1/3-Incomplete Response in Late-Life Depression: Getting to Remission

描述（由申请人提供）：治疗晚期抑郁症（LLD）的不完全反应是一个巨大的公共卫生挑战：至少50%的老年人对抗抑郁药物治疗没有充分反应，即使在最佳治疗条件下。难治性晚期抑郁症增加了早期复发的风险，破坏了对共存疾病的坚持治疗，加重了残疾和认知障碍，给家庭照顾者带来了更大的负担，并增加了包括自杀在内的早期死亡风险。达到并维持缓解是治疗的主要目标，然而缺乏关于如何最好地管理TRLLD的对照研究。为了解决这一差距，我们建议建立一个三站点合作R01，将匹兹堡大学的高级干预和服务研究中心与多伦多大学和圣路易斯华盛顿大学的LLD研究卓越中心联系起来。我们小组的一项试点研究发现，阿立哌唑在24例对序次SSRI和SRNI药物治疗不完全缓解的患者中，50%的患者在加用阿立哌唑的12周内缓解。基于这些数据，我们假设对于对文拉法辛XR反应不完全的老年患者，阿立哌唑增强治疗在带来和维持缓解方面优于安慰剂。我们建议在三个地点招募500名年龄在60岁及以上的重度抑郁症患者，并使用文拉法辛XR（高达225 mg/d）公开治疗12周（1期）。符合不完全缓解标准的参与者（N=200）将被随机分配接受阿立哌唑（2.5- 15mg /d；目标剂量：10mg /d）或安慰剂增强文拉法辛治疗12周（2期），目标是实现缓解（连续两次评估的MADRS<10）。在第2期（N=80）缓解的患者将接受持续治疗，与他们随机分配的双盲干预（第3期）相同，持续12周以确定缓解的稳定性。根据疗效和耐受性数据，我们将估计治疗所需的数量和危害所需的数量，为阿立哌唑增强治疗TRLLD的获益和风险提供临床信息估计。[除了评估这些益处和风险的主要目标外，我们还将通过测试临床（共病焦虑、医疗负担和执行障碍）和遗传（血清素、去甲肾上腺素和多巴胺基因的选择多态性）变量的作用，同时控制药物暴露的可变性，以进行疗效和耐受性分析，从而为LLD的个性化治疗提供证据。]这种方法将使我们能够区分治疗特异性耐药因素与一般预后因素。这是R01 MH083660的A1再提交。晚年抑郁症是一种极其常见的疾病；随着美国和其他发达国家人口结构的变化，公共卫生的重要性将继续增加。至少50%的老年抑郁症患者对一线治疗无效；这些人不仅面临持续痛苦的风险增加，而且残疾、死亡率、抑郁症复发、医疗问题并发症和照顾者负担也会增加。因此，难治性晚期抑郁症（TRLLD）是一个重大的公共卫生问题。TRLLD没有循证药物治疗；因此，本研究试图解决治疗抑郁症的证据基础上的一个主要差距。

DESCRIPTION (provided by applicant): Incomplete response in the treatment of late-life depression (LLD) is a large public health challenge: at least 50% of older people fail to respond adequately to antidepressant pharmacotherapy, even under optimal treatment conditions. Treatment resistant late-life depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater burden on family caregivers, and increases the risk for early mortality, including suicide. Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of controlled studies of how best to manage TRLLD. To address this gap, we propose a three-site collaborative R01 linking the Advanced Center for Interventions and Services Research at the University of Pittsburgh with centers of excellence for LLD research at the University of Toronto and at Washington University in St. Louis. A pilot study by our group of aripiprazole augmentation in 24 incomplete responders to sequential SSRI and SRNI pharmacotherapy found that 50% remitted over 12 weeks with the addition of aripiprazole. Based on these data, we hypothesize that aripiprazole augmentation will be superior to placebo for bringing about and sustaining remission in elderly patients who respond incompletely to venlafaxine XR. We propose to enroll 500 patients aged 60 and older with major depressive disorder at the three sites and treat them openly for 12 weeks with venlafaxine XR (up to 225 mg/d) (phase 1). Participants meeting criteria for incomplete response (N=200) will be randomly assigned to receive either aripiprazole (2.5-15 mg/d; target dose: 10 mg/d) or placebo augmentation of venlafaxine for 12 weeks (phase 2), with the goal of achieving remission (MADRS<10 for two consecutive assessments). Those who remit in phase 2 (N=80) will receive continuation treatment, with the same double-blinded intervention to which they were randomly assigned (phase 3), for 12 weeks to determine the stability of remission. Based on efficacy and tolerability data, we will estimate number needed to treat and number needed to harm, providing a clinically informative estimate of benefits and risks of aripiprazole augmentation for TRLLD. [In addition to the primary goal of assessing these benefits and risks, we will develop evidence advancing personalized treatment for LLD by testing the roles of clinical (comorbid anxiety, medical burden, and executive impairment) and genetic (selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while controlling for variability in drug exposure for efficacy and tolerability analyses. This approach will allow us to distinguish treatment-specific resistance factors versus general prognostic factors.] This is the A1 resubmission of R01 MH083660. Late-life depression is an extremely common illness; with the changing demographics in the U.S. and other developed nations its public health importance will continue to increase. At least 50% of elderly persons with depression will fail to respond to first-line treatments; such individuals are at increased risk not only for continued suffering but also increased disability, mortality, recurrence of depression, complication of medical issues, and caregiver burden. Thus, treatment-resistant late-life depression (TRLLD) is a significant public health problem. There are is no evidence-based pharmacotherapy for TRLLD; thus, this study seeks to address a major gap in the evidence base for treating depression. PUBLIC HEALTH RELEVANCE: Late-life depression is an extremely common illness; with the changing demographics in the U.S. and other developed nations its public health importance will continue to increase. At least 50% of elderly persons with depression will fail to respond to first-line treatments; such individuals are at increased risk not only for continued suffering but also increased disability, mortality, recurrence of depression, complication of medical issues, and caregiver burden. Thus, treatment-resistant late-life depression (TRLLD) is a significant public health problem. There are is no evidence-based pharmacotherapy for TRLLD; thus, this study seeks to address a major gap in the evidence base for treating depression.