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% 的老年抑郁症患者在一线抗抑郁药物治疗后获得缓解和功能恢复。大多数患者都会留下明显的残留症状，使他们面临慢性、复发性疾病、虚弱和自杀的风险。大脑老化可能是治疗反应不佳的原因。我们的试验数据表明，老年抑郁症患者经常发生淀粉样蛋白和 tau 蛋白结合增加导致的神经退行性变化，以及大脑微血管变化，正如使用新型神经影像技术（即 MRI 和 [F-18] FDDNP PET）所记录的那样。更好地了解大脑衰老与治疗反应相关的神经生物学可以改善对具有大脑衰老生物标志物或轻度认知障碍（MCI）的抑郁老年人的个性化治疗。即使老年人的抑郁症状得到改善，认知障碍，尤其是记忆和执行功能领域的障碍仍然存在，并且这些症状对单独的血清素治疗反应不佳。研究神经保护性谷氨酸药物有令人信服的理由，例如美金刚（MEM）可以针对大脑衰老并提供认知增强作用。我们的试点数据也支持了这一点，该数据记录了艾司西酞普兰和 MEM 组合的抗抑郁反应增强以及执行认知功能和记忆测试的改善。我们假设，在血清素药物艾司西酞普兰中添加美金刚可能会改善晚年抑郁症的情绪和认知结果，这将为患有神经退行性和微血管脑变化或 MCI 的老年抑郁症患者亚群制定更加个性化的治疗策略。 目前的申请将在为期 6 个月的随机双盲安慰剂对照试验中，与艾司西酞普兰和安慰剂相比，评估艾司西酞普兰和美金刚组合治疗反应的预测因素和调节因素。我们将确定大脑结构是否发生变化，包括1.白质高信号（WMH）的体积和定位； 2.区域灰质和白质体积； 3.海马厚度； 4.[F-18]FDDNP-PET 总结合和局部结合可预测治疗反应。我们还将研究遗忘性轻度认知障碍（MCI）和抑郁症发病年龄在预测治疗反应中的作用。我们将招募134名患有重度抑郁症的老年非痴呆受试者。参与者将被随机分配到两个治疗组：一组接受艾司西酞普兰和美金刚组合治疗，第二组接受艾司西酞普兰和安慰剂治疗。所有受试者将在基线时接受 MRI 和 PET，并在基线时和研究过程中接受全面的医学、神经精神和认知评估，包括 12 个月的随访以检测抑郁症复发。我们的研究将提供有关美金刚在老年抑郁症中使用的独特信息，并将调查治疗反应的潜在机制以及优先治疗美金刚的亚组。