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

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.