Brain aging and treatment response in geriatric depression

老年抑郁症的大脑衰老和治疗反应

• 批准号: 8497500
• 负责人: Helen Lavretsky
• 金额: $ 76.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-16 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497500
• 关键词: Acute; Address; Age; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Antidepressive Agents; Area; Atrophic; Behavior assessment; Behavioral; Binding; Biological Markers; Blood Vessels; Brain; Brain Pathology; Caring; Characteristics; Chronic; Clinical; Cognition; Cognitive; Communities; Controlled Clinical Trials; Data; Depressed mood; Diagnosis; Disease; Disease remission; Double-Blind Method; Elderly; Escitalopram; Functional disorder; Genetic; Glutamatergic Agents; Health; Heritability; Hippocampus (Brain); Image; Impaired cognition; Individual; Intervention; Knowledge; Lead; Left; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Medical; Memantine; Memory; Mental Depression; Mental Health; Mental disorders; Moods; Morbidity - disease rate; National Institute of Mental Health; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neuroprotective Agents; Outcome; Oxidative Stress; Participant; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Placebo Control; Placebos; Population; Positron; Positron-Emission Tomography; Prevalence; Protein Binding; Publishing; Randomized; Recovery of Function; Recruitment Activity; Relapse; Reporting; Research; Residual state; Risk; Role; Sampling; Serotonin Agents; Strategic Planning; Structure; Subgroup; Suicide; Symptoms; Techniques; Testing; Therapeutic Studies; Thick; aging brain; cerebrovascular; cognitive enhancement; cognitive function; depressive symptoms; design; disability; double-blind placebo controlled trial; executive function; experience; follow-up; frailty; geriatric depression; geriatric major depression; gray matter; high risk; hippocampal atrophy; improved; in vivo; mild cognitive impairment; mortality; neuroimaging; neuropsychiatry; novel; older patient; public health relevance; response; tau Proteins; therapy development; tomography; trait; treatment effect; treatment response; treatment strategy; treatment trial; white matter; working group

DESCRIPTION (provided by applicant): Fewer than 50% of elderly depressed patients achieve remission and functional recovery in response to first-line antidepressant pharmacotherapy. The majority of patients are left with significant residual symptoms, putting them at risk of chronic, relapsing illness, frailty, and suicide. Brain aging may be responsible fo poor treatment response. Our pilot data indicate that neurodegenerative changes with increased amyloid and tau protein binding, as well as microvascular brain changes frequently occur in older depressed individuals, as documented by using novel neuroimaging techniques (i.e., MRI and [F-18] FDDNP PET). Improved understanding of the neurobiology of brain aging in relation to treatment response can lead to the improved personalized treatment of depressed elderly with biomarkers of brain aging or with mild cognitive impairment (MCI). Cognitive impairment, especially, in the domains of memory and executive functions, persists even after amelioration of depressive symptoms in older adults, and these symptoms are poorly responsive to serotonergic treatment alone. There is a compelling rationale for the study of neuroprotective glutamatergic agents, such as memantine (MEM) that can target brain aging and provide cognitive enhancement. This is also supported by our pilot data that documented enhanced antidepressant response and improvement in executive cognitive function and memory tests to a combination of escitalopram and MEM. We hypothesize that the addition of memantine to the serotonergic drug, escitalopram, may result in better mood and cognitive outcomes of late life depression that will create a more personalized treatment strategy for a subgroup of older depressed individuals with neurodegenerative and microvascular brain changes or MCI. The current application will evaluate the predictors and moderators of treatment response to the combination of escitalopram and memantine compared to escitalopram and placebo in the 6 month randomized double- blind placebo controlled trial. We will determine whether brain structural changes, including 1. Volume and localization of white matter hyperintensities (WMH); 2.Regional gray and white matter volumes; 3. Hippocampal thickness; and 4.[F-18]FDDNP-PET total and regional binding are predictive of treatment response. We will also examine the role of amnestic mild cognitive impairment (MCI) and age of depression onset in predicting treatment response. We will recruit 134 elderly non-demented subjects with major depression. Participants will be randomly assigned to two treatment groups: one group will receive combination of escitalopram and memantine, the second group will receive escitalopram and placebo. All subjects will undergo MRI and PET at baseline and comprehensive medical, neuropsychiatric, and cognitive assessments at baseline and over the course of the study, including 12 months follow up to detect depression relapse. Our study will provide unique information on the use of memantine in geriatric depression, and will investigate the underlying mechanism of treatment response, and subgroups with preferential treatment to memantine.

描述（由申请人提供）：不到50％的老年抑郁症患者可以响应一线抗抑郁药药物治疗，从而获得缓解和功能恢复。大多数患者都有明显的残留症状，使他们处于慢性，复发，脆弱和自杀的风险。大脑衰老可能是治疗反应不佳的原因。我们的试点数据表明，随着老年抑郁症个体的淀粉样蛋白和tau蛋白结合的增加以及微血管脑的变化，神经退行性的变化经常发生，如使用新型神经影像学技术（即MRI和[F-18] FDDNP PET）所记录的。与治疗反应有关的大脑衰老神经生物学的了解可以改善对抑郁症的个性化治疗，并通过脑衰老或轻度认知障碍（MCI）的生物标志物（MCI）对抑郁症的抑郁症治疗进行了改善。认知障碍，尤其是在记忆和执行功能领域的认知障碍，即使在老年人的抑郁症状改善后仍然存在，并且这些症状仅对血清素能治疗的反应很差。有一个引人注目的理由，用于研究神经保护性谷氨酸能剂，例如美金刚（MEM），可以靶向脑衰老并提供认知增强。我们的试验数据也支持了这一点，该数据记录了增强的抗抑郁药反应，并改善了执行认知功能和记忆测试，以结合依然诺丙兰氏症和MEM的组合。我们假设将美灵氨酸添加到血清素药物苏联药物中，可能会导致晚期抑郁症的情绪和认知结果更好，这将为具有神经退行性和微血管脑变化或MCI的老年抑郁症患者的亚组创建更具个性化的治疗策略。 当前的应用将评估与依他普兰和安慰剂在6个月的随机双盲安慰剂对照试验中，与依他普兰和安慰剂相比，对依此所和美容组合的治疗反应的预测因子和主持人。我们将确定大脑结构的变化，包括1。量和白质超强度的定位（WMH）； 2.区域灰色和白色物质； 3。海马厚度； 4. [F-18] FDDNP-PET总和区域结合是治疗反应的预测。我们还将研究敏感的轻度认知障碍（MCI）和抑郁症的年龄在预测治疗反应中的作用。我们将招募134名患有严重抑郁症的老年人。参与者将被随机分配给两个治疗组：一组将接受依源妥拉兰和美容的组合，第二组将接受依源妥优兰和安慰剂。所有受试者将在基线和综合医学，神经精神病学以及基线和研究过程中进行综合医学，神经精神病学和认知评估，其中包括12个月后跟进以检测抑郁症复发。我们的研究将提供有关在老年抑郁症中使用纪念碑的独特信息，并将研究治疗反应的潜在机制，以及对美容氨酸的优先处理的亚组。