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Currently, there are 350,000 Americans who receive maintenance dialysis for renal failure, and this predominantly elderly population with multiple comorbidities is growing.
Psychiatrists are often asked to medicate patients with chronic kidney disease (CKD). Currently, there are 350,000 Americans who receive maintenance dialysis for renal failure, and this predominantly elderly population with multiple comorbidities is growing. In selecting psychotropic medications, psychiatrists need to be aware of the effects of renal dysfunction on medication absorption (ie, bioavailability), volume of distribution, metabolism, and excretion of the parent drug and the respective metabolites.
A few psychotropic medications, such as lithium, are primarily excreted by the kidneys, whereas most others are fat-soluble and are metabolized by the liver. Although the Physicians’ Desk Reference routinely recommends the use of partial dosages of psychotropic medications for renal patients, the data that support these recommendations are limited. There are even fewer empirical data available about psychotropic medication use for children. Thus, the clinician will find it necessary to engage in medication trials that are influenced by individual patient tolerability, response, and changes in clinical status.
In 2005, more than 106,000 patients with newly diagnosed end-stage renal disease (ESRD) began dialysis therapy, joining a dialysis population of 341,000 people and a transplant population of 144,000.1 Kidney disease involves people of all ages, including children, but most individuals fall into the adult and geriatric categories.
As shown in Table 1, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative has divided chronic kidney disease into 5 stages. This article emphasizes the management of persons who fall into stages 4 and 5, in which renal function is greatly compromised, necessitating renal replacement therapy. In the nephrology literature, they have traditionally been labeled as having ESRD (the stages of CKD are a more recent taxonomy)-the term we will use throughout this article.
Although the psychiatric epidemiological literature has glaring limitations, clinicians need to familiarize themselves with the prevalence and hazards posed by psychiatric disorders in renal patients.2 For example, precisely quantifying the rate of depression in dialysis patients is limited by heterogeneity in study design, assessment procedures, and sample composition. Reported rates of depression have ranged from 0% to 100%. This variation underscores the need for a more refined and systematic approach to evaluating depression in renal patients. Furthermore, medication-related problems are extraordinarily frequent and were identified in 98% of a sample of 133 hemodialysis patients.3 In this study, patients had a mean of 6 ± 2.3 comorbid illnesses; 11 ± 4.2 different drugs were prescribed per patient, and a total of 475 medication-related problems were detected.
Pharmacokinetics in ESRD
Patients with renal failure may evince alterations in any pharmacokinetic parameter-absorption, volume of distribution, metabolism, or excretion (Table 2).4 Consequently, medication-related problems are frequent occurrences. Two other factors may be of equal or even greater importance, and both influence pharmacokinetics: Many ESRD patients are elderly, and the prevalence of associated severe comorbid disorders (eg, diabetes, hypertension) is high.
Bioavailability is the extent to which a dose of drug enters the systemic circulation. An oral dose is first absorbed from the GI tract; it subsequently passes through the liver, where metabolism and biliary excretion may occur. A decrease in bioavailability for some agents occurs at the level of drug absorption from the GI tract. Alterations in gastric alkalinity (caused by excessive urea generation by the internal urea-ammonia cycle) result in alterations in gastric pH that affect the absorption of psychotropic drugs.
Rival mechanisms that affect absorption in patients with renal failure include nausea and vomiting as well as delayed gastric emptying (from diabetic gastroparesis). Diabetes mellitus is a common cause of ESRD and is an important factor to consider when prescribing because of the relationship between atypical neuroleptics and increased serum glucose levels.
Volume of distribution entails the effects of dilution or concentration of medications in the body. The 2 overarching factors that influence distribution are the volume of distribution and protein binding. It is not uncommon in ESRD for elderly patients to become cachectic. These patients have less fluid and less body mass and a decreased volume of distribution. Consequently, a given dose results in a greater concentration of medication in a cachectic patient than in a non-cachectic patient.
The issue of protein binding is especially significant in ESRD. The principle plasma protein responsible for binding to acidic drugs is albumin, while for alkaline drugs, it is α1-acid glycoprotein.3 Proteinuria and hypoalbuminemia are frequently found in renal failure, and there is an accumulation of endogenous binding inhibitors (eg, organic acids, uremic toxins). Binding inhibitors compete with drugs for the carrier protein binding site, and albumin undergoes conformational changes with hypothesized changes in binding properties. The results are diminished protein binding and an increase in the bioactive free fraction of acidic drugs in plasma. All other factors remaining constant, the greater the protein binding of a medication, the lower the dose of the drug required in ESRD, since there is a greater risk of toxicity when increased amounts of the free, unbound forms of acidic drugs are in the plasma.
Another factor to consider is that the circulating concentration of α1-acid glycoprotein may increase in patients maintained with renal transplant or hemodialysis. The effect may be a decrease in the unbound circulating fraction and diminished biological activity of the drug.
The metabolism or degradation of a medication is probably the area of pharmacokinetics that is least familiar, particularly because the intermediate products of metabolism are difficult to isolate and identify. The rate of renal metabolism by the renal brush border is predicted to decrease as the glomerular filtration rate (GFR) declines. In addition, evidence suggests that metabolism by the liver is variably altered in ESRD. Both the expression and function of cytochrome P-450 (CYP) 2C9 and CYP3A4 are decreased in severe ESRD.5 Although the literature is sometimes contradictory, it appears that in renal failure there is a general slowing of chemical reduction and hydrolysis, but there are normal rates of glucuronidation, microsomal oxidation, and sulfate conjugation.
Excretion takes place through the GI tract and from the kidney to the bladder, and this latter avenue is obviously absent following renal failure. Glomerular filtration, active tubular secretion, and passive tubular reabsorption are the 3 distinct mechanisms of excretion by the kidney, and all of them are affected in ESRD. The artificial substitution by a dialysis machine results in intermittent excretion rather than the continual process performed by healthy kidneys. Drugs are only occasionally metabolized to pharmacologically active compounds that are then normally excreted in urine. Fortunately, most psychotropic medications are metabolized by the liver, eliminated in bile, and excreted in feces.
Prescribing medications for adults
There is a paucity of data documenting the efficacy and pharmacokinetics of psychotropic agents in patients with renal impairment.6,7 Most research is based on a handful of subjects, and well-controlled trials in psychopharmacology are rare. There are very few in vivo studies of pharmacokinetics in persons without kidney disease or patients with ESRD. Accordingly, in the absence of empirical data, clinical experience suggests that the majority of psychotropic medications can be safely used in the ESRD population. Some important considerations and exceptions are noted below.
Most psychotropic medications are fat-soluble and have large volumes of distribution. They are metabolized in the liver and metabo-lites are eliminated in urine and bile. Most of these drugs easily pass the blood-brain barrier, and they are not dialyzable. Attention needs to be paid to medications that have active metabolites-those that are highly plasma protein–bound, and those that have altered pharmacokinetics or pharmacodynamics.8
Lithium is the only known psychotropic medication in which long-term use is associated with nephrotoxicity, renal insufficiency, and even ESRD. Although renal function will often improve if the drug is stopped, some patients require maintenance dialysis or kidney transplant. Attempts should be made to transition to the classic anticonvulsant medications divalproex and carbamazepine, but they may be inadequate mood stabilizers.
For the minority of bipolar patients with ESRD who continue to require lithium, treatment involves administration of a single dose (usually 600 mg) after each dialysis session. Because lithium is a readily dialyzable, small molecule, it is entirely eliminated by dialysis, and a single post-dialysis dose will result in a steady serum level. Serum lithium levels should be measured immediately before dialysis. If lithium is used to augment the therapeutic effects of antidepressants in treatment-resistant unipolar depression, a smaller dose (eg, 300 mg) may be given after dialysis sessions.
Prescribing medications for children
The ultimate goal for children with ESRD is kidney transplant. However, many will live years before transplant occurs, and many may need psychiatric care before and after the transplant. With the exception of recommended dosing of anticonvulsants, 2 treatment reviews do not list any psychotropic medications in their Tables of dosing considerations for children with significant renal impairment.9,10 The review by Trompeter11 predates the dramatic increase in use of psychoactive medications for children with a variety of internalizing and externalizing behavioral conditions.
Pediatric ESRD differs from the adult version in which diabetes mellitus and hypertension are more frequent long-standing comorbid disorders.12 Pediatric psychopharmacology ideally determines dosing on the basis of body surface area instead of body weight, but minimal information is available concerning either application with psychotropic medications.10 For children on dialysis and in need of psychiatric management, rely on the pediatric axiom for dosing: “start low and go slow.”13
Many of the psychotropic medications-with the exception of the typical neuroleptics and somnolent tranquilizers-are used in pediatric psychiatry. In this population, some are relied on more often than others (eg, fluoxetine is preferred over paroxetine because of its longer half-life and research data that support its indication and use). Conservative initial dosing for pediatric indications would frequently be a 50% to 75% lower dose than the typical adult dose, with allowances to increase dosing during subsequent care, depending on tolerability, response, and changes in clinical status. This is especially the case for stimulant compounds such as amphetamine and methylphenidate, which have a higher proportion of elimination through the kidneys than many other medications.14
Because there are no available data, even the package inserts for the stimulant medications do not specify any dosing adjustments to be made for children with ESRD. It appears that methylphenidate or the clearance of its inactive hepatic metabolite, ritalinic acid, is not as sensitive to the alkalinization of urine as amphetamine products.15
With renal dysfunction and ESRD, lower dosing and slower increases during the clinical use of mixed amphetamine salts and dextroamphetamine is prudent. The alkalinization of urine associated with renal disease reduces the clearance of amphetamine and its metabolites to as low as 1%, while acidification increases clearance and can there-fore reduce levels. Consulting psychiatrists, in coordination with the primary care team and nephrolo-gists, can be of assistance with assessing the indications for and judicious use of psychiatric medications in any child with ESRD and psychiatric comorbidities. Families need to be fully informed as to treatment shortcomings.
Psychopharmacological pearls and renal failure
There are no formal guidelines for the treatment of psychiatric disorders in patients with renal failure, so the following points are based on clinical experience.
• ESRD is defined as a GFR of less than 15 mL/min/1.73 m2, in most cases accompanied by signs and symptoms of uremia
• Individuals with ESRD are in need of dialysis/transplant; some patients may require dialysis or transplant at a GFR of 15 mL/min/1.73 m2 or greater because of symptoms of uremia
• Practitioners who prescribe psychotropic agents should consider obtaining postdialysis blood drug levels to inform decisions regarding dose titration when reference levels are known
• Drug dialyzability is determined by the physical and chemical characteristics of the agent (eg, molecular size, protein binding, water solubility, volume of distribution) and the dialysis procedure (eg, dialysis membrane and flow rates)
• Peritoneal dialysis is generally much less efficient at removing agents than hemodialysis
• An agent incapable of being removed by hemodialysis cannot be removed by peritoneal dialysis
• The predominant form of CKD associated with lithium therapy is chronic tubulointerstitial nephropathy, which often presents with insidious development of renal insufficiency with minimal proteinuria
• The prevalence of reduced GFR associated with long-term lithium therapy is approximately 15%; a much smaller number of lithium-treated patients eventually have renal insufficiency that leads to dialysis
• Patients with mild to moderate chronic renal insufficiency associated with lithium can expect gradual improvement in GFR after lithium discontinuation
• Uninterrupted lithium exposure decreases the kidney’s endogenous ability for cellular regeneration; although a consensus does not currently exist as to the discontinuation threshold for lithium treatment because of diminished kidney function, it is suggested that repeated serum cre-atinine concentrations exceeding 140 μmol/L (1.6 mg/dL) indi-cate the need for nephrologist consultation
• Individuals with serum creatinine concentrations of more than 2.5 mg/dL are at very high risk for progression to ESRD compared with individuals who have serum creatinine concentrations of less than 2.5 mg/dL. Moreover, in individuals with a creatinine clearance of 40 mL/min or less, there is a higher probability of continued renal deterioration at lithium discontinuation than in those who have a creatinine clearance of more than 40 mL/min
• In patients with ESRD, a reduction in the lithium dose is required to prevent further toxicity, and a single dose of lithium is recommended after dialysis sessions; serum lithium levels obtained before and after dialysis are used to established appropriate dosing
• In treating depression, SSRIs (eg, fluoxetine) appear to be generally safe and well-tolerated; venlafaxine levels markedly increase in patients with renal failure, which theoretically could intensify hypertension, a common morbidity in ESRD; tricyclic antidepressants are generally avoided because of concern for safety and tolerability; duloxetine levels increase markedly in patients who have ESRD compared with patients who have normal renal function, and this medication is not recommended
Sizable numbers of patients have compromised renal function, and it is highly likely that psychiatrists will need to collaborate with primary care providers and nephrologists when prescribing psychotropic medications. There are unfortunately few formal pharmacological research studies that have investigated this subject, and clinicians must rely on basic knowledge of the factors that influence the effects and metabolism of psychoactive substances. This requires an appreciation of pharmacokinetics, including absorption, volume of distribution, metabolism, and excretion of the parent drug and metabolites.
Most psychotropic medications are not metabolized or excreted by the kidneys. In the absence of systematic data, caution is always necessary, but most of these medications are well tolerated and produce their accustomed beneficial effects. Renal dysfunction should not theoretically be associated with any unusual drug interactions.
Serum levels of medications such as the anticonvulsants/mood stabilizers should be monitored, especially if patients receive a renal transplant and immunosuppressants. Lithium is the only psychotropic medication associated with nephrotoxicity with long-term use.
Caution is especially required in the treatment of the pediatric population, but this group should also not be neglected because of the absence of research. Lastly, this review underscores the need for psychiatrists and primary care physicians to urge the pharmaceutical industry and other organizations to cease ignoring this subject and to begin sponsoring empirical research.
United States Renal Data System. 2011 Annual Data Report. http://www.usrds.org/adr.htm. Accessed September 30, 2011.
Levy NB, Cohen LM. End-stage renal disease and its treatment: dialysis and transplantation. In: Stoudemire A, Fogel BS, Greenberg D, eds.
Psychiatric Care of the Medical Patient.
2nd ed. New York: Oxford University Press; 2000:791-800.
Manley HJ, McClaran ML, Overbay DK, et al. Factors associated with medication-related problems in ambulatory hemodialysis patients.
Am J Kidney Dis.
McIntyre RS, Baghdady NT, Banik S, Swartz SA. The use of psychotropic drugs in patients with impaired renal function.
Turpeinen M, Koivuviita N, Tolonen A, et al. Effect of renal impairment on the pharmacokinetics of bupropion and its metabolites.
Br J Clin Pharmacol.
Cohen LM, Tessier EG, Germain MJ, Levy NB. Update on psychotropic medication use in renal disease.
Levy NB, Mirot AM. The dialysis and kidney transplant patient. In: Leigh H, Streltzer J, eds.
Handbook of Consultation-Liaison Psychiatry
. New York: Springer; 2007:205-220.
Mirot AM, Tessier, EG, Germain MG, Cohen LM. Neuropsychiatric complications and psychopharmacology of end stage renal disease. In: Berl T, Himmelfarb J, Mitch W, et al, eds.
Therapy in Nephrology and Hypertension: A Companion to Brenner & Rector’s the Kidney.
3rd ed. Philadelphia: Saunders/Elsevier; 2009:795-817.
Veltri MA, Neu AM, Fivush BA, et al. Drug dosing during intermittent hemodialysis and continuous renal replacement therapy: special considerations in pediatric patients.
Daschner M. Drug dosage in children with reduced renal function.
Trompeter RS. A review of drug prescribing in children with end-stage renal failure.
Smith PS. Management of end-stage renal disease in children.
Gleason MM, Egger HL, Emslie GJ, et al. Psychopharmacological treatment for very young children: contexts and guidelines.
J Am Acad Child Adolesc Psychiatry.
Dollery CT, ed.
. Edinburgh: Churchill Livingstone; 1991.
Patrick KS, Caldwell RW, Ferris RM, Breese GR. Pharmacology of the enantiomers of threo-methylphenidate.
J Pharmacol Exp Ther.