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

1/3-晚年抑郁症的不完全反应：走向缓解

• 批准号: 8102067
• 负责人: CHARLES F. REYNOLDS
• 金额: $ 50.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102067
• 关键词: Acute; Address; Adherence; Agitation; Akathisia; Antidepressive Agents; Anxiety; Area; Benefits and Risks; Biological databases; Caregiver Burden; Clinical; Clinical Data; Clinical Treatment; Controlled Study; Data; Developed Countries; Disease; Disease remission; Dopamine; Dose; Double-Blind Method; Drug Exposure; Drug Kinetics; Elderly; Enrollment; Evidence based treatment; Family Caregiver; Genes; Genetic; Genetic Polymorphism; Geriatrics; Goals; Grant; Health Services Research; Impaired cognition; Impairment; Individual; Intervention; Link; Major Depressive Disorder; Measures; Medical; Medicine; Mental Depression; Mental disorders; National Institute of Mental Health; Norepinephrine; Obesity; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Placebos; Prognostic Factor; Protocols documentation; Public Health; Randomized; Recruitment Activity; Recurrence; Relapse; Research; Research Personnel; Resistance; Risk; Role; Safety; Selective Serotonin Reuptake Inhibitor; Serotonin; Site; Suicide; Symptoms; Testing; Treatment outcome; Universities; Washington; aged; aripiprazole; base; clinically significant; demographics; depressive symptoms; disability; evidence base; geriatric depression; innovation; intervention program; medical complication; meetings; mortality; novel; older patient; open label; primary outcome; public health relevance; randomized placebo controlled trial; resistance factors; response; secondary outcome; treatment strategy; venlafaxine

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.

描述（由申请人提供）：老年抑郁症（LLD）治疗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。难治性晚年抑郁症（TRLLD）增加了早期复发的风险，破坏了对共存医学疾病治疗的依从性，放大了残疾和认知障碍，给家庭照顾者带来了更大的负担，并增加了早期死亡的风险，包括自杀。达到并维持缓解是治疗的主要目标，但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，我们提出了一个三个网站的合作R 01连接先进的干预和服务研究中心在匹兹堡大学与卓越中心的LLD研究在多伦多大学和华盛顿大学在圣路易斯。本研究组在24名对SSRI和SRNI药物治疗不完全应答者中进行了阿立哌唑增强的初步研究，发现在添加阿立哌唑的情况下，50%的患者在12周内缓解。基于这些数据，我们假设阿立哌唑加强治疗在对文拉法辛XR反应不完全的老年患者中实现和维持缓解方面优于安慰剂上级。我们计划在三个研究中心招募500名60岁及以上的重度抑郁症患者，并开放性地使用文拉法辛XR（高达225 mg/d）治疗12周（第1阶段）。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（2.5-15 mg/d;目标剂量：10 mg/d）或文拉法辛的安慰剂增强治疗12周（2期），目标是实现缓解（连续两次评估MADRS<10）。在第2阶段缓解的患者（N=80）将接受连续治疗，采用与随机分配（第3阶段）相同的双盲干预，持续12周，以确定缓解的稳定性。根据疗效和耐受性数据，我们将估计需要治疗的人数和需要伤害的人数，提供阿立哌唑增加TRLLD的获益和风险的临床信息估计。[In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（5-羟色胺、去甲肾上腺素和多巴胺基因的选定多态性）变量的作用，同时控制药物暴露的变异性，以进行疗效和耐受性分析，从而获得推进LLD个性化治疗的证据。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R 01 MH 083660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统计数据的变化，其公共卫生重要性将继续增加。至少有50%的老年抑郁症患者对一线治疗没有反应;这些人不仅持续遭受痛苦的风险增加，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增加。因此，难治性晚年抑郁症（TRLLD）是一个重要的公共卫生问题。目前还没有针对TRLLD的循证药物治疗;因此，这项研究旨在解决治疗抑郁症的证据基础中的一个主要空白。 公共卫生关系： 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统计数据的变化，其公共卫生重要性将继续增加。至少有50%的老年抑郁症患者对一线治疗没有反应;这些人不仅持续遭受痛苦的风险增加，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增加。因此，难治性晚年抑郁症（TRLLD）是一个重要的公共卫生问题。目前还没有针对TRLLD的循证药物治疗;因此，这项研究旨在解决治疗抑郁症的证据基础中的一个主要空白。