Orexin Receptor Antagonists as Modulators of Threat Sensitivity in individuals with Alcohol Use Disorder

摘要 酒精使用障碍影响数百万人，是全球可预防死亡的主要原因之一。在美国， AUD的药物治疗利用不足;与只有三种FDA批准的药物 治疗AUD患者。这些药物对某些人效果很好，但对某些人的影响较小， 饮酒的结果。开发更有效的AUD药物治疗是一项重要的公共卫生 要务精神病药物开发的一个最近的重点是使用可靠的人类实验室 AUD功能障碍的措施，以测试有前途的化合物，以直接告知和动力大规模的机制， 临床试验PI Gorka和Co-I Phan开发了一种应激反应性测定法， 饮酒行为和AUD。该测定反映了AUD的负强化模型，并且可靠地捕获 在实验室中使用互补的客观心理生理学（即，惊吓眨眼增强）和 功能性神经影像学测量。使用该模型，我们发现suvorexant（SUV）-一种双重 一种食欲素系统的受体拮抗剂，FDA批准用于失眠症， 健康成年人，同时保留其他应激反应标志物的变化。令人信服的动物和人类 所有证据表明，食欲素系统与压力相关的酒精使用密切相关。的 R21建议的总体目标是系统地推进这一工作，以揭示是否、如何以及如何 食欲素拮抗作用改变了AUD的脑行为应激目标，为未来的大规模研究提供信息和动力。 临床试验本研究是一项有针对性的双盲、受试者间、随机临床试验设计， 实验室评估总共80名患有AUD的受试者将完成我们的心理生理应激范式， 基线。他们将在几天后返回实验室，在给予单剂量的 10 mg SUV或安慰剂（40例受试者/组）。然后指导参与者每天服用10 mg胶囊， 在返回进行治疗后实验室评估之前，在接下来的4周内使用SUV或安慰剂。每日报告 将通过智能手机收集药物依从性、副作用、睡眠、酒精使用和情绪。本研究 高风险，高回报，为了与R21机制的范围相匹配，我们将重点关注惊吓眨眼 增强作为主要结局;尽管每组20例受试者的亚组（共40例）也将完成我们的 同时进行惊吓和功能性磁共振成像（fMRI）过程中的应激任务， 治疗这种创新的多模式设计允许一个良好的控制测试是否急性剂量的SUV (Aim 1）和/或每日使用SUV（目的2）改变AUD功能障碍的脑行为目标，特别是在 具有高客观基线应激反应的个体。我们还将研究日常SUV是否变化 酒精行为，以及这种行为变化是否与大脑行为变化有关（目标3）。的结果 这项研究将提供关键的新知识，关于食欲素拮抗作用是否以及如何可以利用来治疗 澳元。研究结果还将用于为SUV治疗AUD的大规模机制临床试验提供信息和动力。

ABSTRACT Alcohol use disorder affects millions and is one of the leading causes of preventable death worldwide. In the US, pharmacotherapy for AUD is under-utilized; related to the fact that there are only three FDA-approved drugs to treat patients with AUD. These medications work well for some but have small to moderate effect sizes on drinking outcomes. The development of more efficacious pharmacotherapies for AUD is a top public health priority. A recent emphasis in psychiatric medication development is the use of reliable human laboratory measures of AUD dysfunction to test promising compounds to directly inform and power large-scale mechanistic clinical trials. PI Gorka and Co-I Phan have developed an assay of stress reactivity that is robustly related to drinking behavior and AUD. This assay reflects a negative reinforcement model of AUD and is reliably captured in the lab using complimentary objective psychophysiological (i.e., startle eyeblink potentiation) and functional neuroimaging measures. Using this model, we have uncovered that suvorexant (SUV) – a dual receptor antagonist of the orexin system, FDA-approved for insomnia – acutely modifies our AUD target in healthy adults, while sparing changes in other markers of stress reactivity. Compelling animal and human evidence together suggests that the orexin system is critically involved in stress-related alcohol use. The overarching goal of this R21 proposal is to systematically advance this line of work to uncover if, how, and for whom orexin antagonism modifies brain-behavior stress targets of AUD to inform and power future large scale clinical trials. The study is a targeted double-blind, between-subjects, randomized clinical trial design with repeat lab assessment. A total of eighty subjects with AUD will complete our psychophysiological stress paradigm at baseline. They will return to the lab days later to repeat the protocol following administration of a single dose of either 10mg SUV or placebo (40 subjects/arm). Participants are then instructed to take daily 10mg capsules of SUV or placebo for the next 4-weeks before returning for a post-treatment lab assessment. Daily reports of medication adherence, side-effects, sleep, alcohol use, and mood will be collected via smartphones. This study is high-risk, high-reward, and to match the scope of the R21 mechanism we will focus on startle eyeblink potentiation as the primary outcome; although a subset of 20 subjects per arm (40 total) will also complete our stress task during simultaneous startle and functional magnetic resonance imaging (fMRI), pre- and post- treatment. This innovative multimodal design allows for a well-controlled test of whether an acute dose of SUV (Aim 1) and/or daily use of SUV (Aim 2) modifies brain-behavior targets of AUD dysfunction, particularly within individuals with high objective baseline stress reactivity. We will also examine whether daily SUV changes alcohol behavior, and whether this change in behavior is linked to brain-behavior change (Aim 3). Findings from this study will provide critical new knowledge regarding if and how orexin antagonism can be leveraged to treat AUD. The findings will also be used to inform and power a large-scale mechanistic clinical trial of SUV for AUD.