CKD)


4.2 h (severe CKD)

No=C

ND=HP

U=P

4,10,33

Antiepileptics

Carba- mazepine

ND Vd: 0.8 kg


ND Clearance: 1% via kidney, 99% via liver

Valproic acid, felbemate. Digoxin, cyclosporin

10-25 kg/day maintenance dose (healthy)

No dose adjust-ment for CKD

t½:

9-15 h (healthy)

CKD: ND

No=C

Yes=HP

No=P

4,34,35

Valproic acid ND Protein binding: 90%

Primarily via liver

Clearance: 1%-3% excreted unchanged via urine

ND No dosage adjust-ment for CKD

ND No=C

ND=HP

No=P

4,34

Gabapentin Bioavailability when dose

(300 mg=57%, 1600 mg=35%)

Vd: 0.7 kg ND Primarily renal excretion

Clearance: 80% via urine

ND Dosage adjust-ment for CKD

400-600 mg t.i.d. (healthy)

200-300 mg b.i.d. (mild-moderate CKD)

100-150 mg/day (severe CKD)

t½:

5-7 h (healthy)

CKD: ND

Yes=C

L=HP

ND=P

4,34-36


Adv Ther (2009) 26(4):404-424. 421





Lamotrigine Bioavailability: 98%

Vd: 0.5-0.7 kg (healthy and CKD)

Protein

ND Clearance:

10% renal

90% liver

Other anti-epileptic drugs change the t½ of lamotrigine immensely


Dose adjustment for CKD

t½:

24-35 h (healthy)

42.9 h (CKD)

13 h (during hemodialysis)

No=C

20% =HP

U=P

4,34,35,37

Oxcarbazepine Almost completely absorbed


Primarily hepatic

Clearance: 50% excreted via urine

ND CrCl >30 mL/min 300-600 mg b.i.d.

CrCl 15-30 mL/min 50% of starting dose

CrCl <15 mL/min lacking data

t½: 8-10 h (healthy)

ND=C

ND=HP

ND=P

4,34

Pregabalin *AUC (µg h/mL):

15.9 (healthy)

28.2 (mild CKD)

52.3 (moderate CKD)

101 (severe CKD)

*Vd (oral):

42.1 L (healthy)

42.4 L (mild CKD)

35.7 L (moderate CKD)

34.9 L (severe CKD)

Protein binding: 0%

ND >90% of drug eliminated unchanged via urine

ND *150-600 mg/day b.i.d or t.i.d. (healthy)

75-300 mg/day b.i.d. or t.i.d. (mild CKD)

25-150 mg/day b.i.d. or q.d. (mod-erate CKD)

25-75 mg/day q.d.

*t½: as CKD

9.11 h (healthy)

16.7 h (mild CKD)


48.7 h (severe CKD)

Yes=C

L=HP

ND=P

4,5,34

Topiramate ND Protein binding: 15%-20%

ND Excreted unchanged via urine: 40%-80%

ND 100-200 mg b.i.d. (healthy)

50-100 mg b.i.d. (mild-severe CKD)

ND Yes=C

L=HP

ND=P

4,34

Psychostimulants

Dexamphet-amine

ND ND ND ND ND 2.5 mg q.d. initial (healthy)

t½: 12 h (healthy)

ND=C

ND=HP

ND=P

4,8

Methyl-phenidate

ND ND ND 50% excreted via bile

ND No dosage adjustment for CKD

ND U=C

ND=HP

U=P

4,8,38

Modafinil 40%-65% absorp-tion (oral)

*AUC (mg/h/L): 56.9 (healthy) on 200 mg

AUC with CKD

*Vd: 0.8 L/kg (healthy)


Primarily hepatic

<10% of oral dose excreted unchanged

Modafinil sulfone inhibits CYP2C19

200 mg (initial) (healthy)

t½:

11.7 h (healthy) on 200 mg

with CKD

ND=C

ND=HP

ND=P

8,39

*Indicates that data were obtained from a study.†Indicates that the drug is not available in the USA. AUC=area under concentration-time curve; C=conventional hemodialysis; CAPD=continuous ambulatory peritoneal dialysis; CKD=chronic kidney disease; ESRD=end-stage renal disease; GFR=glomerular filtration rate; HP=high-permeability hemodialysis; L=no published data exists, extrapolated information from studies using conventional hemodialysis techniques indicates significant drug removal is likely ; MAOI=monoamine oxidase inhibitors; NaSSA=noradrenergic and specific serotonergic antidepressant; ND=no data available; P=peritoneal dialysis; RIMA=reversible inhibitor of monoamine oxidase-A; SNRI=serotonin and norepinephrine reuptake inhibitors; SSRE=selective serotonin reuptake enhancer; SSRI=selective serotonin reuptake inhibitor; t½=elimination half life; U=significant drug removal unlikely (based on pharmacokinetic drug qualities); Vd=volume of distribution; Yes=dialysis increases plasma clearance by 30% or greater, dosing to supplement might be needed or dosing after dialysis is recommended.

422 Adv Ther (2009) 26(4):404-424.

CONCLUSIONS

Taken together, deterioration in renal function significantly affects the pharmacokinetic profile of psychotropic agents. The use of these agents in this patient population is not uncommon due to the co-occurrence of mental and renal disor-ders. In this context, caution is warranted when prescribing psychotropic agents to individuals with impaired renal function. Guiding priciples include, but are not limited to, slow titration of doses, low-dose treatment initiation, and careful monitoring of clinical response.

ACKNOWLEDGMENTS

RSM has received research or grants from Stanley Medical Research Institute, and National Alliance for Research on Schizophrenia and Depression (NARSAD). He has also received pharmaceutical research grants from Eli Lilly, Janssen-Ortho, and Shire. He has also served on advisory boards for AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen-Ortho, Solvay/Wyeth, Eli Lilly, Organon, Lundbeck, Biovail, Pfizer, Shire, and Schering-Plough. He has taken part in speaker bureaus for Janssen-Ortho, AstraZeneca, Eli Lilly, Lundbeck, Biovail, and Wyeth; and has taken part in CME activities for AstraZeneca, Bristol-Myers Squibb, France Foundation, I3CME, Solvay/Wyeth, Physicians’ Postgraduate Press, and CME outfitters.

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Psychotropic drugs and renal failure: Translating the evidence for clinical practice