Needs Assessment: This article facilitates knowledge as it relates to the safe and judicious 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.
• 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 planning 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 disclosure 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.
Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.
To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. 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: January 1, 2008. Termination date: January 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.
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@example.com.
This 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 antidepressants, 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 associated 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 individualized for each such agent. Strong pronouncements regarding contraindication 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.
Several definitions and operational criteria have been proposed 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-occurrence of mental and renal disorders invites the need for familiarity with the safety, pharmacokinetic profile, and efficacy of psychotropics in individuals with SRF. Hitherto, the evidentiary 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 conventionally categorized into absorption (ie, bioavailability), distribution, 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
Bioavailability 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 gastrointestinal 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 aluminium- or calcium-containing antacids, commonly prescribed 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 partitioning across the gastrointestinal tract membrane with a consequent 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
Following absorption, a drug is distributed across body fluids, tissues, and compartments. The two overarching factors 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 hypoalbuminemia 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 hypoalbuminemia 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 decrement 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
As 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
Drugs 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 observation 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
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/minute/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 mortality.2 Some patients may need dialysis or transplantation at GFR ≥15 mL/minute/1.73 m2 because of symptoms of uremia. 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 attention 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 physical 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 associated 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 nephrogenic diabetes insipidus. It is unequivocally established that long-term lithium administration may induce CTIN leading to renal failure (ESRD).54 A review of lithium nephrotoxicity, 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 lithium-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 associated 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 insufficiency 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 individuals 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 discontinued in the context of diminishing kidney function. For example, it has been suggested that repeat serum creatinine 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 documented that serum creatinine levels could serve as a useful biomarker in categorizing individuals at risk for progression. 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 formula) 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 complications from SRF increases at GFR levels of <60 mL/minute/1.73 m2. Complications include hypertension, malnutrition, 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 progression 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, hypertension); 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, strategies 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 consistently 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 creatinine 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 prognosticating 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 necessarily 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 recurrences 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 anticonvulsants 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 monitored carefully by blood levels (Table 3).4,53 Treatment involves administration of a single dose (usually 600 mg) after each dialysis 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 preferred 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 fluoxetine is unchanged in anephric patients.62 Additional preliminary evidence has shown that depressive symptoms were markedly ameliorated in patients who completed a 12-week course of treatment with sertraline, bupropion, or nefazodone, despite low rates of compliance overall.34,67
There are several non-SSRI antidepressants that should be used with caution with ESRD. Tricyclic antidepressants (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 completely 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 antidepressants (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 maprotiline 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, duloxetine 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 transplantation 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 paroxetine (a weak inhibitor).62
Taken 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 individualized for each psychotropic agent. Strong pronouncements 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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