Brain aging and treatment response in geriatric depression

描述（由申请人提供）：只有不到50%的老年抑郁症患者通过一线抗抑郁药物治疗获得缓解和功能恢复。大多数患者留下了明显的残余症状，使他们面临慢性、复发性疾病、虚弱和自杀的风险。脑老化可能是治疗效果差的原因。我们的试点数据表明，神经退行性改变与淀粉样蛋白和tau蛋白结合增加，以及微血管脑改变经常发生在老年抑郁症患者中，正如使用新的神经成像技术（即MRI和[F-18] FDDNP PET）所记录的那样。提高对脑老化与治疗反应相关的神经生物学的理解，可以改善具有脑老化生物标志物或轻度认知障碍（MCI）的抑郁症老年人的个性化治疗。认知障碍，特别是在记忆和执行功能领域，即使在老年人抑郁症状改善后仍然存在，这些症状对单独的血清素能治疗反应较差。有一个令人信服的理由研究神经保护谷氨酸能药物，如美金刚（MEM），可以针对大脑老化并提供认知增强。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联合使用后抗抑郁反应增强，执行认知功能和记忆测试改善。我们假设，在羟色胺能药物艾司西酞普朗的基础上加入美金刚，可能会改善晚年抑郁症患者的情绪和认知结果，这将为患有神经退行性和微血管脑改变或轻度认知障碍的老年抑郁症患者亚组创造更个性化的治疗策略。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评估艾司西酞普兰和美金刚联合治疗反应的预测因素和调节因素，与艾司西酞普兰和安慰剂相比。我们将确定大脑结构是否发生变化，包括1。白质高信号的体积和定位；2.区域灰质和白质体积；3. 海马厚度;和4。[F-18]FDDNP-PET总量和区域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联合治疗，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检查，并在基线和整个研究过程中进行全面的医学、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。我们的研究将提供关于美金刚在老年抑郁症中的应用的独特信息，并将调查治疗反应的潜在机制，以及对美金刚优先治疗的亚组。

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.