Pilot Combination Treatment Trial of Mild Cognitive Impairment with Depression

描述（由申请人提供）：患有抑郁症（DEP）和认知障碍（CI）（DEP-CI）的患者代表了一个独特的、研究不足的人群，难以诊断、治疗和估计预后。我们的试验数据，由文献支持，表明许多DEP-CI患者表现出认知能力下降，并经常转化为痴呆症，主要是阿尔茨海默病（AD）。在DEP-CI中，缺乏关于情绪症状对抗抑郁药治疗的治疗反应的数据，特别是认知缺陷对认知增强剂治疗的数据。我们在一项双盲研究中的初步数据显示，多奈哌齐在改善抗抑郁药治疗的DEP-CI患者的记忆方面优于安慰剂上级。在第二项初步研究中，开放标签的es-citalopram加美金刚治疗导致痴呆的转化率较低。在这项初步临床试验中，我们将评估、治疗和随访80名在NYSPI/哥伦比亚大学医学中心和杜克大学医学中心精神病学、神经病学和内科就诊的DEP-CI患者。在治疗方案中，所有80名DEP-CI患者将接受为期4周的西酞普兰开放式抗抑郁治疗。在4周时，患者将被随机分配至添加多奈哌齐或安慰剂。再过12周后（进入试验的16周），患者将另外接受用于多奈哌齐细胞的附加美金刚和用于安慰剂细胞的附加安慰剂，即，（多奈哌齐+美金刚）对比（安慰剂+安慰剂）。在试验期间，患者将接受为期18个月的连续开放式抗抑郁药治疗随访。基于我们的试点数据，我们选择研究多奈哌齐加美金刚与安慰剂的比较，以增加获得信号的可能性。如果结果是积极的（与安慰剂相比，痴呆转化率降低，认知结果更好），则可以在后续试验中澄清这种效果是否是由于多奈哌齐或美金刚或其组合。在为期18个月的试验中，将探讨载脂蛋白E e4基因型、气味识别缺陷和MRI海马和内嗅皮质萎缩作为多奈哌齐/美金刚反应的预测因素。在这一高危人群中，改善认知和延迟转换为痴呆症的临床诊断将提高生活质量，减轻家庭负担，并显着降低整体医疗保健费用。基于这些结果，未来MCI和AD的认知增强剂治疗试验可能需要考虑包括共病抑郁症患者。该研究还将提供关于DEP-CI治疗反应和过程的神经生物学调节剂的重要信息。

DESCRIPTION (provided by applicant): Patients presenting with depression (DEP) and cognitive impairment (CI), DEP-CI, represent a unique, understudied population that is difficult to diagnose, treat and estimate prognosis. Our pilot data, supported by the literature, suggest that many DEP-CI patients show cognitive decline and often convert to dementia, primarily Alzheimer's disease (AD). In DEP-CI, there is a lack of data on treatment response of mood symptoms to antidepressant treatment and particularly of cognitive deficits to cognitive enhancer treatment. Our initial pilot data in a double-blind study showed that donepezil was superior to placebo in improving memory in antidepressant-treated DEP-CI patients. In a second pilot study, open label es-citalopram plus memantine treatment led to a low rate of conversion to dementia. In this proposed pilot clinical trial, we will evaluate, treat and follow a broad sample of 80 DEP-CI patients who present to the departments of Psychiatry, Neurology and Internal Medicine at NYSPI/Columbia University Medical Center and Duke University Medical Center. In the treatment protocol, all 80 DEP-CI patients will receive open antidepressant treatment with citalopram for 4 weeks. At 4 weeks, patients will be randomized to add-on donepezil or placebo. After another 12 weeks (16 weeks into the trial), patients will receive in addition add-on memantine for the donepezil cell and add-on placebo for the placebo cell, i.e., (donepezil + memantine) versus (placebo + placebo). Patients will be followed for a total period of 18 months with continuous open antidepressant treatment during the trial. We chose to study donepezil plus memantine compared to placebo based on our pilot data and to increase the likelihood of obtaining a signal. If the results are positive (reduction in conversion to dementia and better cognitive outcome compared to placebo), whether the effect is due to donepezil or memantine or their combination can be clarified in subsequent trials. Apolipoprotein E e4 genotype, odor identification deficits, and MRI hippocampal and entorhinal cortex atrophy will be explored as predictors of donepezil/memantine response in the 18-month trial. Improving cognition and delaying conversion to a clinical diagnosis of dementia in this high risk group will enhance quality of life, reduce family burden, and markedly diminish overall health care costs. Based on the results, future cognitive enhancer treatment trials for MCI and AD may need to consider including patients with comorbid depression. The study will also provide important information on neurobiological moderators of treatment response and course in DEP-CI.