Navigating the intersection of mental health and kidney health: a systematic review of antidepressant safety in renal impairment

Abstract

Depression is a prevalent mental health condition that significantly impacts adults with impaired renal function, yet the safety and efficacy of antidepressants in this population remain inadequately explored. Understanding how renal impairment affects antidepressant pharmacokinetics and clinical outcomes is essential for optimizing treatment strategies. This systematic review adhered to PRISMA 2020 guidelines, conducting a comprehensive literature search across multiple databases, including PubMed, ScienceDirect, ClinicalTrial.gov, and Medline. Studies were included if they evaluated the use of antidepressants in adults with renal impairment, assessing both safety and efficacy outcomes. The review identified 11 studies that met the inclusion criteria, with sample sizes ranging from 30 to 101,409 participants, yielding a total sample size of 192,684. The quality assessment of the included studies was conducted based on the type of study design, focusing on methodological rigor and relevance to the research question. While certain antidepressants demonstrate efficacy, their pharmacokinetic profiles necessitate careful monitoring and dose adjustments in patients with different levels of renal impairment. These insights underscore the need for individualized treatment approaches and highlight areas for future research to enhance care for this vulnerable population.

Introduction

Major Depressive Disorder (MDD), affecting approximately 5% of US adults, is a significant mental health condition characterized by persistent sadness, guilt, despair, and disinterest in daily activities [1, 2]. Among individuals with chronic kidney disease (CKD), the burden of depression is disproportionately high. Studies estimate that 39% of CKD patients in the United States experience depression, with this prevalence reaching as high as 48% in those undergoing hemodialysis [3, 4]. The coexistence of these conditions not only diminishes the quality of life but also presents unique challenges in management and treatment.

CKD, a progressive disease, is categorized into five stages based on estimated glomerular filtration rate (eGFR): Stage 1 (≥ 90 mL/min/1.73 m²), Stage 2 (60–89 mL/min/1.73 m²), Stage 3a (45–59 mL/min/1.73 m²), Stage 3b (30–44 mL/min/1.73 m²), Stage 4 (15–29 mL/min/1.73 m²), and Stage 5 (< 15 mL/min/1.73 m² or requiring dialysis) [5]. Each stage of chronic kidney disease progressively impairs renal function, affecting both the glomerular filtration of metabolites and the pharmacokinetics of medication metabolism and clearance [5]. This complexity poses significant hurdles in the management of comorbid conditions [6, 7].

The link between CKD and depression is multifaceted, driven by factors such as chronic pain, fatigue from anemia, cognitive impairments due to uremia, disrupted sleep patterns, and diminished appetite [6]. Depression further complicates CKD management, contributing to poor medication adherence, compromised immune function, and malnutrition, which can accelerate disease progression [7]. Additionally, individuals with depression face increased risks of hospitalization, cardiovascular events, and the need for maintenance dialysis [8].

The kidneys’ role in drug clearance makes CKD patients particularly vulnerable to medication-related complications. Antidepressants, commonly used to treat MDD, have been associated with adverse effects such as QT interval prolongation, which can lead to severe cardiac events [9, 10]. These risks are heightened in CKD patients due to frequent electrolyte imbalances, a high prevalence of cardiovascular disease, and polypharmacy, which increases the potential for drug-drug interactions [10].

The objective of this systematic review is to evaluate the safety and efficacy of antidepressant therapy in patients with CKD, emphasizing the need for treatment tailored to specific CKD stages. This review addresses the critical aspects of managing depression in this population, where altered pharmacokinetics and increased susceptibility to adverse drug reactions necessitate careful, stage-specific prescribing practices.

We aim to identify antidepressants that are both effective and safe, while also highlighting potential adverse effects. Furthermore, the review emphasizes the importance of regular depression screening and monitoring, as untreated depression is associated with poorer outcomes, including increased mortality and hospitalization rates. By synthesizing current evidence, this review seeks to refine therapeutic strategies and advocate for further research to enhance health outcomes for this vulnerable population.

Review

Methods

This systematic review follows the PRISMA 2020 guidelines [11] to evaluate the safety and effectiveness of antidepressants in patients with renal impairment.

Literature search

A comprehensive search for relevant literature was conducted to identify studies investigating the safety of antidepressants in adult patients with impaired renal function. Three electronic databases and one register—PubMed, Medline, ScienceDirect, and ClinicalTrials.gov—were systematically searched from July 25 to August 5, 2024. The search strategy employed a combination of keywords and Medical Subject Headings (MeSH) terms related to antidepressants, major depressive disorder, renal failure, and adult populations. A detailed overview of the search strategy is presented in Table 1.

Table 1.

Search strategy

Search Strategy	Databases/registers	Number of studies before and after filters	Filters applied
(((((((((((“Antidepressive Agents”[MeSH]) OR (“antidepressant”) OR (“antidepressants”)) AND (“Depression”[MeSH])) OR (“Major Depressive Disorder”[MeSH])) OR (“Depressive Disorder”[MeSH])) OR (“depression”)) OR (“MDD”)) AND (“Kidney Diseases”[MeSH])) OR (“Renal Insufficiency”[MeSH])) OR (“renal impairment”)) OR (“kidney dysfunction”)	PubMed/Medline	22,473/2825	Clinical studies, randomized controlled trials, clinical trials, equivalence trials, and observational studies, published in English within the last 5 years, involving adults aged 19 and older, with full-text available and conducted on human participants
Intervention: Antidepressants Disease: Depression, Eligibility Criteria: Renal Impairment	ClinicalTrials.gov	16/5	Completed studies | adults 18–64, 65 +| Studies with results
Title, abstract, keywords: (“antidepressant” OR “antidepressants”) AND (“depression” OR “major depressive disorder”) AND (“renal impairment” OR “chronic kidney disease” OR “renal insufficiency”)	Science Direct	114/31	Article type: Research article, years, 2019, 2020, 2021, 2022, 2034, 2024

Eligibility criteria

The review focused on studies that investigate the safety and efficacy of antidepressants in adult patients with impaired renal function. Specifically, only peer-reviewed articles published within the last 5 years, from January 2019 to August 5, 2024, were considered. Eligible studies involved adult participants (18 years and older) diagnosed with major depressive disorder or depression and having documented renal impairment (Table 2).

Table 2.

Inclusion and exclusion criteria

Category	Inclusion Criteria	Exclusion Criteria
Population	Adults (18 years old and above) with depression and impaired renal functions	Children and adolescents (0–17 yrs)
Intervention	Primary intervention: antidepressant medication	Combined medical interventions/behavioral therapy
Outcomes	Studies that focus on the safety and/or efficacy of antidepressants in patients with renal impairment and/or hemodialysis	Studies that do not measure the safety or efficacy of antidepressant use in patients with renal dysfunction
Study Design	RCTs, CCTs, observational studies (cohort studies, case–control studies, cross-sectional studies)	Case reports, case series, editorials, commentaries, no comparison group/baseline data
Publication Type	Peer-reviewed articles and trials (completed with results)	Non-peer-reviewed articles, conference abstracts/posters (without full data), trials (non-completed or completed without results)
Language	English	Other than English
Time Frame	Last 5 years (1 January, 2019–August 5, 2024)	Published before 2019 and after August 5, 2024
Subjects	Human	Animal
Quality of Studies	Moderate and high-quality studies (some concerns and low risk of bias)	Low-quality studies (high risk of bias)

RCT Randomized control trial; CCT Controlled Clinical Trial

The exclusion criteria eliminated studies involving participants with severe psychiatric disorders other than depression, those with acute renal failure, or individuals undergoing combined medical interventions or behavioral therapies. This ensured that the selected studies are relevant and that the participant population is appropriately defined.

Data extraction and management

A standardized data extraction form was created to systematically gather essential information from the included studies, such as authorship, publication year, study design, intervention details, study objectives, and key findings. All authors received training and detailed instructions on the data extraction process. The extraction was carried out collaboratively by two authors and carefully reviewed by a third co-author, who also acted as a mentor. Any disagreements were resolved through discussion, with the mentor offering guidance when needed.

Quality assessment/risk of bias

The quality of the included studies was evaluated using relevant tools tailored to the study design. The quality assessment was conducted jointly by two authors and thoroughly evaluated by a third co-author, who provided mentorship throughout the process. For RCTs, the Cochrane Risk of Bias 2 (RoB 2) tool was employed to assess bias across five key domains: the randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and the selection of reported results. Each domain was classified as ‘low risk,’ ‘some concerns,’ or ‘high risk’ [12].

The CCT studies were assessed using the Cochrane Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool, which provides a systematic framework for evaluating the risk of bias in non-randomized studies [13]. This tool assesses multiple domains, such as confounding, participant selection, intervention classification, deviations from planned interventions, missing data, outcome measurement, and the selection of reported results. Each domain is examined to identify potential bias, providing a thorough evaluation of the study’s methodological quality [13]. In our assessment, we included only studies with a ‘low risk of bias’ and those with ‘moderate risk’ while excluding any studies classified as ‘high risk’ or ‘critical risk’.

For observational studies, the Newcastle–Ottawa Scale (NOS) was employed to assess the quality of the studies [14]. This tool evaluates studies based on three broad perspectives: selection of study groups, comparability of groups, and exposure or outcome assessment. Each study was assigned a score based on these criteria, with higher scores indicating better quality. We applied a threshold for quality assessment, ensuring that all included studies had an NOS score of at least 77% (minimum 7 out of 9).

Data synthesis and analysis

Data synthesis and analysis involved a narrative synthesis to summarize the findings from the included studies regarding the safety and efficacy of antidepressants in patients with impaired renal function.

Results

A comprehensive search across three electronic databases and one register yielded 2861 articles. To streamline the screening process, the Rayyan app^® was employed [15]. After removing duplicates (n = 3), 2858 articles were available for further evaluation. Data preparation involved standardizing outcome measures across studies where variations in reporting existed. Studies with incomplete data that could not be reliably estimated were excluded from synthesis. Outcomes were categorized by CKD stage and antidepressant type to facilitate comparison, and heterogeneity across studies was assessed and addressed narratively in the synthesis process. Applying the inclusion and exclusion criteria, 2845 studies were excluded. Ultimately, 11 studies were deemed eligible for inclusion in the review and underwent quality appraisal. Details are provided in Fig. 1.

Fig. 1.

PRISMA flow diagram. (PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses). * Studies excluded: ineligible population (n = 114), ineligible study design (n = 115), irrelevant outcome (n = 453), inappropriate intervention (n = 352), studies not addressing depression (n = 1639), and studies not addressing CKD (n = 172)

Results of risk of bias assessment

The risk of bias for each study was assessed using the appropriate risk of bias assessment tool: Cochrane RoB 2 for Randomized control trial (RCT) studies [12], Newcastle Ottawa Scale (NOS) for observational studies [14], and ROBINS I for Controlled Clinical Trial (CCT) studies [13]. The results of the risk of bias assessment are summarized in Table 3, and Figs. 2 and 3. Figures 2 and 3 were created using Robvis Tool [16].

Table 3.

Quality appraisal using Newcastle Ottawa scale

Authors/year	Type of study	Selection	Comparability	Outcome	The overall risk of bias/comments
Vangala et al. [19]	Case–control study	✔✔✔✔	✔	✔✔✔	Low risk of bias. 8 out of 9 points Concerns may arise if not all potential confounders were accounted for, but the study controlled for key factors
Hernandez et al. [20]	Prospective cohort study	✔✔✔✔	✔	✔✔✔	Low risk of bias. 8 out of 9 points Concerns may arise if not all potential confounders were accounted for, but the study controlled for key factors
Guirguis et al. [24]	Prospective Cohort	✔✔✔✔	✔✔	✔✔	Low risk of bias. 8 out of 9 The study has limitations in follow-up adequacy
Assimon and Flythe [34]	Retrospective cohort	✔✔✔✔	✔✔	✔✔✔	Low risk of bias. 9 out of 9
Zhu et al. [22]	Retrospective cohort	✔✔✔✔	✔✔	✔✔✔	Low risk of bias.9 out of 9

Fig. 2.

Quality appraisal using ROBINS I for controlled clinical trials

Fig. 3.

Quality appraisal using Rob 2 Cochrane risk of bias

Overall, the assessment revealed a mix of low and moderate risk across the studies, highlighting the need for careful interpretation of the findings. Given that no studies were classified as high or critical risk of bias, we decided to include all studies in this systematic review.

Summary of included studies

This systematic review includes 11 studies investigating the use of antidepressants in patients with impaired renal function. The studies involved adult populations with age ranges from 18 to 80 years and sample sizes ranging from small groups of 30 participants to large cohorts of 101,409 participants. The primary aims included evaluating the safety and efficacy of antidepressants in managing depression among patients with CKD or those undergoing maintenance hemodialysis, exploring pharmacokinetics and tolerability in varying degrees of renal impairment, and examining the impact of antidepressant use on clinical outcomes such as hospitalizations, mortality, and fracture risks.

Key outcomes measured included changes in depression severity scores using validated scales like the Hamilton Depression Rating Scale (HAMD), Beck Depression Inventory-II (BDI-II), and Patient Health Questionnaire-9 (PHQ-9), along with safety profiles, biomarkers such as high-sensitivity C-reactive protein (hsCRP), and adverse events, including hypotension and fracture risks. Key studies include RCTs assessing the efficacy of sertraline for managing depression in hemodialysis patients [17] and its effects on intradialytic hypotension [18]. Observational studies explore broader outcomes, such as the risk of hip fractures with SSRI use [19] and increased hospitalizations and mortality linked to antidepressant use in non-dialysis CKD patients [20]. Pharmacokinetic studies highlight dosing considerations, including esmethadone safety in varying degrees of renal impairment [21] and SSRI dose adjustments based on kidney function [22]. These studies provide a comprehensive view of the clinical applications and considerations of antidepressants in this population. The findings from these studies are summarized in Table 4.

Table 4.

Summary of included studies

Author/year	Study design	Aim of study	Key findings
Vangala et al. [19]	Case–Control Study	Impact of SSRIs on hip fractures among patients with kidney failure treated by hemodialysis	SSRI use was associated with an increased risk of hip fractures. The adjusted OR for any SSRI use was 1.25 (95% CI, 1.17–1.35)
Hernandez et al. [20]	Observational Cohort Study	Investigate how the use of antidepressant medication affects clinical outcomes in adults with CKD who are not on dialysis	For patients not on dialysis, antidepressant use was linked to an increased risk of hospitalizations (HR = 1.38; 95% CI, 1.34–1.43) and all-cause mortality (HR = 1.31; 95% CI, 1.13–1.50) compared to those not using antidepressants. After adjusting for other variables, antidepressant use showed comparable risks for CKD progression
Guirguis et al. [24]	Prospective Cohort	Evaluate antidepressant (citalopram) treatment practices in patients undergoing hemodialysis per NICE guidelines for managing depression in adults with chronic physical health conditions	BDI-II Score reduced from 26 to 21 (p = 0.015) PHQ-9 Score decreased from 12 to 10.5 (p = 0.091) High depressive symptoms (BDI-II ≥ 16): 30 at baseline; 22 at follow-up; 8 improved Improved patients: Lower BDI-II (p = 0.006), shorter dialysis vintage (p = 0.035), Lower serum albumin (p = 0.019), higher clinical events (p = 0.036) Predictors of deterioration, longer dialysis vintage (OR 1.046, p = 0.012), clinical events (OR 7.118, p = 0.026)
Assimon and Flythe [34]	Retrospective cohort	Examine the relationship between starting zolpidem versus trazodone therapy and the 30-day risk of fall-related fractures requiring hospitalization in patients undergoing maintenance hemodialysis	Starting zolpidem was associated with a higher risk of hospitalized fall-related fractures compared to trazodone (HR: 1.71; 95% CI 1.11–2.63; RD: 0.17%; 95% CI 0.07–0.29%). This risk was greater for higher doses of zolpidem (HR: 1.85; 95% CI 1.10–3.01; RD: 0.20%; 95% CI 0.04–0.38%) compared to trazodone. Lower doses of zolpidem also showed an increased risk (HR: 1.60; 95% CI 1.01–2.55; RD: 0.14%; 95% CI 0.03–0.27%)
Zhu et al. [22]	Retrospective cohort	Evaluate starting and maintenance SSRI doses prescribed to middle-aged and older patients based on kidney function	54.1% of new SSRI users experienced reductions in their initial dose, while 34.1% had their maintenance dose reduced. Despite this, around 40% of patients with an eGFR below 30 mL/min/1.73 m2 were prescribed. Compared to those with an eGFR of 90–104 mL/min/1.73 m2, OR for initial dose reduction in individuals with eGFR below 30 mL/min/1.73 m2 was 1.18 (95% CI 1.03, 1.36), and for maintenance dose reduction, it was 1.49 (95% CI 1.29, 1.72)
Zhang et al. [17]	RCT	To determine the safety and efficacy of Sertraline in managing depression in patients on Hemodialysis	After 12 weeks, the depression scores in the sertraline group decreased significantly, achieving an effective rate of 96.8%. Complete remission of depression was observed in 16.1% of these patients. The treatment group demonstrated significant improvements, as evidenced by the highly significant Z-scores (ranging from -5.192 to -6.619) and p-values (all p < 0.001)
Molin et al. [18]	Double-blind, crossover clinical trial	To study the effect of sertraline on the blood pressure of patients undergoing hemodialysis	Sertraline does not have a significant impact on the frequency of hypotension episodes in patients undergoing hemodialysis (p = 0.207). The likelihood of needing interventions for IDH was 60% greater in the placebo group compared to the sertraline group (RR = 1.59; 95% CI 1.03–2.48, p = 0.034) The risk of experiencing IDH symptoms was 40% greater in the placebo group compared to those receiving sertraline (RR = 1.42; 95% CI 1.02–2.02, p = 0.038)
Gregg et al. [31]	RCT	Assess levels of inflammatory biomarkers like hsCRP at baseline and after 12 weeks of Sertraline therapy	Elevated baseline levels of hsCRP were linked to somatic depressive symptoms (r = 0.21, P = 0.01), fatigue (r = 0.22, P = 0.005), and decreased physical functioning (r = − 0.26, P = 0.001). In the sertraline group, hsCRP levels remained stable. However, in the placebo group, hsCRP rose from a median of 3.7 mg/L (IQR, 1.7–10.0 mg/L) at the start to 4.9 mg/L (IQR, 1.8–8.8 mg/L) at the end of the study (P = 0.01)
Zomorodi et al. [23]	CCT	Assess how a single dose of solriamfetol (75 mg) is processed in individuals with varying kidney function	Renal impairment significantly affected AUC and t1/2 but not Cmax or tmax. AUC increased from 5273 to 23,650 ng∙h/mL, and t1/2 increased from 7.6 h to 29.6 h with worsening renal function
Claros-Erazo et al. [30]	RCT	Assess the impact of antidepressant treatment on GFR in patients with MDD and identify predictors of changes in renal function during treatment	After 7 weeks of DBPCRAT, HAMD scores decreased by 11.8 points in the treatment group compared to 9.3 points in the placebo group (p < 0.0001). The eGFR dropped by 0.28 mL/min/1.73 m2 in the antidepressant group and by 0.88 mL/min/1.73 m2 in the placebo group (p = 0.17). Key predictors of HAMD score at week 7 were baseline HAMD score (B = 0.237; p < 0.001) and the use of antidepressants (B = − 2.28; p < 0.001). Predictors for eGFR changes included baseline eGFR (B = 0.651; p < 0.0001), age (B = − 0.194; p < 0.0001), and being female (B = − 0.984; p = 0.013
Ferri et al. [21]	CCT	Evaluate the pharmacokinetics, tolerability, and safety of esmethadone, particularly in subjects with CKD	Mild-to-moderate renal impairment did not significantly alter esmethadone’s plasma exposure, but severe renal impairment increased exposure by 138.2–176.9% compared to healthy controls, with statistically significant differences in Cmax and AUC0-last (p = 0.0130 and p = 0.0497, respectively). For patients with ESRD, IHD did not significantly affect esmethadone clearance, indicating that dose adjustment is unnecessary for those on dialysis

RCT Randomized Control Trial; CCT Clinical Controlled Trial; IDH Intradialytic Hypotension; RR Relative Risk; CI Confidence Interval; SSRI Selective Serotonin Reuptake Inhibitors; OR odds ratio; CKD Chronic Kidney Disease; HR Hazard Ratio; HsCRP High sensitivity C-Reactive Protein; IQR Interquartile range; ESRD End Stage Renal Disease; AUC Area Under Curve; Cl/F Clearance; DBPCRAT Double-blind, placebo-controlled, randomized antidepressant treatment; BDI Beck Depression Inventory; PHQ-9 Patient Health Questionnaire-9; HAMD Hamilton Depression Rating scale; eGFR Glomerular filtration rate; RD risk difference; IHD Intermittent hemodialysis

Table 5 summarizes the use of antidepressants in patients with varying degrees of renal function and the corresponding dose adjustments. Key findings include that sertraline is recommended to start at 25–50 mg daily for patients on hemodialysis, with a maximum of 100 mg, while other studies on SSRIs generally do not specify dose adjustments [17]. Solriamfetol requires adjustments for moderate to severe renal impairment, and esmethadone does not need adjustments for mild to moderate impairment but may require caution in severe cases [21, 23]. Overall, many studies highlight the importance of monitoring and adjusting doses, particularly in vulnerable populations.

Table 5.

Antidepressant use and dose adjustments in patients with renal impairment

Author/year	Antidepressants	Renal function (eGFR)/stage of CKD/hemodialysis	Recommended dose adjustment
Vangala et al. [19]	SSRIs	Participants across all kidney stages, predominantly in Stage 2 (mild reduction, eGFR 60–89 mL/min/1.73 m2) and Stage 3 (moderate reduction, eGFR 30–59 mL/min/1.73 m2), with fewer in Stage 1 (normal kidney function, eGFR ≥ 90 mL/min/1.73 m2) and Stage 4 (severe reduction, eGFR 15–29 mL/min/1.73 m2)	Not mentioned
Hernandez et al. [20]	SSRI, tricyclic and older antidepressants (eg, monoamine oxidase inhibitors), and newer antidepressants (eg, tetracyclic antidepressants)	Mild to moderate CKD	Not mentioned
Guirguis et al. [24]	Citalopram, Fluoxetine, Sertraline, Mirtazapine, Venlafaxine, Escitalopram, Paroxetine, Dothiepin, Nortriptyline, and Duloxetine	Hemodialysis	Not mentioned
Assimon and Flythe [34]	Zolpidem and trazodone	Hemodialysis	Begin with lower doses (≤ 1.75 mg/day for sublingual tablets addressing night awakenings, ≤ 5 mg/day for regular, spray, or sublingual tablets for sleep initiation, and ≤ 6.25 mg/day for controlled-release tablets), particularly in elderly, female, or frail individuals, as well as those taking CNS-active medications, and closely monitor for any cognitive or motor impairments
Zhu et al. [22]	Citalopram (28.3%), amitriptyline (20.7%), mirtazapine (19.9%), and other SSRI	Participants were grouped by kidney function, with a median eGFR of 81 mL/min/1.73 m2, while 11.4% had eGFR 45–59, 5.3% had eGFR 30–44, and 2.0% had eGFR below 30 mL/min/1.73 m2	No recommendations
Zhang et al. [17]	Sertraline	Patients undergoing regular hemodialysis 3 times a week for at least 3 months	Start sertraline treatment at a dose of 25–50 mg daily and gradually adjust the dose based on the patient’s response, with a maximum daily dose not exceeding 100 mg. The maintenance dose for elderly patients or those with a body weight under 50 kg is 25–50 mg per day
Molin et al. [18]	Sertraline	Patients undergoing hemodialysis 3 times a week for at least 3 months	Not mentioned
Gregg et al. [31]	Sertraline	CKD stages 3–5	Not mentioned
Zomorodi et al. [23]	solriamfetol	Group 1 as the control (eGFR ≥ 90 mL/min/1.73 m2), Groups 2, 3, and 4 representing mild (60–89 mL/min/1.73 m2), moderate (30–59 mL/min/1.73 m2), and severe (< 30 mL/min/1.73 m2) renal impairment, respectively, and Group 5 including participants with ESRD requiring ≥ 3 hemodialysis sessions per week for the past 3 months	Patients with mild renal impairment do not require dosage changes for solriamfetol, but those with moderate to severe impairment need adjustments. Solriamfetol is not recommended for patients with end-stage renal disease (ESRD) due to greatly increased drug exposure and extended half-life
Claros-Erazo et al. [30]	duloxetine (84.9% of participants), paroxetine (14.6% of participants), and escitalopram (0.5% of participants)	Participants were grouped by kidney function: 5% were in Stage 1, 69% in Stage 2, 26% in Stage 3, and 0.25% in Stage 4	Not mentioned
Ferri et al. [21]	esmethadone	Subjects were divided into five groups based on renal function: healthy control (n = 12, GFR ≥ 90 mL/min), mild impairment (n = 8, GFR 60–89 mL/min), moderate impairment (n = 9, GFR 30–59 mL/min), severe impairment without IHD (n = 9, GFR 15–29 mL/min), and ESRD with IHD (n = 11, GFR < 15 mL/min)	No dose adjustments are needed for esmethadone in mild-to-moderate renal or hepatic impairment or ESRD patients on dialysis. Dose reduction may be considered for severe renal impairment due to modestly increased drug exposure

SSRIs Selective serotonin reuptake inhibitors; CKD Chronic kidney disease; eGFR Estimated glomerular filtration rate; ESRD End stage renal disease; IHD Intradialytic hypotension; CNS Central nervous system

Discussion

The current systematic review highlights the significant prevalence of depression among patients with CKD and ESKD and evaluates the safety and efficacy of antidepressants in this vulnerable population. The findings indicate that while antidepressants can be effective, their safety profiles vary significantly based on renal function.

Impact of antidepressant use on health outcomes in CKD patients

Hernandez et al. [20] conducted an observational cohort study on 4839 adults aged 21–74 years with CKD not undergoing dialysis, investigating the impact of antidepressants, including selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), Monoamine oxidase inhibitors (MAOI), and tetracyclic antidepressants. Over an 8.3-year follow-up, antidepressant users had a 38% higher risk of hospitalization and a 31% higher risk of death compared to non-users [20]. However, after adjusting for other factors, the risk of CKD progression was similar between both groups [20].

Assimon and Flythe [24] conducted a retrospective cohort study of 31,055 patients with MDD on hemodialysis, comparing the 30-day risk of hospitalized fall-related fractures between zolpidem and trazodone. Zolpidem, a non-benzodiazepine that enhances GABA-A receptor function, was linked to a significantly higher fracture risk than trazodone, a second-generation antidepressant that acts as a serotonin antagonist and reuptake inhibitor [24–26]. The risk increased with higher doses of zolpidem (Hazard Ratio: 1.85), while even lower doses showed elevated risk (Hazard Ratio: 1.60). The findings suggest zolpidem, especially at higher doses, poses a greater risk of fall-related fractures in this population [24].

Safety profiles of antidepressants

Zhang et al. [17] conducted an RCT study to evaluate the safety and efficacy of sertraline in treating depression in adults undergoing maintenance hemodialysis (MHD). Sertraline, a widely prescribed antidepressant, functions as an SSRI [27]. Among the 125 participants, the sertraline group showed a significant reduction in depression scores after 12 weeks, with an effectiveness rate of 96.8% and 16.1% of participants achieving complete remission. The study demonstrated substantial improvements, confirming the safety and effectiveness of sertraline in managing depression in this population [17].

In a double-blind, crossover clinical trial conducted by Molin et al. [18], 30 hemodialysis patients were examined to assess the impact of sertraline on hypotensive episodes during dialysis [18]. While the study found that sertraline did not significantly alter the frequency of low blood pressure episodes (p = 0.207), it did improve symptoms related to intradialytic hypotension (IDH) and reduced the need for medical interventions. Specifically, the placebo group exhibited a 60% higher risk of requiring interventions for IDH (relative risk [RR] = 1.59, p = 0.034) and a 40% greater risk of experiencing IDH symptoms (RR = 1.42, p = 0.038) [18]. These findings underscore the potential benefits of sertraline in mitigating IDH-related complications.

Further exploring the safety of antidepressants, Vangala et al. [19] conducted a case–control study involving 53,312 participants aged 18 years and older to investigate the impact of SSRIs on the risk of hip fractures among patients with kidney failure undergoing hemodialysis [19]. The study revealed that SSRI use was associated with an increased risk of hip fractures, with an adjusted odds ratio (OR) for any SSRI use of 1.25 (95% CI, 1.17–1.35), indicating a significant association between SSRI use and higher fracture risk in this population [19].

Ferri et al. [21] conducted a CCT to assess the pharmacokinetics, tolerability, and safety of esmethadone in 49 participants with varying degrees of CKD [21]. Esmethadone, the opioid-inactive dextro-isomer of the racemic mixture (S, R)-methadone, is distinct from the opioid-active R-isomer, which is primarily responsible for methadone’s analgesic effects [28]. The participants in the study had a mean age of 55.2 years, with 73.5% being male. The study found that mild-to-moderate renal impairment did not significantly affect esmethadone’s plasma exposure. However, severe renal impairment resulted in a 138.2–176.9% increase in exposure compared to healthy controls (p = 0.0130 and p = 0.0497 for Cmax and AUC0-last, respectively). Notably, intermittent hemodialysis did not significantly alter esmethadone clearance in end-stage renal disease (ESRD) patients, suggesting no need for dose adjustments in this group [21].

Dosing adjustments and pharmacokinetics

Pharmacokinetic considerations are essential for safe prescribing in patients with renal impairment. Zomordi et al. (2019) conducted a CCT assessing the pharmacokinetics of a single 75 mg dose of solriamfetol in 24 participants with varying kidney function [23]. Solriamfetol acts as a selective dopamine (DA) and norepinephrine (NE) reuptake inhibitor (DNRI), increasing the availability of these neurotransmitters in the brain [29]. The study revealed that renal impairment significantly affected the area under the curve (AUC) and half-life (t1/2) of solriamfetol, with AUC increasing from 5273 ng∙h/mL in individuals with normal function to 23,650 ng∙h/mL in those with severe impairment. The half-life extended from 7.6 h to 29.6 h as renal function declined, indicating that dosage adjustments may be necessary for patients with kidney issues [23].

Zhu et al. [22] performed a retrospective cohort study involving 101,409 new users of antidepressants, focusing on SSRI dosing based on kidney function [22]. The majority of antidepressants studied were SSRIs with citalopram being most commonly prescribed. Other antidepressants such as amitriptyline and mirtazapine were also studied. They found that 54.1% of new SSRI users had their initial doses reduced, and 34.1% had maintenance doses decreased [22]. This underscores the importance of kidney function in determining SSRI dosing.

Claros-Erazo et al. [30] conducted an RCT with 1600 patients with MDD to evaluate the impact of treatment with antidepressants, including Duloxetine, paroxetine, escitalopram, on glomerular filtration rate (GFR) [30]. After 7 weeks, the treatment group showed a significant reduction in Hamilton Depression Rating Scale (HAMD) scores (11.8 points vs. 9.3 points in placebo, p < 0.0001). Although the estimated GFR decreased slightly in both groups, the difference was not statistically significant (p = 0.17) [30]. Key predictors of HAMD score reduction included baseline scores and antidepressant treatment, suggesting that antidepressants can improve depressive symptoms without significantly affecting kidney function in the short term.

Comparative effectiveness of antidepressants

The effectiveness of antidepressants varies across populations. Gregg et al. [31] assessed the impact of sertraline on inflammatory biomarkers in 193 participants with CKD stages 3–5 and MDD [31]. Higher baseline levels of high-sensitivity C-reactive protein (hsCRP) correlated with depressive symptoms. In the sertraline group, hsCRP levels remained stable, while levels in the placebo group increased significantly (p = 0.01), indicating that sertraline may help stabilize inflammation in CKD patients [31].

Guirguis et al. [24] evaluated citalopram treatment in 41 adults on hemodialysis [24]. Depressive symptoms improved, with Beck Depression Inventory-II (BDI-II) scores decreasing from 26 to 21 (p = 0.015). Predictors of improvement included lower baseline BDI-II scores and shorter dialysis vintage, suggesting citalopram’s effectiveness in managing depression among hemodialysis patients, especially those with less severe symptoms [24].

This systematic review has elucidated that while certain antidepressants, particularly sertraline, demonstrate efficacy in mitigating depressive symptoms among adults with impaired renal function, significant safety concerns persist. Specifically, the increased risks of hospitalization and mortality associated with antidepressant use in non-dialysis CKD patients highlight the complexities inherent in managing depression within this population. Furthermore, the variability in pharmacokinetics necessitates a tailored approach to prescribing that considers individual renal function.

Clinical implications

The systematic review on antidepressants in adults with impaired renal function highlights significant clinical implications, emphasizing the need for personalized treatment plans. Tailoring antidepressant therapy to the patient’s renal status, comorbidities, and potential drug interactions is critical for optimizing outcomes and minimizing adverse effects. Regular monitoring of both psychiatric and renal health is essential, especially for patients with moderate to severe renal impairment, to evaluate treatment efficacy, detect adverse effects early, and make timely medication adjustments. For instance, Zhu et al. [22] found that patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² were more likely to receive reduced doses of antidepressants, with odds ratios of 1.18 for initial doses and 1.49 for maintenance doses compared to those with normal eGFR levels, effectively mitigating associated risks [22]. The use of antidepressants in patients with varying degrees of renal function and the corresponding dose adjustments. Key findings include that sertraline is recommended to start at 25–50 mg daily for patients on hemodialysis, with a maximum of 100 mg, while other studies on SSRIs generally do not specify dose adjustments. Solriamfetol requires adjustments for moderate to severe renal impairment, and esmethadone does not need adjustments for mild to moderate impairment but may require caution in severe cases. Overall, many studies highlight the importance of monitoring and adjusting doses, particularly in vulnerable populations.

Beyond pharmacological considerations, the review stresses the need for culturally competent care. The underrepresentation of minority groups in studies highlights the importance of fostering inclusivity through open discussions about treatment preferences, which can improve adherence and therapeutic outcomes. Patient education on the risks and benefits of antidepressants empowers individuals, facilitating shared decision-making and promoting better engagement in care.

Comparison with other evidence

The safety and efficacy of antidepressants in CKD remain underexplored, with limited systematic reviews or meta-analyses available. This review contrasts with prior systematic reviews and meta-analyses on antidepressant use in CKD, highlighting differences in scope, methodology, and study inclusion.

A 2012 systematic review specifically focused on the safety and efficacy of antidepressants in stages 3–5 CKD [32]. Although it included RCTs, non-randomized trials, and case reports, its conclusions were constrained by incomplete endpoint data and insufficient methodological rigor [32]. The review noted adverse events such as cardiac arrest and neuroleptic syndrome associated with older antidepressants like maprotiline, nortriptyline, and amoxapine [32]. In contrast, our review encompasses 11 high-quality studies involving 192,684 participants across diverse CKD stages, including both dialysis and non-dialysis populations. Furthermore, we incorporated newer antidepressants, and placed greater emphasis on pharmacokinetics and stage-specific dose adjustments, leading to more robust conclusions.

A 2016 systematic review analyzed antidepressant use in ESRD patients on hemodialysis, including three RCTs with SSRIs and placebo and one comparing SSRIs to psychological support [33]. The studies included in the review were short-term (≤ 12 weeks) and meta-analyses included fewer than 120 participants [33]. The review offered limited evidence on antidepressant efficacy with short-term SSRI use, noting potential benefits for depression scores but raising concerns about side effects [33]. Our review expands on this by including a broader population in varying stages of CKD and emphasizing stage-specific dosing.

Other differences arise from advances in study methodology and pharmacological understanding. The inclusion of solriamfetol and esmethadone in our review provides insights into newer treatment options that were absent in previous analyses. These medications highlight the necessity for tailored dosing strategies across CKD stages, particularly in advanced stages and ESRD, where drug exposure and clearance vary significantly.

Overall, while prior reviews offered foundational insights, this review expands upon existing evidence by incorporating a broader population, newer medications, and updated dosing considerations. These findings emphasize the importance of regular monitoring, culturally competent care, and stage-specific prescribing to optimize safety and efficacy in managing depression among CKD patients. Despite these insights, a critical gap remains in establishing comprehensive clinical guidelines that delineate optimal prescribing practices for antidepressants in patients with varying degrees of renal impairment.

Strengths and limitations of the review and included studies

This systematic review presents several notable strengths in its evaluation of the safety and efficacy of antidepressants for treating depression in adults with impaired renal function. A key strength lies in the comprehensive literature search conducted following the PRISMA 2020 guidelines utilizing multiple reputable databases and registers, including PubMed, ScienceDirect, ClinicalTrials.gov, and Medline. This extensive search strategy enhances the robustness and inclusivity of the review, ensuring that relevant studies are not overlooked.

Another significant strength is the inclusion of diverse study designs, which encompasses RCTs, CCTs, observational cohort studies, and case–control studies. This variety provides a multifaceted understanding of antidepressant safety and efficacy, allowing for a more comprehensive assessment of the available evidence. Moreover, the review specifically targets adults with renal impairment, a demographic often underrepresented in clinical research. This focus addresses a critical gap in the literature regarding the intersection of mental health and renal health, thus contributing valuable insights to the field.

The rigorous quality assessment employed in this review further strengthens its findings. By utilizing established tools such as the Newcastle–Ottawa Scale, the Cochrane RoB 2, and ROBINS I tools, the review ensured that only studies with moderate to low risk of bias were included [12–14]. This methodological rigor enhances the credibility of the conclusions drawn from the review. Additionally, the identification of pharmacokinetic variability among antidepressants highlights the importance of individualized treatment plans for patients with varying degrees of renal function, underscoring the need for careful consideration in prescribing practices.

However, the review also has notable limitations that must be acknowledged. The variability in study designs, populations, and outcome measures complicates the synthesis of results. Differences in the severity of renal impairment, comorbid conditions, and demographic factors across studies may introduce confounding variables that affect the overall conclusions drawn from the review.

Additionally, most studies focused on short-term outcomes, with limited data available regarding the long-term safety and efficacy of antidepressants in this patient population. The absence of long-term follow-up data makes it difficult to assess the sustained effects of treatment, which is crucial for managing chronic conditions like depression. Inconsistent reporting of side effects across studies further complicates the evaluation of the true safety profile of antidepressants. Variability in definitions and measurement methods for adverse effects can hinder effective comparisons and may obscure important safety concerns.

Future research directions

Future research on the safety and efficacy of antidepressants in adults with impaired renal function should focus on several key areas to address existing gaps. First, there is a critical need for longitudinal studies that evaluate the long-term effects of antidepressant therapy, as most current research primarily examines short-term outcomes. Extending follow-up periods will provide insights into sustained efficacy and safety, essential for managing chronic depression.

Additionally, studies should aim for larger and more diverse populations to enhance the generalizability of findings. Increased representation of minority groups and varying comorbid conditions will help develop tailored treatment protocols that meet the unique needs of different patient demographics. Exploring pharmacokinetic variations of antidepressants in patients with different levels of renal function is another important direction. Understanding how renal impairment affects drug metabolism and clearance will enable more informed prescribing decisions, potentially improving therapeutic outcomes.

Research should also investigate the impact of antidepressant therapy on specific clinical outcomes related to renal health, such as kidney disease progression and hospitalization rates. This will clarify the broader implications of antidepressant use in this population. Finally, qualitative studies that capture patient experiences and preferences regarding antidepressant treatment can inform more patient-centered care strategies. By focusing on these areas, future research can significantly enhance the management of depression in adults with impaired renal function.

Conclusion

This systematic review highlights the critical need for a nuanced understanding of the safety and efficacy of antidepressants in adults with impaired renal function. By addressing the unique pharmacokinetic considerations, emphasizing individualized treatment plans, and advocating for regular monitoring and culturally competent care, healthcare providers can optimize therapeutic outcomes for this vulnerable population. The review also identifies critical gaps in the existing literature, including a lack of long-term data on the safety and efficacy of antidepressants in CKD patients and the underrepresentation of diverse populations. Current evidence highlights the importance of dose adjustments and regular monitoring, particularly in patients with severe renal impairment or on dialysis. Despite these insights, clinical guidelines for antidepressant use in CKD remain limited, underscoring the need for further research. Future research directions aimed at long-term effects and diverse patient representation will further enhance clinical practices and improve patient care in managing depression among individuals with renal impairment.

Author contributions

H. S., M. Z., and N. H. contributed to the concept and design of the study. H. S., E. V., R. D., and I. M. were responsible for data acquisition, analysis, and interpretation. H. S. wrote the main manuscript text. H. S., M. Z., N. H., E. V., R. D., and I. M. provided critical reviews for important intellectual content and approved the final version. M. Z., N. H., and I. M. supervised the project. All authors reviewed and approved the manuscript, ensuring accountability for all aspects of the work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.