Pilot Combination Treatment Trial of Mild Cognitive Impairment with Depression

描述(由申请人提供)：出现抑郁(DEP)和认知障碍(CI)的患者，DEP-CI代表了一个独特的、研究不足的人群，很难诊断、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DEP-CI患者表现出认知能力下降，并经常转变为痴呆症，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治疗的治疗反应的数据，特别是认知障碍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验数据显示，多奈哌齐在改善接受抗抑郁药物治疗的DEP-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ES-西酞普兰加美金刚治疗导致了较低的痴呆转化率。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DEP-CI患者的广泛样本，这些患者提交给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、神经内科和内科。在治疗方案中，所有80例DEP-CI患者都将接受西酞普兰的开放抗抑郁治疗，为期4周。4周后，患者将被随机分成多奈哌齐和安慰剂两组。再过12周(试验16周)后，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+美金胺)与(安慰剂+安慰剂)。在试验期间，患者将接受持续开放的抗抑郁药物治疗，总共为期18个月。基于我们的试验数据，我们选择对多奈哌齐加美金刚与安慰剂进行比较研究，以增加获得信号的可能性。如果结果是肯定的(转化为痴呆症的减少和比安慰剂更好的认知结果)，无论是由于多奈哌齐或美金刚还是它们的组合，都可以在随后的试验中得到澄清。在这项为期18个月的试验中，将探索载脂蛋白E e4基因型、气味识别缺陷以及MRI海马区和内嗅皮层萎缩作为多奈哌齐/美金刚反应的预测因子。在这一高危人群中，改善认知并推迟向临床诊断痴呆症将提高生活质量，减轻家庭负担，并显著降低总体医疗费用。根据这一结果，未来针对MCI和AD的认知增强剂治疗试验可能需要考虑纳入合并抑郁症的患者。这项研究还将提供有关DEP-CI治疗反应和病程的神经生物学调节因素的重要信息。 公共卫生相关性：抑郁症和认知障碍是老年人最常见的神经精神障碍。几乎所有的治疗研究都集中在老年抑郁症或MCI或痴呆症患者身上，几乎没有关于DEP-CI治疗的数据。这项研究考察了这些患者使用抗抑郁药物加上多奈哌齐和美金刚的联合治疗或安慰剂的治疗，以比较转化为痴呆症和认知能力下降的风险。这项研究具有重大的公共卫生意义，因为改善认知，特别是推迟DEP-CI高危人群向痴呆症的转变将提高生活质量，减轻家庭负担，并减少医疗费用。此外，认知增强剂治疗MCI和AD的试验可能需要考虑纳入合并抑郁症的患者。这项研究将为开发针对DEP-CI患者的个性化治疗提供关键信息。

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. PUBLIC HEALTH RELEVANCE: Depression and cognitive disorders are the most common neuropsychiatric disorders in the elderly. Nearly all treatment studies have focused on patients with late-life depression or MCI or dementia, with little data on treatment of DEP-CI. This study examines treatment of these patients with antidepressants plus either a combination of donepezil and memantine or placebo in order to compare risk of conversion to dementia and cognitive decline. The study has major public health implications because improving cognition and, in particular, delaying conversion to dementia in the high risk DEP-CI group will improve quality of life, reduce family burden, and diminish health care costs. Further, cognitive enhancer treatment trials for MCI and AD may need to consider including patients with comorbid depression. This study will provide critical information to develop personalized treatment for patients with DEP-CI.