Gabapentin for Relapse Prevention: Alc. Withdrawal-Brain GABA/Glutamate Effects

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DESCRIPTION (provided by applicant): Pharmacotherapy of alcohol dependence is limited and the medications with proven efficacy clearly do not work for everyone. In the field of medicine, there is a great desire, and need, for more personalized treatment approaches. To achieve this laudable goal, there needs to be better matching of novel medications that are safe, affordable, and efficacious to clinical and/or biological subgroups of alcoholics. One understudied alcohol use disorder subgroup are those that experience alcohol withdrawal (AW) syndrome, a well-defined constellation of signs and symptoms present in a significant number of those who abruptly stop drinking. We have found in two completed and published clinical trials that gabapentin (a well-studied and ubiquitously prescribed generic medication), that had previously shown efficacy in treatment of acute AW, might also be efficacious in preventing relapse over a more prolonged period in those with a "history of AW". Since gabapentin was combined with other medications in those studies and given for a relatively short duration (six weeks), a longer prospective controlled trial is necessary to prove its efficacy when given alone, in those with an AW history. Basic science investigation postulates that dysregulation in two prominent neurochemical systems, the glutamate and GABA systems, underlies the expression of AW and may be modified by gabapentin. By using advanced magnetic resonance imaging technology (1H-MRS) to measure brain levels of glutamate and GABA, and by genotyping functional variants in certain glutamate and GABA receptors, we have the opportunity to explore the involvement of these systems in predicting relapse and in the mechanism of gabapentin action - providing an important translational science component to a well-conducted clinical trial. To that end, 190 individuals with alcohol use disorder will be screened, and after 3-7 days of abstinence 90 individuals, who meet DSM-5 criteria for a history of AW, will be randomized to a 16-week trial of gabapentin or placebo. All subjects will undergo 1H-MRS prior to treatment randomization and again between days 17-24 of treatment and all subjects will be genotyped for specific variation in glutamate 8 receptor and GABA2A genes. Subjects will be evaluated over 16 weeks (and post-treatment at weeks 20 and 28) for drinking and other salient outcome variables. The main outcome variable will be "percent of subjects relapsing to a heavy drinking day". Change in brain glutamate and/or GABA levels and genetic variants will be evaluated as mediators or moderators respectively of treatment-response. Positive results would provide another medication option, while advancing a more personalized approach to pharmacotherapy of alcohol use disorder. Also, providing new information on brain and genetic mechanisms underlying AW risk and treatment adds scientific value. As such, advancement in understanding the biology and treatment of individuals with alcohol dependence would be greatly enhanced.