Brain aging and treatment response in geriatric depression

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。大多数患者留下了显著的残留症状，使他们处于慢性复发性疾病、虚弱和自杀的风险中。大脑老化可能是治疗效果差的原因。我们的初步数据表明，老年抑郁症患者经常发生淀粉样蛋白和tau蛋白结合增加的神经退行性变化以及微血管脑变化，如使用新型神经成像技术（即，MRI和[F-18] FDDNP PET）。对脑老化与治疗反应相关的神经生物学的更好理解可以改善具有脑老化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。认知障碍，特别是记忆和执行功能领域的认知障碍，即使在老年人抑郁症状改善后仍持续存在，并且这些症状对单用多巴胺能治疗反应不良。有一个令人信服的理由研究神经保护剂，如美金刚（MEM），可以针对大脑老化和提供认知增强。这也得到了我们的初步数据的支持，这些数据记录了艾司西酞普兰和MEM联合使用增强的抗抑郁反应和执行认知功能和记忆测试的改善。我们假设，在多巴胺能药物艾司西酞普兰中加入美金刚，可能会导致更好的情绪和认知结果的晚年抑郁症，这将创造一个更个性化的治疗策略，为一个亚组的老年抑郁症患者，神经退行性和微血管脑变化或MCI。 本申请将在6个月随机双盲安慰剂对照试验中评价艾司西酞普兰和美金刚联合治疗与艾司西酞普兰和安慰剂相比的治疗反应的预测因子和调节因子。我们将确定是否大脑结构的变化，包括1。白色高信号（WMH）的体积和定位; 2.区域性灰和白色物质体积; 3.海马厚度;和4. [F-18]FDDNP-PET总体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：一组将接受艾司西酞普兰和美金刚的组合，第二组将接受艾司西酞普兰和安慰剂。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（包括12个月随访）接受全面的医学、神经精神病学和认知评估，以检测抑郁症复发。我们的研究将提供独特的信息，使用美金刚在老年抑郁症，并将调查治疗反应的潜在机制，和亚组优先治疗美金刚。

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.