Randomized trial of sertraline treatment of depression in Chronic Kidney Disease

描述（由申请人提供）：抑郁症在透析患者中很常见，是住院和死亡的独立风险因素。我的实验室最近的研究表明，约20%的慢性肾脏病（CKD）患者未接受透析治疗，患有重度抑郁发作（MDE），与未接受MDE的患者相比，住院、开始透析或在一年内死亡的可能性是其两倍。然而，只有少数患有抑郁症的CKD患者接受抗抑郁药治疗。CKD患者治疗率低的一个主要原因是缺乏支持CKD患者抗抑郁药疗效和安全性的研究。舍曲林抗抑郁剂心脏病发作随机试验显示舍曲林对心血管结局有益，但排除了中度至重度CKD患者。鉴于CKD患者的心血管（CV）死亡率过高，研究这些患者的抑郁症治疗是否安全有效变得势在必行。需要这些信息来设计一个结果试验，以确定抑郁症的治疗是否可以挽救生命并提高这一人群的生活质量。在这个应用中，我提出了一个试点研究，以测试的假设，短期治疗的MDE舍曲林将导致改善抑郁症状的严重程度和生活质量的患者透析前阶段3b-5 CKD。我进一步假设舍曲林治疗MDE在这些患者中安全且耐受性良好。本研究的目的是：1）确定舍曲林治疗与安慰剂相比，是否能改善抑郁症状的严重程度和整体功能及生活质量。我将使用一项随机、双盲、安慰剂对照、灵活剂量、为期12周的试验，纳入200例透析前3-5期CKD受试者;分别评估工作和社会适应量表和肾脏疾病生活质量调查（KDQOL-SF）; 2）确定舍曲林与安慰剂相比是否耐受和安全。这将通过以下方式进行评估：a）每组中发生严重不良事件（包括需要输血或住院的出血）的比例; B）在治疗后出现的不良反应的系统评估量表上报告的副作用的类型和严重程度; c）每组中发生副作用的比例（在副作用的频率、强度和负担评定量表上报告）; d）与安慰剂组相比，舍曲林中血小板聚集和活化从基线降低，以及这种降低是否与较高的血浆舍曲林水平相关; 3）在探索性分析中，我还将通过评估以下方面的变化来研究舍曲林可能影响结局的机制：a）营养状况; B）处方药物的依从性; c）认知功能;和d）炎症标志物;我还将收集随机化后6个月和12个月时死亡、住院和透析开始的数据。后一信息将用于功效计算，以确定进行大规模试验的可行性，以调查抑郁症治疗是否改善CKD的结局。

DESCRIPTION (provided by applicant): 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.