Zonisamide Treatment of Alcohol Use Disorder: An Evaluation of Efficacy and Mechanism of Action

 描述（由申请人提供）：唑尼沙胺是一种非常有前途的抗惊厥药物，用于治疗酒精使用障碍（AUD）。唑尼沙胺可减少AUD受试者的饮酒、饮酒渴望和焦虑。我们完成了一项唑尼沙胺治疗酒精依赖的随机、安慰剂对照试验，结果显示，使用该药物后，大量饮酒、总体饮酒和酒精渴望都有所减少。在初步研究中，唑尼沙胺的耐受性非常好。最近，另一项关于唑尼沙胺的小型安慰剂对照试验显示，该药物在减少饮酒方面优于安慰剂。然而，没有明确的ZNS治疗酒精中毒的研究已经进行，目前也没有这样的研究正在进行中的平民。我们已经收到了来自VA临床研究研发（CSR&D）服务的优异奖资助通知，以进行为期5年的临床试验，评估唑尼沙胺在160名美国退伍军人中的疗效。在本R01申请中，我们建议在研究中增加一个平民组，由160名饮酒的平民组成 使用Disorder。研究药物对平民（以及退伍军人）的影响将使我们能够 我们还建议在合并的320名受试者（退伍军人加平民）样本中加入机制和翻译成分，这将使我们更好地了解唑尼沙胺和其他用于治疗酒精中毒的抗惊厥药的作用机制，并有助于识别预测更好治疗反应的可观察特征。我们还提出了一种新的药物基因组学组成部分，增加了创新和补充国家的最先进的试验方法提出。

 DESCRIPTION (provided by applicant): Zonisamide is an extremely promising anticonvulsant medication for the treatment of alcohol use disorder (AUD). Zonisamide reduces drinking, craving for alcohol, and anxiety in subjects with AUDs. We completed a randomized, placebo-controlled trial of zonisamide for treating alcohol dependence, which showed reductions in heavy drinking, overall drinking, and alcohol craving with the medication. Zonisamide was very well tolerated in the pilot study. Recently, another small placebo-controlled trial of zonisamide showed advantages of the medication over placebo in reducing drinking. However, no definitive study of ZNS treatment for alcoholism has been performed, and there is no such study currently underway in civilians. We have received notice of funding through a Merit Award from the VA Clinical Studies Research and Development (CSR&D) service to conduct a 5-year clinical trial evaluating the efficacy of zonisamide in 160 U.S. Military Veterans with alcoholism. In this R01 application, we propose to add a civilian arm to the study consisting of 160 civilians with Alcohol Use Disorder. Studying the medication's effects in civilians (as well as veterans) will allow us to fully evaluate its efficacy and will make the results more generalizable to the population at large We also propose to add mechanistic and translational components to the combined 320 subject (veteran plus civilian) sample that will allow us to understand better the mechanism of action of zonisamide and other anticonvulsants used to treat alcoholism, as well as help identify observable traits that predict better treatment response. We also propose a novel pharmacogenomic component that adds to the innovation and complements the state-of- the-art trial methods proposed.