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

项目总结/摘要 酒精使用障碍（AUD）是一个令人担忧的公共卫生问题，美国的成本超过2490亿美元 每年。AUDs会导致各种各样的负面健康结果，包括显著的 高血压、中风、胰腺炎、肝硬化、阿尔茨海默病、多种癌症的风险增加， 多种认知功能障碍双硫仑，纳洛酮和阿坎酸是唯一FDA批准的 治疗AUD的药物，只有适度有效。唑尼沙胺（ZON）是一种抗惊厥药 具有GABA能、多巴胺能和单胺能作用的药物， 在动物和人类实验室环境中，以及治疗AUD的小型临床试验。ZON可以代表 对于临床医生来说是一种重要的新工具，但以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，没有客观证据的药物依从性），这项研究 旨在克服。在成瘾神经临床评估的理论框架内， 核心域中的假设机制（即，激励突显、负性情绪与认知 功能），并从一个合理的科学前提出发，我们将目标减少酒精使用的澳元 使用精心设计的应急管理（CM，或激励措施）组合， 以换取客观核实的行为证据），在前4- 几周的ZON治疗来开始减少饮酒。在剩余的8周ZON期间，CM将 在每周访视时提供，以换取100%或更高药物依从性的证据。这个目标 本研究旨在完成一项双盲、安慰剂对照的随机对照试验，以评估ZON显著改善 减少寻求治疗的AUD成年人的酒精使用。受试者将被随机分配至2个试验组之一 将接受：1）ZON加标准治疗（ST），其中包括采取控制阅读疗法模块， CM至12周治疗期（ZON+ST），或2）匹配的安慰剂加ST（PLO+ST）。主 结果将是治疗期间经生化验证的酒精使用情况。我们将使用一个为期两周的，单一的- 设盲安慰剂诱导期，要求受试者证明75%的药物 在继续进入12周治疗期之前的依从率。将在1、6和12个月时进行随访。 我们的具体目标是：1）确定ZON+ST是否比PLO+ST更有效地减少生物化学- 验证酒精使用和其他酒精使用结果; 2）识别基于ANA的治疗反应介质 3）确定a.）如果生物性别、基线抑郁和基线严重程度 酒精使用与治疗分配相互作用，在我们的原发性和继发性 结果;和B.）各组在不良事件或药物依从性方面是否存在差异。该项目的重点是 采用双盲安慰剂对照设计，评估一种有前景的药物治疗AUD的疗效， 严格测量酒精使用和药物依从性。

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.