Depression and chronic kidney disease (CKD) are both increasingly common conditions that affect large proportions of the US population. According to the National Institute of Mental Health, in 2015 an estimated 16.1 million US adults aged 18 years or older had at least 1 major depressive episode within the prior year.1 The incremental economic burden of US adults with major depressive disorder (MDD; calculated by comparison with adults without MDD and matched for multiple factors including comorbidities) has been estimated at $200 billion annually,2 and the World Health Organization ranks depression as the leading cause of disability worldwide.3
More than 30 million US adults are affected by CKD, with 15 million or more having significantly reduced kidney function as indicated by an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 (CKD stage ≥3).4 There is a complex interplay between psychiatric and nonpsychiatric illness, and perhaps a clear dichotomization of the 2 concepts is not possible. Depression affects people with chronic nonpsychiatric illness more than those without any. Some estimates suggest that as many as one-quarter of adults with CKD may be affected by depression, suggesting more than 7 million US adults may have coexistent CKD and depression.5,6
Selective serotonin reuptake inhibitors (SSRIs) have been a mainstay of depression treatment for decades.7 Most large trials of SSRIs and other antidepressants have been performed in physically healthy persons, and studies among persons with physical comorbidities have been smaller and at risk of publication bias.8 Studies of antidepressant medications in persons with CKD are few and generally of low quality.9 The physiological basis for depressive symptoms may be different for individuals with vs without chronic physical illness, and persons with multiple physical comorbidities may be prone to adverse medication effects from antidepressant therapy, bringing into question the appropriateness of generalizing results from studies in physically healthy populations to other populations. A Kidney Disease: Improving Global Outcomes report10 identified the mismatch between the burden of depression in CKD and evidence for effective therapies as a major barrier to quality care.
In this issue of JAMA, Hedayati et al11 report the findings of a clinical trial evaluating the effect of sertraline on depressive symptoms in patients with MDD and CKD who were not receiving dialysis. This randomized, placebo-controlled, parallel-group, investigator- and clinician-masked trial was performed at 3 centers affiliated with the University of Texas Southwestern Medical Center. Persons with CKD stage 3, 4, or 5 (eGFR <60 mL/min/1.73 m2) not receiving dialysis were initially eligible; however, during the study the eGFR threshold was reduced to less than 45 mL/min/1.73 m2. Depressive symptom screening was performed in primary care and CKD clinics with the 16-item Quick Inventory of Depressive Symptomatology–Self-Reported (QIDS-SR16), and patients were eligible if they scored 11 or greater (score range, 0-27). Those who screened positive were then given the Mini International Neuropsychiatric Interview to confirm MDD and exclude other psychiatric conditions. Persons who were taking antidepressants or recently received psychotherapy were excluded.
Participants who met these criteria received a placebo for 1 week to assess for adherence and placebo-responsive depressive symptoms, and those who were nonadherent were excluded. Participants also completed the 16-item Quick Inventory of Depression Symptomatology–Clinician Rated (QIDS-C16) and those who scored less than 11 on this clinician-rated scale were excluded. The remaining patients (ie, those who took ≥65% of study drug by pill count during the run-in phase and had a score ≥11 on the QIDS-C16) were randomized to receive an initial sertraline dose of 50 mg/d or matching placebo, and the dose of sertraline was increased by 50 mg/d (or identical-appearing change to placebo) every 2 weeks for the initial 6 weeks until 200 mg/d was reached, an effect was seen, or intolerable adverse effects occurred, and then continued receiving a stable dose for the remaining 6 weeks, for a total of 12 weeks of therapy.
Of the 261 patients who started the placebo run-in phase, 201 successfully completed this phase and were randomized. At least 1 follow-up assessment was completed by 97 of 102 persons in the sertraline group and by 96 of 99 persons in the placebo group; overall, 84% completed the full 12 weeks. Median eGFR was 27.5 mL/min/1.73 m2 in both study groups, reflecting quite advanced CKD in the majority of patients, and the 2 groups were reasonably balanced on most baseline characteristics. The median final sertraline dose was 150 mg/d. The primary outcome was change in depressive symptom severity as measured by the QIDS-C16 (has a minimal clinically important difference of 2 points), which was administered over 12 weeks by trained clinicians masked to treatment assignment. The mean baseline QIDS-C16 score was similar in the 2 groups (14.0 in the sertraline group vs 14.1 in the placebo group).
The authors found no meaningful difference in the change in depressive symptoms between the 2 groups (change in QIDS-C16 score, −4.1 in the sertraline group vs −4.2 in the placebo group; between-group difference, 0.1 [95% CI, −1.1 to 1.3]). They also found no difference between the groups in change in the Kidney Disease Quality of Life Survey–Short Form, a measure of subjective overall health status, or in several other secondary outcomes. Gastrointestinal adverse effects (nausea, vomiting, and diarrhea) were more frequent in the sertraline group, but there was no difference in the number of serious adverse events between the 2 groups.
This well-conceived, well-conducted, methodologically sound trial, the largest and best to this point addressing one of the most important challenges facing the CKD population, found that therapy with one of the most promising antidepressants for this population is largely no more effective than placebo and has adverse effects. Although most of the adverse effects were not severe, gastrointestinal symptoms are already common and bothersome among patients with CKD and cannot be disregarded. The study was adequately powered so that the effect estimate for depressive symptom change excludes the clinically important benefit. The findings are likely generalizable, considering that the diverse, multimorbid, medicated patient sample seems to reflect the CKD population at large.
From a psychiatric point of view, although the study was well conducted, there are some limitations. This study used a score of 11 on the QIDS-SR16 scale as a cut off for screening eligibility and also used a score of 11 on the QIDS-C16 for inclusion, which reflect moderate depression, a phenomenon that may not fully improve in the patient’s perspective until he or she physically feels better. In addition, SSRIs have been shown to lead to gastrointestinal adverse effects (although there is suggestion that these may differ among the agents in this class),12,13 and therefore, the finding of increased gastrointestinal adverse events is not unexpected.
As multimorbidity becomes the rule rather than the exception in much of clinical practice, trials targeting specific subpopulations, pragmatic trials, and personalized trials (including n-of-1 trials) are necessary to help determine whether prescribing a certain medication is more likely to help or to harm. Large, highly-selected and standardized efficacy trials, excluding those with CKD or other comorbidities, may have little relevance to the care of patients with complex multimorbidities. Two studies of antidepressants in patients with heart failure, namely the Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF; using escitalopram)14 and the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF; using sertraline),15 failed to show significant improvements in depression despite using clinician-rated depression scales (Montgomery-Åsberg Depression Rating Scale and Hamilton Depression Rating Scale, respectively). Furthermore, essentially all studies of SSRIs have shown that their efficacy to treat moderate depression is usually close to 40%, and the placebo effect is close to 30%, with more robust antidepressant response seen in patients with severe depression. The 2 studies in patients with heart failure14,15 and the study by Hedayati et al11 selected patients with moderate depression.
Patients with CKD constitute an especially important subpopulation, given its size and pathophysiological differences, and accumulating evidence that interventions that had been shown to be efficacious in populations mostly free from advanced CKD may not be effective in patients with chronically reduced kidney function. The illustrative experience of statin therapy, repeatedly shown ineffective at improving cardiovascular outcomes in patients with chronic kidney failure requiring dialysis, is an object lesson that even the most important and effective therapies in more general populations must be tested in CKD before clinicians can be confident of benefit. Thus, Hedayati et al11 have made an important contribution to the care of patients with CKD. The nephrology and psychiatry communities now have the responsibility to conduct further trials that use rigorous criteria for identifying depression, include more severely depressed patients, and evaluate other SSRIs to further probe for effective and safe treatments for depression in patients with CKD.
Corresponding Author: Wolfgang C. Winkelmayer, MD, MPH, ScD, Baylor College of Medicine, Section of Nephrology, One Baylor Plaza, ABBR R705, Houston, TX 77030 (email@example.com).
Published Online: November 3, 2017. doi:10.1001/jama.2017.17553
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Winkelmayer reported serving as an advisor or consultant to AMAG, Akebia, Amgen, AstraZeneca, Bayer, Medtronic, Fibrogen, Relypsa, and Vifor Fresenius Medical Care Renal Pharma, all unrelated to the subject matter of this editorial. No other disclosures were reported.
Carl P. Walther, Asim A. Shah, Wolfgang C. Winkelmayer. Treating Depression in Patients With Advanced CKDBeyond the Generalizability Frontier. JAMA. Published online November 03, 2017. doi:10.1001/jama.2017.17553