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

描述（由申请人提供）：酒精依赖的药物治疗是有限的，已经证明有效的药物显然不是对每个人都有效。在医学领域，人们非常渴望和需要更个性化的治疗方法。为了实现这一值得称赞的目标，需要更好地匹配对临床和/或生物学上的酗酒亚群安全、负担得起和有效的新型药物。一个未被充分研究的酒精使用障碍亚组是那些经历酒精戒断（AW）综合征的人，这是一种明确的体征和症状，出现在大量突然停止饮酒的人身上。我们在两项已完成和已发表的临床试验中发现，加巴喷丁（一种经过充分研究和普遍使用的仿制药），先前在治疗急性AW方面显示出疗效，可能对那些有AW史的人在较长时间内预防复发也有效。由于加巴喷丁在这些研究中与其他药物联合使用，且持续时间相对较短（6周），因此有必要进行更长的前瞻性对照试验，以证明其在有AW病史的患者中单独使用时的疗效。基础科学研究假设两个重要的神经化学系统（谷氨酸和GABA系统）的失调是AW表达的基础，并可能被加巴喷丁修饰。通过使用先进的磁共振成像技术（1H-MRS）来测量大脑中谷氨酸和GABA的水平，并通过对某些谷氨酸和GABA受体的功能变异进行基因分型，我们有机会探索这些系统在预测复发和加巴喷丁作用机制中的作用-为进行良好的临床试验提供重要的转化科学组成部分。

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.