Effect of Sertraline on Depressive Symptoms in Patients With Chronic Kidney Disease Without Dialysis Dependence: The CAST Randomized Clinical Trial

Abstract

Importance: Major depressive disorder (MDD) is prevalent among patients with chronic kidney disease (CKD) and is associated with morbidity and mortality. The efficacy and adverse events of selective serotonin reuptake inhibitors in these patients are unknown.

Objective: To determine whether treatment with sertraline improves depressive symptoms in patients with CKD and MDD.

Design, setting, and participants: The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) was a randomized, double-blind, placebo-controlled trial involving 201 patients with stage 3, 4, or 5 non-dialysis-dependent CKD, who were enrolled at 3 US medical centers. The Mini Neuropsychiatric Interview was used to establish MDD. The first participant was randomized in March 2010 and the last clinic visit occurred in November 2016.

Interventions: After a 1-week placebo run-in, participants were randomized to sertraline (n = 102) for 12 weeks at an initial dose of 50 mg/d (escalated to a maximum dose of 200 mg/d based on tolerability and response) or matching placebo (n = 99).

Main outcomes and measures: The primary outcome was improvement in depressive symptom severity from baseline to 12 weeks determined by the 16-item Quick Inventory of Depression Symptomatology-Clinician Rated (QIDS-C16) (score range, 0-27; minimal clinically important difference, 2 points). Secondary outcomes included improvement in quality of life (Kidney Disease Quality of Life Survey-Short Form; score range, 0-100; higher scores indicate more favorable quality of life) and adverse events.

Results: There were 201 patients (mean [SD] age, 58.2 [13.2] years; 27% female) randomized. The primary analysis included 193 patients who had at least 1 outcome assessment after randomization. The mean (SD) baseline QIDS-C16 score was 14.0 (2.4) in the sertraline group (n = 97) and 14.1 (2.4) in the placebo group (n = 96). The median participation time was 12.0 weeks and the median achieved dose was 150 mg/d, which was not significantly different between the groups. The QIDS-C16 score changed by -4.1 in the sertraline group and by -4.2 in the placebo group (between-group difference, 0.1 [95% CI, -1.1 to 1.3]; P = .82). There was no significant between-group difference in change in patient-reported overall health on the Kidney Disease Quality of Life Survey (median score, 0 in the sertraline group vs 0 in the placebo group; between-group difference, 0 [95% CI, -10.0 to 0]; P = .61). Nausea or vomiting occurred more frequently in the sertraline vs placebo group (22.7% vs 10.4%, respectively; between-group difference, 12.3% [95% CI, 1.9% to 22.6%], P = .03), as well as diarrhea (13.4% vs 3.1%; between-group difference, 10.3% [95% CI, 2.7% to 17.9%], P = .02).

Conclusions and relevance: Among patients with non-dialysis-dependent CKD and MDD, treatment with sertraline compared with placebo for 12 weeks did not significantly improve depressive symptoms. These findings do not support the use of sertraline to treat MDD in patients with non-dialysis-dependent CKD.

Trial registration: clinicaltrials.gov Identifier: NCT00946998.

Conflict of interest statement

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rush reported receiving consulting fees from Brain Resource Ltd, Curbstone Consultant LLC, Eli Lilly, Emmes Corp, MindLinc, Montana State University, University of Texas Southwestern Medical Center, Sunovion, and Texas Tech University; speaking fees from Stanford University, Global Medical Education Inc, Sing-Health, University of Montana, Montana State University, and John Peter Smith Health Network; and royalties from Guilford Press and the University of Texas Southwestern Medical Center. Dr Toto reported receiving consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Novo Nordisk, Reata, Relypsa, and ZS Pharma. Dr Trivedi reported serving as an advisor or consultant to Abbott Laboratories, Akzo (Organon Pharmaceuticals), Allergan Sales LLC, Alkermes, Arcadia Pharmaceuticals Inc, AstraZeneca, Axon Advisors, Brintellix, Bristol-Myers Squibb, Cephalon Inc, Cerecor, Eli Lilly & Co, Evotec, Fabre Kramer Pharmaceuticals Inc, Forest Pharmaceuticals, GlaxoSmithKline, Global Medical Education Inc, Health Research Associates, Janssen, Johnson & Johnson, Lundbeck, MedAvante, Medscape, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America Inc, MSI Methylation Sciences Inc, Nestle Health Science-PamLab Inc, Naurex, Neuronetics, One Carbon Therapeutics Ltd, Otsuka Pharmaceuticals, Parke-Davis Pharmaceuticals, Pfizer, PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products Ltd, Sepracor, SHIRE Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories. No other disclosures were reported.

Figures

Figure 1.. Patient Enrollment in the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST)

aDefined as a 16-item Quick Inventory of Depressive Symptomatology–Clinician Rated (QIDS-C16) score of less than 11 after the placebo run-in phase. bIncluded self-reported tremor, hypersomnolence, insomnia, diarrhea, and headache. cDefined as having taken less than 65% of drug by pill count. dEstimated glomerular filtration rate greater than 60 mL/min/1.73 m2 in 3 patients, ongoing substance dependence in 1 patient, suicidal ideation in 1 patient, and unable to obtain blood for laboratory tests in 1 patient. eExited the trial prior to the first QIDS-C16 outcomes assessment after randomization (before week 2) and lacked any primary outcome data for analysis. Of the 5 patients in the sertraline group, 1 withdrew consent, 2 withdrew due to adverse effects, and 2 did not return for visits; of the 3 patients in the placebo group, 2 withdrew consent and 1 was hospitalized and no longer wanted to participate.

Figure 2.. Serial Changes in the 16-Item Quick Inventory of Depressive Symptomatology–Clinician Rated (QIDS-C16) Scores

Participants completed at least 1 assessment after randomization and were included in the primary analysis. Error bars indicate SDs, which were calculated separately for each time point. Each of the 16 QIDS-C16 items can yield a score of 0 to 3 on a Likert scale. The score range is 0 to 27; higher scores indicate more severe depression; a score of 0 to 5 corresponds to a normal affect; 6 to 10 to a mild affect; 11 to 15 to a moderate affect; 16 to 20 to a severe affect; and 21 or greater to very severe depression.

Figure 3.. Paired Baseline and End of Study 16-Item Quick Inventory of Depressive Symptomatology–Clinician Rated (QIDS-C16) Scores

Parallel line plot of the QIDS-C16 scores. Each patient is represented by a vertical line, with participants plotted by group assignment (sertraline, n = 97; placebo, n = 96) and sorted by baseline value.