Antidepressants
Comorbidity rates of depression in patients with renal disease range from 14% to 30%, making use of antidepressants in renal disease common.4 Antidepressants primarily are metabolized hepatically and excreted renally. Table 217-27 summarizes recommended dosing adjustments for antidepressants.
Selective serotonin reuptake inhibitors.Escitalopram is the (S)-enantiomer of the racemic antidepressant citalopram, both of which have been shown to decrease renal clearance in patients with mild or moderate renal impairment. However, according to the package insert, no dosage adjustments are needed.17 No extensive studies have been conducted on escitalopram or citalopram, but each should be initiated at a reduced dosage and the titration schedule should be prolonged in patients with severe renal impairment or ESRD.17,18
The plasma concentration of paroxetine has been noted to be elevated in patients with severe renal impairment, and the half-life can increase to nearly 50%.4 Paroxetine should be initiated at 10 mg/d, and then titrated slowly in patients with severe renal impairment.19,28
The pharmacokinetics of fluoxetine are unchanged in any stage of renal impairment. Patients in active renal dialysis report good tolerability and efficacy.4
Serotonin-norepinephrine reuptake inhibitors. Venlafaxine and its metabolite O-desmethylvenlafaxine (desvenlafaxine) are primarily excreted via renal elimination. Studies have shown that mild renal impairment can have an effect on plasma levels of the drug, and that moderate or severe impairment can increase the venlafaxine plasma concentration. According to the package insert, a dosage reduction of 50% is recommended for desvenlafaxine and venlafaxine.20,21
No significant pharmacokinetic changes with duloxetine have been noted in patients with mild or moderate renal impairment.22 However, duloxetine’s major metabolites, which are excreted renally, have been measured to be as much as 7 to 9 times higher in patients with ESRD compared with healthy subjects; therefore, it is recommended to avoid duloxetine in patients with severe renal disease.4,22 Our review of the literature produced limited recommendations on dosing milnacipran and its enantiomer levomilnacipran in renally impaired patients. The milnacipran package insert cautions its use in moderate renal impairment and recommends a 50% dosage reduction to 100 mg/d (50 mg twice daily) in patients with severe renal impairment.23 Dosage recommendations for levomilnacipran are 80 mg/d for moderate renal impairment and 40 mg/d for severe impairment. Both agents have relative contraindications for ESRD.23,24
Tricyclic antidepressants (TCAs) are predominantly metabolized hepatically, glucuronidated, and then eliminated renally. Desipramine, imipramine, and nortriptyline have nonspecific package insert recommendations for modified dosing in geriatric patients because of an age-related decrease in renal clearance.29-31 Review articles assert that elevated glucuronidated metabolites could increase patients’ sensitivity to side effects of TCAs. Because of concerns regarding elevated glucuronidated metabolites, it has been proposed to initiate TCAs at a low dosage, titrate slowly, and maintain the lowest effective dosage in patients with renal impairment.25
Monoamine oxidase inhibitors (MAOIs) and other antidepressants. The package inserts of the MAOIs isocarboxazid, phenelzine, selegiline, and tranylcypromine provide limited data and dosage recommendations for use in the context of renal impairment.32-36 Isocarboxazid should not be used in patients with severe renal impairment, according to the prescribing information.32 There are no dosing recommendations for transdermal selegiline in mild, moderate, or severe renal impairment.37 Extra vigilance is required when using MAOIs in patients with renal disease because of an increased risk of dialysis-induced hypotension (orthostatic hypotension is a common adverse effect of MAOIs).38
Bupropion is primarily metabolized hepatically to the active metabolite hydroxybupropion. Plasma levels of this metabolite at steady state are reported to be 10 times greater than bupropion’s concentration levels in healthy subjects; plasma levels are further increased in mild renal impairment.26 Hydroxybupropion is not dialyzable, which can increase the risk of toxicity with bupropion therapy in patients with renal impairment.3 If bupropion effectively treats depression in patients with declining renal function, specifically severe renal impairment and ESRD, then decreasing the dosage to 150 mg every 3 days is recommended to lessen the risk of toxicity. 27
Mood stabilizers
Lithium has the most published literature on dosing adjustments with renal impairment. Many providers are inclined to discontinue lithium use at the first sign of any change in renal function; however, monitoring, prevention, and treatment guidelines for lithium are well established after many years of research and clinical use.39 Lithium’s prescribing information recommends dosage adjustment in mild to moderate renal impairment and lists severe renal impairment and ESRD as relative contraindications.40
A recent study proposes more assertive use of lithium in patients with renal impairment of any severity. Rej et al41 compared continued lithium treatment to discontinuing treatment in geriatric patients with chronic renal failure, and reported (1) a statistically insignificant difference in renal function between groups at 2 years and (2) a “trending decrease” in renal function at 5 years in the lithium treatment group. With closely monitored plasma levels, lithium treatment is considered a workable treatment for patients with moderate renal impairment when mood stabilizer treatment has been effective.42