2/3-Incomplete Response in Late-Life Depression: Getting to Remission

2/3-晚年抑郁症的不完全反应：走向缓解

• 批准号: 7899914
• 负责人: Eric J Lenze
• 金额: $ 40.32万
• 依托单位: WASHINGTON UNIVERSITY
• 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/7899914
• 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）：治疗后期抑郁症（LLD）的不完全反应是一个巨大的公共卫生挑战：即使在最佳治疗条件下，至少有50％的老年人也无法对抗抑郁药疗法做出充分的反应。抗治疗后期抑郁症（TRLLD）会增加早期复发的风险，破坏对共存医疗疾病的治疗，放大残疾和认知障碍，对家庭护理人员施加更大的负担，并增加早期死亡率的风险，包括自杀。进行并维持缓解是治疗的主要目标，但是关于如何最好地管理TRLLD的对照研究很少。为了解决这一差距，我们提出了一个三个站点的合作R01，将匹兹堡大学的高级干预与服务研究中心与多伦多大学和圣路易斯华盛顿大学的LLD研究中心联系起来。我们的Aripiprazole组的一项试点研究对24个不完整的响应者对顺序SSRI和SRNI药物治疗的反应者进行了一项，发现50％在12周内添加了50％，并添加了Aripiprazole。基于这些数据，我们假设Aripiprazole的增强将优于安慰剂，可以在对Venlafaxine XR不完全反应的老年患者中造成和维持缓解。我们建议在三个部位招募500名60岁及60岁以上患有重度抑郁症的患者，并用Venlafaxine XR公开治疗12周（最多225 mg/d）（第1阶段）。符合不完全反应标准（n = 200）的参与者将被随机分配以接收阿立哌唑（2.5-15 mg/d;目标剂量：10 mg/d）或安慰剂加强Venlafaxine 12周（第2阶段），以实现两次连续评估的目标，以实现两次。那些在第2阶段（n = 80）中汇的人将接受连续处理，并与他们随机分配的相同双盲干预（第3阶段），持续12周，以确定缓解的稳定性。根据疗效和耐受性数据，我们将估计损害所需的治疗和数量所需的数量，从而提供有关TRLLD的Aripiprazole增强效益和风险的临床信息估算。 [除了评估这些收益和风险的主要目标外，我们还将通过测试临床（合并焦虑症，医疗负担和执行损害）和遗传性（在5-羟色胺，去甲肾上腺素基因和多巴胺基因中的多种多年型中的多态性多态性）来确保可变性的可变性和可变性的可变性，从而，我们还将开发证据推进LLD的个性化治疗方法。这种方法将使我们能够区分特定的抗性因子与一般预后因素。]这是R01 MH083660的A1重新提交。晚期抑郁症是一种极为普遍的疾病。随着美国和其他发达国家的人口变化，其公共健康重要性将继续增加。至少有50％的抑郁症患者将无法对一线治疗做出反应；这样的人不仅对持续痛苦，而且还增加了残疾，死亡率，抑郁症的复发，医疗问题并发症以及照料者负担的风险增加。因此，耐药后期抑郁症（TRLLD）是一个重大的公共卫生问题。没有针对TRLLD的循证药物疗法。因此，本研究试图解决治疗抑郁症的证据基础的主要差距。 公共卫生相关性： 晚期抑郁症是一种极为普遍的疾病。随着美国和其他发达国家的人口变化，其公共健康重要性将继续增加。至少有50％的抑郁症患者将无法对一线治疗做出反应；这样的人不仅对持续痛苦，而且还增加了残疾，死亡率，抑郁症的复发，医疗问题并发症以及照料者负担的风险增加。因此，耐药后期抑郁症（TRLLD）是一个重大的公共卫生问题。没有针对TRLLD的循证药物疗法。因此，本研究试图解决治疗抑郁症的证据基础的主要差距。