Combination of Novel Therapies for CKD Comorbid Depression (CONCORD)

项目摘要 我们研究的总体目标是确定重度抑郁症（MDD）的治疗是否 改善慢性肾病（CKD）患者的预后。我们发现MDD存在于 25%的CKD患者，与CKD进展为终末期肾病独立相关， 住院和死亡。抑郁症也被证明与以患者为中心的不良结局有关 例如生活质量（QOL）降低、疲劳、睡眠差以及不坚持饮食和药物。然而，在这方面， 常用抗抑郁药物或非药物的疗效和耐受性证据 CKD患者的治疗非常有限。既往数据主要来自透析依赖患者， 受样本量小、缺乏随机化和控制、持续时间短和脱落率高的限制。我们 组是第一个进行双盲随机对照试验的MDD治疗201例患者， 非透析CKD，并显示舍曲林，一种常用的选择性5-羟色胺再摄取抑制剂（SSRI）， 在改善抑郁症状方面并不比安慰剂更有效。鉴于抑郁症的高患病率 在CKD中，其与不良结局的相关性，以及缺乏支持常规治疗有效性的数据， 因此，测试治疗CKD患者中MDD的新策略变得势在必行。我们建议 与对照组相比，两种新的治疗策略的疗效和耐受性-（1）行为 激活远程治疗（BAT）16周，并添加安非他酮，一种非SSRI抗抑郁药，在8 对于抑郁症未缓解的患者（非缓解者），持续16周;以及（2）安非他酮，持续16周， 对于非缓解者，在第8周时增加最佳可行技术。在目标1中，我们将研究这两种药物的疗效和耐受性。 在201例患者中，治疗策略与对照组在改善抑郁症状的主要终点方面进行了比较（67例患者中， 组），在2个研究中心患有非透析CKD 3b-5期和MDD，按1：1：1随机分配至策略组或对照组 临床管理+安慰剂组。我们假设，任何一种方法与对照组相比， 盲法确定的抑郁症状改善2分的最小临床重要差异 抑郁症状快速调查表在目标2中，我们将研究疗效和耐受性 8周的（1）单盲BAT+安慰剂或（2）双盲安非他酮+临床管理与 控制抑郁症状的改善。在目标3中，我们将比较这两种治疗的疗效 用于改善CKD患者为中心的结果的策略与控制，包括a.药物依从性 和保健访问; B.疲劳; c.睡眠;和d.整体功能。迫切需要进行临床试验来解决 CKD患者中MDD治疗存在的证据缺口。确定2种不同策略的有效性 因此，如果发现有效，患者最可接受的选择可以 在临床实践中提供。我们有成功开展CKD多中心试验的记录， 已在2个地点组建了一支高素质的调查员队伍，以确保项目顺利完成。

Project Abstract The overall goal of our research is to determine whether treatment of a Major Depressive Disorder (MDD) improves the outcomes of patients with chronic kidney disease (CKD). We showed that MDD is present in up to 25% of CKD patients and independently associated with progression of CKD to End-Stage Kidney Disease, hospitalization, and death. Depression was also shown to be associated with adverse patient-centered outcomes such as lower quality of life (QOL), fatigue, poor sleep, and non-adherence to diet and medications. However, evidence for efficacy and tolerability of commonly-used antidepressant medications or nonpharmacologic treatments are very limited in CKD patients. Previous data, primarily derived from dialysis-dependent patients, were limited by small samples, lack of randomization and control, short durations, and high dropout rates. Our group was the first to conduct a double-blind randomized controlled trial for MDD treatment in 201 patients with non-dialysis CKD, and showed that sertraline, a commonly used selective serotonin reuptake inhibitor (SSRI), was no more efficacious than placebo for improving depressive symptoms. Given the high prevalence of MDD in CKD, its association with adverse outcomes, and lack of data to support efficacy of conventional treatments, it becomes imperative to test novel strategies to treat MDD in CKD patients. We propose to compare with a control group, the efficacy and tolerability of two novel treatment strategies - (1) Behavioral Activation Teletherapy (BAT) for 16 weeks, with the addition of bupropion, a non-SSRI antidepressant, at 8 weeks for patients whose depression has not remitted (non-remitters); and (2) bupropion for 16 weeks, with the addition of BAT at 8 weeks for non-remitters. In Aim 1, we will investigate the efficacy and tolerability of these 2 strategies vs. control for improvement in a primary endpoint of depressive symptoms in 201 patients (67 per group) with non-dialysis CKD stages 3b-5 and MDD at 2 sites, randomized 1:1:1 to either strategy or a control group of Clinical Management plus placebo. We hypothesize that either approach vs. control will result in a minimal clinically important difference of 2 points improvement in depressive symptoms, as ascertained blindly by the Quick Inventory of Depressive Symptomatology. In Aim 2 we will investigate the efficacy and tolerability of 8 weeks of (1) single-blind BAT plus placebo or (2) double-blind bupropion plus Clinical Management vs. control for improvement in depressive symptoms. In Aim 3, we will compare the efficacy of these 2 treatments strategies vs. control for improvement in CKD patient-centered outcomes including a. adherence to medications and healthcare visits; b. fatigue; c. sleep; and d. overall functioning. A clinical trial is urgently needed to address the evidence gap that exists for MDD treatment in CKD patients. Establishing the efficacy of 2 different strategies would be imperative, so that if found to be comparably efficacious, the option most acceptable to patients could be offered in clinical practice. We have a track-record of successfully conducting multicenter trials in CKD and have assembled a team of highly qualified investigators at 2 sites to ensure successful project completion.