Pilot Combination Treatment Trial of Mild Cognitive Impairment with Depression

描述（由申请人提供）：表现为抑郁症（DEP）和认知障碍（CI） （DEP -CI）的患者是一个独特的、研究不足的人群，难以诊断、治疗和估计预后。我们的试点数据得到文献的支持，表明许多deep - ci患者表现出认知能力下降，并经常转化为痴呆，主要是阿尔茨海默病（AD）。在deep - ci中，缺乏关于情绪症状对抗抑郁药物治疗反应的数据，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试点数据显示，多奈哌齐在改善接受抗抑郁治疗的depo - ci患者的记忆方面优于安慰剂。在第二项试点研究中，开放标签的西酞普兰加美金刚治疗导致低转化率转化为痴呆。在这项拟议的试点临床试验中，我们将评估、治疗和跟踪80名depi - ci患者，这些患者在NYSPI/哥伦比亚大学医学中心和杜克大学医学中心的精神病学、神经病学和内科就诊。在治疗方案中，所有80例depi - ci患者将接受西酞普兰4周的开放式抗抑郁治疗。在第4周，患者将被随机分配到额外的多奈哌齐或安慰剂。再过12周（试验16周），患者将接受多奈哌齐细胞的附加美金刚和安慰剂细胞的附加安慰剂，即（多奈哌齐+美金刚）vs（安慰剂+安慰剂）。在试验期间，患者将接受为期18个月的持续开放式抗抑郁治疗。根据我们的试点数据，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，减少痴呆症的转化和更好的认知结果），那么这种效果是由于多奈哌齐还是美金刚或它们的联合作用，可以在随后的试验中加以澄清。载脂蛋白e4基因型、气味识别缺陷、MRI海马和内嗅皮质萎缩将在18个月的试验中作为多奈哌齐/美金刚反应的预测因素进行探讨。在这一高危人群中，提高认知能力和延迟转化为痴呆的临床诊断将提高生活质量，减轻家庭负担，并显着降低总体卫生保健费用。基于这些结果，未来的认知增强剂治疗MCI和AD的试验可能需要考虑包括合并抑郁症的患者。该研究还将提供depo - ci治疗反应和病程的神经生物学调节因子的重要信息。

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.