A Randomized Controlled Trial of N-Acetylcysteine for Alcohol Use Disorder and Comorbid PTSD

摘要 酒精使用障碍（AUD）和创伤后应激障碍（PTSD）是慢性和衰弱的精神疾病 经常发生的情况。如果不治疗，患有AUD和并发PTSD的个体在 出现其他心理健康问题的风险增加（例如，抑郁、焦虑）、自杀意念和 尝试，医疗问题，家庭/关系受损和就业问题。尽管频繁的 与合并AUD/PTSD相关的并发症和有害后果，几乎没有科学的 可用于指导提供护理的证据。拟议的研究直接解决了这一关键问题 通过测试N-乙酰半胱氨酸（NAC）与安慰剂相比在降低 AUD和PTSD严重程度。NAC代表了一种有前途的新型候选药物疗法 患有澳大利亚焦虑症和创伤后应激障碍累积的临床前和初步临床研究表明， NAC通过谷氨酸调节治疗物质使用障碍和PTSD。数据从 一项随机、双盲试点研究最近完成的调查小组在退伍军人与物质 使用障碍（主要是酒精）和PTSD为NAC的治疗潜力提供了令人鼓舞的支持 在治疗AUD和PTSD方面的作用此外，NAC是一种廉价的非处方药，具有良好的生物相容性。 耐受性特征，所有这些都赋予了从研究环境到临床实践的可转移性。在这 第二阶段研究，我们将（1）采用两组随机、双盲、组间实验设计 这将包括12周的治疗与NAC或安慰剂药物;（2）使用标准化，重复 在6个时间点（基线， 第6周、第12周和3个月、6个月和12个月随访）;（3）测量相关精神和 行为健康问题（例如，抑郁、睡眠、自杀、危险性行为、家庭/社会 功能）;和（4）使用功能性磁共振成像（fMRI）和质子磁共振成像 应用磁共振波谱（MRS）研究共病AUD/PTSD的潜在病理生理学和预后 治疗结果的指标。为了实现这些目标，我们组建了一个多学科团队， 在AUD和共病PTSD、临床试验、人体实验室方面具有国家认可的专业知识的研究人员 范式和神经成像谁在过去成功合作，是唯一有资格， 进行这类调查。拟议的项目直接响应了国家人权委员会的使命， 酒精滥用和酒精中毒研究所（NIAAA）和新的AUD/PTSD倡议，以加快对 开发有效的药物治疗这种常见和高度致残的合并症。的 这项研究的结果将提供急需的经验证据，以帮助通知临床实践 指导方针，并加快对AUD和共病PTSD治疗的研究。

ABSTRACT Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are chronic and debilitating psychiatric conditions which frequently co-occur. If left untreated, individuals with AUD and co-occurring PTSD are at increased risk for developing other mental health problems (e.g., depression, anxiety), suicidal ideation and attempts, medical problems, family/relationship impairment, and employment problems. Despite the frequent co-occurrence and deleterious consequences associated with comorbid AUD/PTSD, there is little scientific evidence available to guide the provision of care. The proposed study directly addresses this critical knowledge gap by testing the efficacy of N-acetylcysteine (NAC) as compared to placebo in reducing AUD and PTSD severity. NAC represents a promising and novel candidate pharmacotherapy for individuals with AUD and comorbid PTSD. Accumulating preclinical and preliminary clinical research suggests a role for NAC in the treatment of substance use disorders and PTSD via glutamate modulation. Data from a randomized, double-blind pilot study recently completed by the investigative team in Veterans with substance use disorders (primarily alcohol) and PTSD provides encouraging support for the therapeutic potential of NAC in the treatment of AUD and PTSD. Moreover, NAC is an inexpensive, over-the-counter agent with a favorable tolerability profile, all of which confer ease of transferability from the research setting to clinical practice. In this Stage II study, we will (1) employ a two-arm randomized, double-blind, between-groups experimental design that will consist of 12 weeks of treatment with NAC or placebo medication; (2) use standardized, repeated dependent measures to rigorously assess AUD severity and PTSD symptomatology at 6 time points (baseline, week 6, week 12, and 3-, 6-, and 12-month follow-up); (3) measure impairment in associated mental and behavioral health problems (e.g., depression, sleep, suicidality, risky sexual behaviors, family/social functioning); and (4) use functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (MRS) to investigate the underlying pathophysiology of comorbid AUD/PTSD and prognostic indicators of treatment outcome. To achieve these aims, we have assembled a multidisciplinary team of investigators with nationally-recognized expertise in AUD and comorbid PTSD, clinical trials, human laboratory paradigms, and neuroimaging who have successfully collaborated in the past and are uniquely qualified to implement this type of investigation. The proposed project is directly responsive to the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the new AUD/PTSD initiative to accelerate research on the development of effective pharmacologic treatments for this common and highly disabling comorbidity. The findings from this study will provide critically needed empirical evidence to help inform clinical practice guidelines and accelerate research on the treatment of AUD and comorbid PTSD.