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

描述(申请人提供)：老年抑郁症(LLD)的治疗反应不完全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足够的反应，即使在最佳治疗条件下也是如此。难治性晚年抑郁症(TRLLD)增加了早期复发的风险，破坏了对共存的内科疾病的坚持治疗，放大了残疾和认知障碍，给家庭照顾者施加了更大的负担，并增加了包括自杀在内的早期死亡的风险。获得并维持缓解是治疗的主要目标，然而，关于如何最好地管理TRLLD的对照研究很少。为了弥补这一差距，我们提出了一个由三个地点组成的协作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。我们小组对24名对序贯SSRI和SRNI药物治疗不完全有效的患者进行了一项试点研究，发现加入阿立哌唑后，50%的患者在12周内缓解。基于这些数据，我们假设在文拉法辛XR不完全起效的老年患者中，阿立哌唑的强化治疗将优于安慰剂，以实现和维持缓解。我们建议在这三个地点招募500名60岁及以上患有严重抑郁障碍的患者，并开放使用文拉法辛XR(最高225 mg/d)(第1阶段)治疗12周。符合不完全应答标准的参与者(N=200)将被随机分配接受阿立哌唑(2.5-15 mg/d；目标剂量：10 mg/d)或文拉法辛安慰剂强化治疗12周(第二阶段)，目的是实现缓解(连续两次评估的MADRS和lt；10)。在第二阶段(N=80)缓解的患者将接受持续治疗，接受与他们随机分配的相同的双盲干预(第三阶段)，为期12周，以确定缓解的稳定性。根据疗效和耐受性数据，我们将估计需要治疗的次数和需要伤害的次数，为TRLLD增加阿立哌唑的益处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之外，我们将通过测试临床变量(共病焦虑、医疗负担和执行障碍)和遗传变量(5-羟色胺、去甲肾上腺素和多巴胺基因中选定的多态)的作用，同时控制药物暴露的可变性进行疗效和耐受性分析，来开发促进LLD个性化治疗的证据。这一方法将使我们能够区分特定治疗耐药因素和一般预后因素。]这是R01 MH083660的A1重新提交。晚年抑郁症是一种非常常见的疾病；随着美国和其他发达国家人口结构的变化，其对公共卫生的重要性将继续增加。至少50%的患有抑郁症的老年人对一线治疗没有反应；这些人不仅面临着持续痛苦的风险，而且还会增加残疾、死亡率、抑郁症的复发、医疗问题的复杂性和照顾者的负担。因此，难治性老年抑郁症(TRLLD)是一个重大的公共卫生问题。目前还没有针对TRLLD的循证药物疗法；因此，这项研究试图解决治疗抑郁症的证据基础中的一个主要缺口。 公共卫生相关性： 晚年抑郁症是一种非常常见的疾病；随着美国和其他发达国家人口结构的变化，其对公共卫生的重要性将继续增加。至少50%的患有抑郁症的老年人对一线治疗没有反应；这些人不仅面临着持续痛苦的风险，而且还会增加残疾、死亡率、抑郁症的复发、医疗问题的复杂性和照顾者的负担。因此，难治性老年抑郁症(TRLLD)是一个重大的公共卫生问题。目前还没有针对TRLLD的循证药物疗法；因此，这项研究试图解决治疗抑郁症的证据基础中的一个主要缺口。

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.