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)是一种慢性的、令人衰弱的精神疾病 经常同时出现的情况。如果不治疗，患有AUD和共发的创伤后应激障碍的人 出现其他心理健康问题(如抑郁、焦虑)、自杀念头和 尝试、医疗问题、家庭/关系损害和就业问题。尽管频繁地 AUD/PTSD共病的共同发生和有害后果，几乎没有科学依据 可用来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)与安慰剂在减少 AUD和创伤后应激障碍的严重性。NAC代表着一种很有前途的个人药物治疗新候选方法 患有澳元和共病的创伤后应激障碍。积累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创伤后应激障碍。数据来自于 调查小组最近在退伍军人中完成的随机双盲试点研究 使用障碍(主要是酒精)和创伤后应激障碍为NAC的治疗潜力提供了令人鼓舞的支持 治疗AUD和创伤后应激障碍。此外，NAC是一种廉价的非处方药，具有良好的 耐受性概况，所有这些都提供了从研究环境到临床实践的易转移性。在这 第二阶段研究，我们将(1)采用双臂随机、双盲、组间实验设计 这将包括12周的NAC或安慰剂治疗；(2)使用标准化的、重复的 在6个时间点严格评估AUD严重性和创伤后应激障碍症状的依赖措施(基线， 6周、12周，以及3、6和12个月的随访)；(3)测量相关的精神和精神障碍 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)；以及(4)使用功能磁共振成像(FMRI)和质子磁共振 磁共振波谱(MRS)研究AUD/PTSD共病的潜在病理生理学及预后 治疗结果的指标。为了达到这些目标，我们组建了一个多学科的团队， 在AUD和合并创伤后应激障碍、临床试验、人体实验室方面拥有国家认可的专业知识的研究人员 范例和神经成像，他们在过去成功地合作，并具有独特的资格 实施这类调查。拟议的项目直接响应了国家 酒精滥用和酒精中毒研究所(NIAAA)和澳大利亚/创伤后应激障碍新倡议，以加快对 开发有效的药物治疗方法来治疗这种常见且高度致残性的共病。这个 这项研究的发现将提供急需的经验证据，以帮助指导临床实践。 指导和加快对AUD和并存的创伤后应激障碍的治疗研究。

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.