Zonisamide for the Treatment of Alcohol Use Disorder in the Addiction Neuroclinical Assessment Framework

项目摘要/摘要 酒精使用障碍(AUD)是一个令人担忧的公共卫生问题，给美国造成了超过2490亿美元的损失 每年一次。急性尿失禁导致一系列破坏性的负面健康后果，包括显著的 高血压、中风、胰腺炎、肝硬变、阿尔茨海默病、多种癌症的风险增加 多种类型的认知功能障碍。双硫仑、纳曲酮和氨基己酸酯是FDA批准的唯一药物 治疗AUD的药物仅有一定的疗效.唑尼沙胺(ZON)是一种抗惊厥药 具有GABA能、谷氨酸能和单胺能作用的药物治疗已显示出重大前景 在动物和人类实验室环境中，以及治疗AUD的小型临床试验中。Zon可以代表 对于临床医生来说，这是一个关键的新工具，但之前的研究受到几个关键因素的限制(例如，没有 客观证据最近饮酒，没有服药依从性的客观证据)这项研究 是为了克服。在成瘾神经临床评估的理论框架内 核心领域的假设机制(即激励性显著、消极情绪性和认知 功能)，从合理的科学前提出发，我们将以减少澳元的酒精使用量为目标 使用精心设计的应急管理(CM或激励)组合进行初级护理的患者 以换取客观核实的行为证据)在前4-4周内每周三次访问- 几周的ZON治疗可以迅速减少饮酒。在ZON的剩余8周内，CM将 在每周就诊时提供，以换取100%或更高的服药依从性证据。这样做的目的是 这项研究是完成一项双盲、安慰剂对照的随机对照试验，以评估ZON显著 减少寻求治疗的成年人的酒精使用量。个人将被随机分成2个试验组中的1个 将接受：1)ZON加标准治疗(ST)，其中包括Take Control阅读疗法模块和 治疗12周(ZON+ST)，或2)安慰剂+ST(PLO+ST)。初级阶段 结果将是在治疗期间使用经过生化验证的酒精。我们将使用为期两周的单人- 盲目安慰剂引导期，参与者将被要求展示75%的药物 持续治疗12周前的依从率。随访时间分别为1、6和12个月。 我们的具体目标是：1)确定ZON+ST在生化方面是否比PLO+ST更有效- 验证酒精使用和其他酒精使用结果；2)确定以ANA为基础的治疗反应介体 跨治疗组；3)确定a。)如果生物性行为、基线抑郁和基线严重程度 酒精使用与治疗分配相互作用，在我们的原发和继发疾病中产生不同的变化 结果；以及b.)两组在不良事件或服药依从性方面是否存在差异。这个项目的重点是 使用双盲安慰剂对照设计治疗AUDS的一种有前途的药物疗法的疗效将 严格测量酒精使用和服药依从性。

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is an alarming public health problem that costs the US more than $249 billion annually. AUDs leads to a devastatingly diverse set of negative health outcomes, including significantly increased risk of hypertension, stroke, pancreatitis, liver cirrhosis, Alzheimer’s disease, multiple cancers, and multiple types of cognitive dysfunction. Disulfiram, naltrexone, and acamprosate are the only FDA-approved medications for the treatment of AUD and are only modestly effective. Zonisamide (ZON) is an anticonvulsant medication with GABAnergic, glutamatergic and monoaminergic effects which has shown significant promise in animal and human laboratory settings, and small clinical trials for the treatment of AUD. ZON could represent a critical new tool for clinicians, but previous studies have been limited by a couple of key factors (e.g., no objective evidence recent alcohol consumption, no objective evidence of medication adherence) that this study is designed to overcome. Theoretically framed within the Addiction Neuroclinical Assessment with hypothesized mechanisms in core domains (i.e., incentive salience, negative emotionality and cognitive function), and proceeding from a sound scientific premise we will target reduced alcohol use among AUD patients in primary care using a carefully designed combination of contingency management (CM, or incentives in exchange for objectively verified evidence of behavior) delivered at thrice-weekly visits during the first 4- weeks of ZON treatment to jumpstart reductions in drinking. For the remaining 8-weeks of ZON, CM will be delivered at weekly visits in exchange for evidence of 100% or higher medication adherence. The goal of this study is to complete a double-blind, placebo-controlled RCT to evaluate the ability of ZON to significantly decrease alcohol use among treatment-seeking AUD adults. Individuals will be randomized into 1 of 2 trial arms that will receive: 1) ZON plus standard treatment (ST), which includes Take Control bibliotherapy modules and CM through the 12-week treatment period (ZON+ST), or 2) Matched placebo plus ST (PLO+ST). The primary outcome will be biochemically-verified alcohol use during the treatment period. We will use a 2-week, single- blind placebo induction period wherein participants will be required to demonstrate a 75% medication adherence rate before continuing into the 12-week treatment period. Follow-up will occur at 1, 6 and 12-months. Our Specific Aims are to: 1) Determine if ZON+ST is more effective than PLO+ST for reducing biochemically- verified alcohol use and other alcohol use outcomes; 2) Identify ANA-based mediators of treatment response across the treatment groups; 3) Determine a.) if biological sex, baseline depression and baseline severity of alcohol use interacts with treatment assignment to produce differential changes in our primary and secondary outcomes; and b.) whether groups differ on adverse events or medication adherence. This project focuses on the efficacy of a promising pharmacotherapy for AUDs using a double-blind placebo-controlled design that will rigorously measure alcohol use and medication adherence.