Depression is common in those on dialysis and is an independent risk factor for hospitalization and death. Recent studies from my laboratory have shown that about 20% of patients with chronic kidney disease (CKD) not on dialysis suffer from a major depressive episode (MDE) and are twice as likely to be hospitalized, initiate dialysis or die within a year as compared to those without a MDE. However, only a minority of CKD patients with depression are treated with antidepressants. A major reason for low treatment rates in those with CKD is lack of studies that support the efficacy and safety of antidepressants in CKD patients. The Sertraline AntiDepressant Heart Attack Randomized Trial showed benefit of serotonin-selective reuptake inhibitor (SSRI) sertraline on cardiovascular outcomes but excluded patients with moderate to severe CKD. Given the excessive rates of cardiovascular (CV) death in CKD patients, it becomes imperative to investigate whether treatment of depression is safe and efficacious in these patients. This information is needed to design an outcomes trial to determine if treatment of depression saves lives and improves quality of life in this population. In this application, I propose a pilot study to test the hypothesis that short-term treatment of a MDE with sertraline will result in improvement in depression symptom severity and quality of life in patients with predialysis stages 3b-5 CKD. I further hypothesize that treatment of MDE with sertraline is safe and well- tolerated in these patients.
The aims of this study are to 1) determine if treatment with sertraline, as compared with placebo, results in an improvement in depression symptom severity and overall function and quality of life. I will use a randomized, double-blinded, placebo-controlled flexible-dose 12-week trial involving 200 subjects with predialysis stages 3-5 CKD; and assess the Work and Social Adjustment Scale and Kidney Disease Quality of Life Survey (KDQOL-SF), respectively; 2) determine if sertraline, as compared with placebo, is tolerable and safe. This will be assessed by a) proportion in each group with serious adverse events including bleeding requiring blood transfusion or hospitalization; b) type and severity of side effects reported on the Systemic Assessment for Treatment Emergent Effects scale; c) proportion in each group with side effects reported on the Frequency, Intensity and Burden of Side Effects Rating scale; d) reduction in platelet aggregation and activation from baseline in the sertraline as compared with placebo group, and whether this reduction correlates with higher plasma sertraline levels; 3) In exploratory analyses, I will also investigate mechanisms by which sertraline may affect outcomes by evaluating change in: a) nutritional status; b) adherence to prescribed medications; c) cognitive functioning; and d) markers of inflammation; I will also collect data on death, hospitalizations, and dialysis initiation at 6 and 12 months after randomization. The latter information will be used for power calculations to determine the feasibility of conducting a large-scale trial to investigate whether treatment of depression improves outcomes in CKD.

Public Health Relevance

The relevance to public health is providing urgently needed data on the efficacy and safety of a typical serotonin-selective reuptake inhibitor in Chronic Kidney Disease (CKD) patients that can be used to power a future multi-center large-scale trial designed to determine whether treatment of depression improves morbidity and mortality in patients with CKD. In addition, this study will elucidate mechanisms, such as increased platelet aggregability, cognitive impairment, non-adherence to medications and poor nutritional status, by which depression may lead to poor outcomes in this patient population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085512-05
Application #
8792383
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Abbott, Kevin C
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
5
Fiscal Year
2015
Total Cost
$345,825
Indirect Cost
$128,325
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Hedayati, S Susan; Gregg, L Parker; Carmody, Thomas et al. (2017) Effect of Sertraline on Depressive Symptoms in Patients With Chronic Kidney Disease Without Dialysis Dependence: The CAST Randomized Clinical Trial. JAMA 318:1876-1890
Toups, Marisa; Carmody, Thomas; Trivedi, Madhukar H et al. (2016) Performance of depression rating scales in patients with chronic kidney disease: an item response theory-based analysis. Gen Hosp Psychiatry 42:60-6
Jain, Nishank; Carmody, Thomas; Minhajuddin, Abu T et al. (2016) Prognostic Utility of a Self-Reported Depression Questionnaire versus Clinician-Based Assessment on Renal Outcomes. Am J Nephrol 44:234-44
Hedayati, S Susan; Daniel, Divya M; Cohen, Scott et al. (2016) Rationale and design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression (ASCEND). Contemp Clin Trials 47:1-11
Jain, Nishank; Li, Xilong; Adams-Huet, Beverley et al. (2016) Differences in Whole Blood Platelet Aggregation at Baseline and in Response to Aspirin and Aspirin Plus Clopidogrel in Patients With Versus Without Chronic Kidney Disease. Am J Cardiol 117:656-663
Colbert, Gates; Jain, Nishank; de Lemos, James A et al. (2015) Utility of traditional circulating and imaging-based cardiac biomarkers in patients with predialysis CKD. Clin J Am Soc Nephrol 10:515-29
Berger, Joseph R; Hedayati, S Susan (2014) When is a conservative approach to advanced chronic kidney disease preferable to renal replacement therapy? Semin Dial 27:253-6
Jain, Nishank; Trivedi, Madhukar H; Rush, A John et al. (2013) Rationale and design of the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST). Contemp Clin Trials 34:136-44
Jain, Nishank; Hedayati, S Susan; Sarode, Ravindra et al. (2013) Antiplatelet therapy in the management of cardiovascular disease in patients with CKD: what is the evidence? Clin J Am Soc Nephrol 8:665-74
Hedayati, S Susan; Yalamanchili, Venkata; Finkelstein, Fredric O (2012) A practical approach to the treatment of depression in patients with chronic kidney disease and end-stage renal disease. Kidney Int 81:247-55