Randomized trial of sertraline treatment of depression in Chronic Kidney Disease

描述(由申请人提供)：抑郁症在接受透析的人中很常见，是住院和死亡的独立危险因素。我的实验室最近的研究表明，在没有接受透析的慢性肾脏疾病(CKD)患者中，约有20%的患者患有严重抑郁发作(MDE)，与没有接受MDE的患者相比，他们在一年内住院、开始透析或死亡的可能性是后者的两倍。然而，只有少数患有抑郁症的CKD患者接受了抗抑郁药物的治疗。CKD患者治疗率低的一个主要原因是缺乏支持抗抑郁药物在CKD患者中的有效性和安全性的研究。舍曲林抗抑郁药心脏病发作的随机试验显示，5-羟色胺选择性再摄取抑制剂(SSRI)舍曲林对心血管结局有好处，但排除了中到重度CKD的患者。鉴于CKD患者心血管(CV)死亡率过高，研究抑郁症的治疗在这些患者中是否安全有效变得势在必行。需要这些信息来设计一项结果试验，以确定抑郁症的治疗是否拯救了这一人群的生命并改善了生活质量。在这项应用中，我建议进行一项试验性研究，以检验这样一种假设，即短期使用舍曲林治疗MDE将导致透析前3b-5CKD期患者抑郁症状严重程度和生活质量的改善。我进一步假设，在这些患者中，舍曲林治疗MDE是安全和耐受性良好的。这项研究的目的是1)确定与安慰剂相比，舍曲林治疗是否能改善抑郁症状的严重程度以及总体功能和生活质量。我将使用一项随机、双盲、安慰剂对照的弹性剂量12周试验，涉及200名透析前3-5期CKD患者；并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可耐受和安全。评估方法包括：a)每组中有严重不良事件的比例，包括需要输血或住院的出血；b)系统性治疗紧急反应评价表中报告的副作用的类型和严重程度；c)每组中有副作用的比例报告的副作用的频率、强度和负担评分表；d)与安慰剂组相比，舍曲林的血小板聚集率和活化程度从基线开始减少，以及这种减少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果的机制：a)营养状况；b)坚持服用处方药；C)认知功能；d)炎症标志物；我还将收集随机分组后6个月和12个月的死亡、住院和开始透析的数据。后一种信息将被用于能量计算，以确定进行大规模试验的可行性，以调查抑郁症的治疗是否改善了CKD的结果。

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.