We conducted a narrative literature review on studies that specifically addressed the pharmacokinetics of antidepressants in patients on hemodialysis. The search included the MEDLINE, LILACS, and Web of Knowledge databases and combined Medical Subject Headings and free-text search terms for chronic kidney disease, end-stage renal disease, renal replacement therapy, depression, and antidepressants; it was limited to studies conducted in humans, with no language or time constraints. The search yielded 212 studies. After screening titles and abstracts, 32 studies were read in full and 11 ultimately met the inclusion criteria and were included in the review. Most of the studies showed no difference in the pharmacokinetics of antidepressant drugs between patients with normal renal function and patients undergoing hemodialysis. However, studies with fluvoxamine and amitriptyline showed that variations in albumin levels might affect serum concentrations of these agents. The included studies have several limitations, and there are many obstacles to the adequate treatment of depression in patients undergoing hemodialysis. Further studies on this topic are needed to support proper treatment of these patients, improving their quality of life and reducing mortality.
Antidepressive agents; depressive disorder; renal dialysis; pharmacokinetics; renal insufficiency, chronic
Studies have shown that 20% of patients with chronic kidney disease (CKD) experience major depressive disorder (MDD), and that MDD is an independent risk factor for hospitalization and mortality in such patients.1,2
However, it remains under recognized and undertreated,3,4
as there are several challenges and limited evidence on how clinicians should address this problem.
First, there is no consensus as to which tool is most suitable to diagnose MDD in this population,5-7
as depressive symptoms are often mixed with the somatic symptoms associated with CKD.8
Second, depression in end-stage renal disease may be resistant to treatment with antidepressants, possibly because the cause of depressive symptoms in these patients may be attributable to physical factors, such as uremia, anemia, and electrolyte disturbances.9,10
In addition, there is very little evidence to support the efficacy and safety of antidepressant medication in CKD patients, especially because these patients are often excluded from major clinical trials because of safety concerns.11,12
What little evidence is available has largely been obtained in nonrandomized, uncontrolled studies with small samples.12
Studies have shown that, in addition to treating depressive symptoms and improving quality of life, sertraline significantly decreases serum levels of proinflammatory substances such as IL-6, which could be a promising strategy to reduce systemic inflammation in CKD patients.13
Most antidepressants are metabolized in the liver and highly protein-bound, and, as such, are not removed significantly by dialysis.10,14
However, the relative activity and mode of excretion of metabolites of these drugs in patients with CKD is often uncertain.15
The latest European Renal Best Practice statement, published in 2014, recommends a trial of selective serotonin reuptake inhibitors for 8 to 12 weeks in dialysis patients who have moderate/major depression. Reevaluation after 12 weeks was recommended to avoid ineffective medicalization.16
Following this recommendation, the Study of Sertraline in Dialysis17
is an ongoing randomized controlled trial to evaluate the effect of sertraline in patients with depression who are undergoing hemodialysis. This may be the first study to give clinicians an evidence-based conclusion regarding the pharmacotherapy of depression in patients with CKD.
In this context, we conducted a narrative literature review on studies that specifically addressed the pharmacokinetics of antidepressant drugs in patients undergoing hemodialysis.METHODS
The MEDLINE, LILACS, and Web of Knowledge databases were searched with a combination of Medical Subject Headings and free-text queries for CKD, end-stage renal disease, renal replacement therapy, depression, and antidepressants. The search was limited to studies conducted in humans, with no language or time constraints. The inclusion criteria were patients undergoing hemodialysis who were on treatment with antidepressants. Studies that reported only side effects of antidepressant treatment in patients going through hemodialysis were not included. There was no limitation on the tools used to diagnose depression, since there is no consensus in the literature on which tool is more suitable for MDD diagnosis in CKD patients. Finally, all the included studies were fully available online.
A flow diagram of study selection is available as Figure 1 below.
Flowchart for the selection of studies of this review.
The search yielded 212 studies. After screening of titles and abstracts, 32 studies were read in full. After exclusion of studies that did not met the inclusion criteria and review of the reference lists of selected studies, a total of 11 studies were included in the review. Table 1 summarizes the characteristics of the included studies.
We found one study regarding pharmacokinetics of tianeptine,18
one on citalopram,19
one on fluvoxamine,20
one on sertraline, 21
one on nefazodone, 22
one on nortriptyline, 23
one on amitriptyline, 24
three on mirtazapine,24-26
and two on fluoxetine27,28
in patients undergoing hemodialysis. Our findings are described below.Tianeptine
A single 12.5 mg oral dose of tianeptine was used to determine dialytic clearance of tianeptine and its metabolite (pentanoic acid analogue of tianeptine) in eight patients undergoing dialysis. The dialyzability of the two substances was found to be low (3.9±9.9 mL/min and 19.2±8.6 mL/min for parent tianeptine and its pentanoic acid analogue, respectively). These results showed that patients can be given tianeptine without considering the dialysis.18Citalopram
The concentration of citalopram and its metabolites (desmethylcitalopram and didesmethylcitalopram) in serum and urine were compared in four patients undergoing hemodialysis and eight healthy controls after a single dose of citalopram. There was a statistically significant difference between groups in renal clearance of citalopram, which was lower in the patients undergoing hemodialysis (1.70 mL/min versus 66.2 mL/min, p < 0.001). Hemodialysis cleared about 1% of citalopram and its metabolites. The authors concluded that hemodialysis does not significantly affect the pharmacokinetic parameters of citalopram and its metabolites.19Fluvoxamine
Plasma fluvoxamine concentrations were examined in three patients on maintenance hemodialysis who had mild depression. Patients took 50 mg/day fluvoxamine maleate for 28 days. Hemodialysis decreased the plasma fluvoxamine concentration by 22.04±1.8%. Albumin concentrations in plasma were also measured before and after dialysis. The mean albumin concentration was 4.02±0.13 g/dL before dialysis, and was raised to 12.15±3.16% by hemodialysis. Although there was no statistically significant association between decreased plasma concentration of fluvoxamine and plasma concentration of albumin, the authors found a tendency for the dialyzed rate of fluvoxamine to become lower when the plasma albumin concentration was higher.20Sertraline
Two patients undergoing hemodialysis were administered 100 mg of sertraline after the procedure. At the next hemodialysis session, blood samples to measure sertraline serum concentrations were taken before, after, and hourly during the procedure. Blood samples were also obtained 20 h after the procedure and prior to the next session. The initial sertraline serum concentrations were compared between the two patients undergoing hemodialysis and subjects with normal renal function who had also received 100 mg of sertraline. There was no significant difference between the groups, implying that absorption and distribution of the drug are not altered by hemodialysis, which suggests that post-hemodialysis supplementation is unnecessary.21Nefazodone
A single case report of a dialysis-dependent patient on 150 mg of nefazodone showed pre- and post-dialysis nefazodone serum concentrations of 0.4 and 0.25 mcg/ mL respectively. These results suggest that drug levels of nefazodone may be affected by dialysis. However, clinical response was not affected.22Nortriptyline
The pharmacokinetics of single oral doses of 75 mg nortriptyline were studied in eight patients undergoing hemodialysis and 12 controls not undergoing hemodialysis. No differences were observed between the dialyzed and non-dialyzed groups. Comparisons of nortriptyline half-life and clearance between the patients and physically healthy subjects revealed no significant differences. These results suggest that CKD is not associated with significant changes in nortriptyline metabolism as measured by its half-life or clearance. However, the study showed extreme interindividual variability, reinforcing the fact that antidepressants should be used with caution in this patient population and concentrations monitored whenever possible.23Mirtazapine
In a study with 17 patients undergoing hemodialysis, mean serum concentrations of mirtazapine decreased significantly after hemodialysis (before, 53.45 ng/mL; after, 38.31 ng/mL; p < 0.036).24
Another study compared a group of 10 patients with severe renal dysfunction, seven of whom were undergoing hemodialysis, and 10 healthy patients given a single oral dose of 15 mg mirtazapine. Patients with renal dysfunction experienced an approximately 50% reduction in clearance and a 215% increase in area under the curve for the plasma concentration compared to the 10 healthy volunteers. These results suggest a potential risk of mirtazapine accumulation in patients with renal dysfunction and the need to use conservative doses.25
However, one case report of a patient also using 15 mg/day mirtazapine found that dialysis with a low-flux hemofilter did not have any significant effect on plasma concentrations of mirtazapine or its metabolite demethylmirtazapine.26Amitriptyline
Mean serum concentrations of amitriptyline and its active metabolite, nortriptyline, were measured in 15 patients undergoing hemodialysis. The first blood sample was obtained immediately after puncture of the dialysis port, and the second just before disconnecting the patient from the dialysis machine. The results showed that the mean serum concentration of the sum of amitriptyline and nortriptyline decreased significantly with hemodialysis (before: 75.52 ng/mL; after: 59.35 ng/mL; p < 0.001).24Fluoxetine
In an open label study, patients undergoing hemodialysis had serum plasma concentrations of fluoxetine and norfluoxetine similar to those of patients with normal renal function.27
Another study compared the steady-state plasma concentrations of the sum of fluoxetine plus its metabolite norfluoxetine in patients undergoing hemodialysis and patients with normal renal function, with both groups completing 8 weeks of treatment with fluoxetine; there was no statistically significant between-group difference.28
Both studies used a dose of 20 mg per day. The results suggest that renal failure and the process of hemodialysis do not substantially alter the pharmacokinetics of fluoxetine or its major metabolite norfluoxetine.DISCUSSION
Most of the studies included in this review found no differences in the pharmacokinetics of antidepressant drugs between patients with normal renal function and patients undergoing hemodialysis. However, studies with fluvoxamine and amitriptyline showed that variations in albumin levels might affect serum levels of these agents. The other studies did not consider this variable. In patients with CKD, albumin levels may become low for several reasons, especially decreased synthesis caused by inadequate nutrition and chronic inflammation, but also because of plasma volume expansion, albumin redistribution, exogenous loss, and an increased fractional catabolic rate.29
The National Kidney Foundation Kidney Disease Dialysis Outcomes Quality Initiative (KDOQI) practice guidelines recommend a target serum albumin level of ≥ 4.0 g/dL for adults who are on hemodialysis, as lower levels are associated with higher mortality.30
It is important to highlight that all the studies included herein had small sample sizes and were uncontrolled and nonrandomized; thus, their findings have several limitations. The studies also did not mention controlling for other variables, such as use of other drugs that might affect the serum levels of antidepressants, which is especially important because polypharmacy is common among patients on hemodialysis.31,32
All the studies recommended further research into the pharmacokinetics of antidepressants in patients undergoing hemodialysis.
The upcoming results of the Study of Sertraline In Dialysis17
may provide some answers on this matter; however, as its name implies, this study only includes sertraline. Considering that the clinical response to psychopharmaceuticals is subject to extreme interindividual variability,33
it is important to carry out further investigations with other antidepressants.
The current recommendation from the British Columbia Renal Agency is to use selective serotonin reuptake inhibitors as first-line therapy for treatment of depression in patients on hemodialysis.34
We consider that sertraline 25 mg/day could be an interesting option, since the current literature suggests that post-hemodialysis supplementation is unnecessary21
and sertraline has no major drug-drug interactions.34
Besides the lack of evidence-based information for clinicians to prescribe and correctly treat depression in patients undergoing hemodialysis, there is also the challenge of adherence to treatment, since studies have shown that these patients often are not open to treatment and do not make regular use of their prescribed medication.35 36
Studies on this topic are important to produce strong evidence on the efficacy and safety of treatment, so that clinicians can work with their patients to improve adherence.
In conclusion, most of the studies included in this review found that the pharmacokinetics of antidepressants agents are unaffected by hemodialysis. However, these findings have several limitations, and there are many obstacles to adequate treatment of depression in patients undergoing hemodialysis. All studies used small samples and yielded results that cannot be generalized. Further studies on this topic are needed to support proper treatment of these correctly, improving their quality of life and reducing mortality.DISCLOSURE
The authors report no conflicts of interest.REFERENCES
1. Shirazian S, Grant CD, Aina O, Mattana J, Khorassani F, Ricardo AC. Depression in chronic kidney disease and end-stage renal disease: similarities and differences in diagnosis, epidemiology, and management. Kidney Int Rep. 2017;2:94-107.
2. Farrokhi F, Abedi N, Beyene J, Kurdyak P, Jassal SV. Association between depression and mortality in patients receiving long-term dialysis: a systematic review and meta-analysis. Am J Kidney Dis. 2014;63:623-35.
3. Jain N, Trivedi MH, Rush AJ, Carmody T, Kurian B, Toto RD, et al. Rationale and design of the chronic kidney disease antidepressant sertraline trial (CAST). Contemp Clin Trials. 2013;34:136-44.
4. Lopes AA, Albert JM, Young EW, Satayathum S, Pisoni RL, Andreucci VE, et al. Screening for depression in hemodialysis patients: associations with diagnosis, treatment, and outcomes in the DOPPS Kidney Int. 2004;66:2047-53.
5. Palmer S, Vecchio M, Craig JC, Tonelli M, Johnson DW, Nicolucci A, et al. Prevalence of depression in chronic kidney disease: systematic review and meta-analysis of observational studies. Kidney Int. 2013; 84:179-91.
6. Hedayati SS, Bosworth HB, Kuchibhatla M, Kimmel PL, Szczech LA. The predictive value of self-report scales compared with physician diagnosis of depression in hemodialysis patients. Kidney Int. 2006; 69:1662-8.
7. Hedayati SS, Minhajuddin AT, Toto RD, Morris DW, Rush AJ. Validation of depression screening scales in patients with CKD. Am J Kidney Dis. 2009;54:433-9.
8. Abdel-Kader K, Unruh ML, Weisbord SD. Symptom burden, depression, and quality of life in chronic and end-stage kidney disease. Clin J Am Soc Nephrol. 2009;4:1057-64.
9. Palmer SC, Natale P, Ruospo M, Saglimbene VM, Rabindranath KS, Craig JC, et al. Antidepressants for treating depression in adults with end-stage kidney disease treated with dialysis. Cochrane Database Syst Rev. 2016;5:CD004541.
10. Hedayati SS, Yalamanchili V, Finkelstein FO. A practical approach to the treatment of depression in patients with chronic kidney disease and end-stage renal disease. Kidney Int. 2012;81:247-55.
11. Nagler EV, Webster AC, Vanholder R, Zoccali C. Antidepressants for depression in stage 3-5 chronic kidney disease: a systematic review of pharmacokinetics, efficacy and safety with recommendations by European Renal Best Practice (ERBP). Nephrol Dial Transplant. 2012;27:3736-45.
12. King-Wing Ma T, Kam-Tao Li P. Depression in dialysis patients. Nephrology (Carlton). 2016;21:639-46.
13. Zahed NS, Sharifi M, Karimi M, Nikbakht H. Impact of sertraline on serum concentration of CRP in hemodialysis patients with depression. J Renal Inj Prev. 2016;6:65-9.
14. Hedayati SS, Finkelstein FO. Epidemiology, diagnosis, and management of depression in patients with CKD. Am J Kidney Dis. 2009;54:741-52.
15. Bautovich A, Katz I, Smith M, Loo CK, Harvey SB. Depression and chronic kidney disease: a review for clinicians. Aust N Z J Psychiatry. 2014;48:530-41.
16. Nagler EV, Webster AC, Bolignano D, Haller MC, Nistor I, van der Veer SN, et al. European Renal Best Practice (ERBP) guideline development methodology: towards the best possible guidelines. Nephrol Dial Transplant. 2014;29:731-8.
17. Friedli K, Almond M, Day C, Chilcot J, Gane Mda S, Davenport A, et al. A study of sertraline in dialysis (ASSertID): a protocol for a pilot randomised controlled trial of drug treatment for depression in patients undergoing haemodialysis. BMC Nephrol. 2015;16: 172.
18. Salvadori C, Merdjan H, Brouard R, Baumelou A, Nicot G, Friès D. Tianeptine and its main metabolite. Disposition in chronic renal failure and haemodialysis. Fundam Clin Pharmacol. 1990;4:663-71.
19. Spigset O, Hägg S, Stegmayr B, Dahlqvist R. Citalopram pharmacokinetics in patients with chronic renal failure and the effect of haemodialysis. Eur J Clin Pharmacol. 2000;56:699-703.
20. Kamo T, Horikawa N, Tsuruta Y, Miyasita M, Hatakeyama H, Maebashi Y. Efficacy and pharmacokinetics of fluvoxamine maleate in patients with mild depression undergoing hemodialysis. Psychiatry Clin Neurosci. 2004;58:133-7.
21. Schwenk MH, Verga MA, Wagner JD. Hemodialyzability of sertraline. Clin Nephrol. 1995;44:121-4.
22. Seabolt JL, De Leon OA. Response to nefazodone in a depressed patient with end-stage renal disease. Gen Hosp Psychiatry. 2001; 23:45-6.
23. Dawlilng S, Lynn K, Rosser R, Braithwaite R. The pharmacokinetics of nortriptyline in patients with chronic renal failure. Br J Clin Pharmacol. 1981;12:39-45.
24. Unterecker S, Müller P, Jacob C, Riederer P, Pfuhlmann B. Therapeutic drug monitoring of antidepressants in haemodialysis patients. Clin Drug Investig. 2012;32:539-45.
25. Bengtsson F, Hoglund P, Timmer C, Hegbrant J. Mirtazapine oral single dose kinetics in patients with different degrees of renal failure. Hum Psychopharmacol. 1998;13:357-65.
26. Schlotterbeck PM, Vehren T, Milenovic S, Hiemke C, Kircher T, Leube D. No influence of dialysis on mirtazapine - a case report. Pharmacopsychiatry. 2008;41:259-60.
27. Blumenfield M, Levy NB, Spinowitz B, Charytan C, Beasley CM Jr, Dubey AK, et al. Fluoxetine in depressed patients on dialysis. Int J Psychiatry Med. 1997;27:71-80.
28. Levy NB, Blumenfield M, Beasley CM Jr, Dubey AK, Solomon RJ, Todd R, et al. Fluoxetine in depressed patients with renal failure and in depressed patients with normal kidney function. Gen Hosp Psychiatry. 1996;18:8-13.
29. Yeun JY, Kaysen GA. Factors influencing serum albumin in dialysis patients. Am J Kidney Dis. 1998;32:S118-25.
30. Amaral S, Hwang W, Fivush B, Neu A, Frankenfield D, Furth S. Serum albumin level and risk for mortality and hospitalization in adolescents on hemodialysis. Clin J Am Soc Nephrol. 2008;3: 759-67.
31. Genestier S, Meyer N, Chantrel F, Alenabi F, Brignon P, Maaz M, et al. Prognostic survival factors in elderly renal failure patients treated with peritoneal dialysis: a nine-year retrospective study. Perit Dial Int. 2010;30:218-26.
32. Riemer E, Werling E, Kribs M, Hamman De Compte A, Dimitrov Y. [Medical prescriptions in haemodialysis patients: critical analysis]. Nephrol Ther. 2005;1:234-40.
33. Mrazek DA. Psychiatric pharmacogenomic testing in clinical practice. Dialogues Clin Neurosci. 2010;12:69-76.
34. BC Provincial Renal Agency. Depression and anxiety: the role of kidney care clinics [Internet]. 2015 May [cited 2018 Nov 22]. www.bcrenalagency.ca/resource-gallery/Documents/Depression%20and%20Anxiety%20Guideline.pdf
35. García-Llana H, Remor E, Selgas R. Adherence to treatment, emotional state and quality of life in patients with end-stage renal disease undergoing dialysis. Psicothema. 2013;25:79-86.
36. Rosenthal Asher D, Ver Halen N, Cukor D. Depression and nonadherence predict mortality in hemodialysis treated end-stage renal disease patients. Hemodial Int. 2012;16:387-93.
August 31 2018.
November 12 2018.