The Combination of Donepezil and Cognitive Training for Treating Alcohol Use Disorder

项目概要/摘要 酒精使用障碍（AUD）是一个严重的公共卫生问题。与酒精有关的大脑缺陷和酒精- 相关的认知障碍有助于AUD的进展。约50-80%的AUD患者 有认知障碍。这些认知障碍持续多年，并随着年龄的增长而恶化。 此外，酒精相关的认知障碍可能会影响AUD的结果，因为执行功能和 记忆是自我调节和学习所必需的，这在恢复过程中很重要。这些认知 损伤在恢复的早期阶段特别普遍，并降低了从 当前AUD治疗先前的研究表明，认知补救疗法（CRT）可能 改善认知功能和AUD治疗结果。有随机临床试验证明 CRT可以减少对酒精的渴望或饮酒。然而，一些研究也报道CRT对 减少饮酒。因此，CRT可能需要通过另一种干预（例如，认知增强 药物治疗）以增加CRT的益处。新出现的神经生物学证据表明， 抗胆碱酯酶剂多奈哌齐可治疗AUD。多奈哌齐目前已获得美国食品和药物管理局（FDA）的批准。 本发明涉及用于治疗阿尔茨海默型痴呆的美国食品药品监督管理局（FDA）的药物组合物。由于多奈哌齐在临床上 作为认知增强剂，多奈哌齐可治疗AUD，同时增强患者的神经认知功能 关于AUD我们的初步数据显示，多奈哌齐+ CRT治疗AUD患者可能是安全有效的 患有AUD和轻度认知障碍因此，我们在这里提出了一个13周，随机，双盲， 安慰剂对照、受试者间试验，比较4组（多奈哌齐+ CRT vs.多奈哌齐单药vs. CRT 单药与安慰剂）作为AUD治疗，共160例AUD患者。 有两个主要目标。 目的#1：评估多奈哌齐+ CRT在减少重度饮酒方面是否上级安慰剂，如通过以下指标测量的 时间线追踪（TLFB）。我们假设多奈哌齐+ CRT（第1组）优于安慰剂（上级） （第4组）在13周的积极干预中减少大量饮酒。我们还假设多奈哌齐 单用CRT（第2组）或单用CRT（第3组）在减少每周大量饮酒方面上级安慰剂（第4组 d，且组1优于组2和组3，上级。 目的#2：评价多奈哌齐+ CRT在改善整体神经认知功能方面是否上级安慰剂。 我们假设多奈哌齐+ CRT在改善患者的整体神经认知功能方面上级安慰剂。 第7周和第13周时的神经认知功能总体指数。 该项目将是第一个测试多奈哌齐治疗AUD的随机对照试验。

Project Summary/Abstract Alcohol use disorder (AUD) is a serious public health problem. Alcohol-related brain defects and alcohol- associated cognitive impairments contribute to the progression of AUD. About 50-80% of patients with AUD have cognitive impairments. These cognitive impairments persist over years and get worse with age. Moreover, alcohol-related cognitive impairments may impact AUD outcomes because executive functions and memory are necessary for self-regulation and learning, which are important during recovery. These cognitive impairments are especially prevalent in the early phase of recovery and reduce the ability to benefit from current AUD treatments. Previous research has suggested that cognitive remediation therapy (CRT) may improve cognitive function and AUD treatment outcomes. There are randomized clinical trials demonstrating that CRT reduces alcohol craving or drinking. However, a few studies also reported that CRT is not effective in reducing drinking. Thus, CRT may need to be augmented by another intervention (e.g., cognitive-enhancing pharmacotherapy) to increase the benefits of CRT. Emerging neurobiological evidence suggests that an anticholinesterase agent donepezil may treat AUD. Donepezil is currently approved by the Food and Drug Administration (FDA) for the treatment of dementia of the Alzheimer's type. Since donepezil has been clinically used as a cognitive enhancer, donepezil may treat AUD while enhancing neurocognitive functioning in patients with AUD. Our pilot data showed that donepezil + CRT might be safe and effective in treating AUD in patients with AUD and mild cognitive impairment. Thus, we here propose a 13-week, randomized, double-blind, placebo-controlled, between-subjects trial comparing 4 groups (donepezil + CRT vs. donepezil alone vs. CRT alone vs. placebos) as a treatment for AUD in a total of 160 patients with AUD. There are two main objectives. Aim #1: To evaluate if donepezil + CRT is superior to placebo in reducing heavy drinking as measured by weekly Time Line Follow Back (TLFB). We hypothesize that donepezil + CRT (group 1) is superior to placebo (group 4) in reducing heavy drinking over 13 weeks of active intervention. We also hypothesize that donepezil alone (group 2) or CRT alone (group 3) is superior to placebo (group 4) in reducing weekly heavy drinking days, and group 1 is superior to groups 2 and 3. Aim #2: To evaluate if donepezil + CRT is superior to placebo in improving global neurocognitive functioning. We hypothesize that donepezil + CRT is superior to placebo in improving global neurocognitive functioning on a global index of neurocognitive function at 7 weeks and at 13 weeks. This project will be the first randomized controlled trial testing donepezil for AUD.