CAP - Doxazosin in the Treatment of Co-Occurring PTSD and Alcohol Use Disorders

 描述(由申请人提供)： 由于过去十年阿富汗和伊拉克持续的军事冲突，越来越多的美国军事人员和退伍军人带着创伤后应激障碍(PTSD)和共病酒精使用障碍(AUD)回国。如果不治疗，患有创伤后应激障碍和药物使用障碍的退伍军人患上其他精神健康问题(如抑郁、焦虑)、自杀念头和企图、身体健康问题、复原力下降和军事准备不足、就业问题、暴力和家庭/关系损害的风险增加。虽然为美国服役人员提供了心理健康服务，但在治疗同时发生的创伤后应激障碍和AUD方面存在很大差距，而且几乎没有科学证据来指导提供护理。这项拟议的研究通过测试长效和选择性的α-1肾上腺素能拮抗剂多沙唑嗪与安慰剂在降低曾在持久自由行动、伊拉克自由行动或新黎明行动(OEF/OIF/OND)中服役的美国军事人员的创伤后应激障碍和AUD严重性方面的有效性，直接解决了这一关键的知识差距。退伍军人中最常见的物质使用障碍是酒精使用障碍(AUD)；因此，拟议的研究针对的是患有创伤后应激障碍和AUD的退伍军人。被研究的药物(多沙唑嗪)代表了一种治疗PTSD/AUD的新方法。虽然哌唑嗪也是一种α-1肾上腺素能拮抗剂，已被证明可以改善患有创伤后应激障碍的军事人员的睡眠和噩梦，并可能有助于降低药物使用的严重性，但它的半衰期很短，只有2-3小时，每天需要多次服用，这是一个显著的限制。在几项试点研究中，多沙唑嗪在显著减少创伤后应激障碍和AUD症状方面表现出了希望，与哌唑嗪相比，它需要每天服用一次，这在将阳性结果转化为常规临床实践方面具有显著优势。在这一阶段的研究中，我们将(1)采用双臂随机、双盲、组间实验设计，包括12周的多沙唑嗪或安慰剂治疗；(2)使用标准化的、重复的依赖措施，在5个时间点(基线、4周、8周、12周和1个月随访)严格评估创伤后应激障碍症状和AUD严重程度；(3)测量相关精神和行为健康问题(例如，抑郁、焦虑、睡眠、危险行为、家庭/社会功能)的损害；(4)使用功能磁共振成像(FMRI)研究PTSD/AUD共病的潜在病理生理学机制，并确定治疗结果的预后指标。为了实现这些目标，我们组建了一个多学科的调查团队，他们在战斗相关的创伤后应激障碍、药物使用障碍和神经成像方面拥有国家公认的专业知识，他们过去曾成功合作，并且唯一有资格实施这种类型的调查。调查人员代表了拉尔夫·H·约翰逊退伍军人事务(VA)医学中心和南卡罗来纳州查尔斯顿医科大学(MUSC)的教职员工合作。拟议的项目直接响应了缓解创伤后应激障碍联合会(CAP)的使命，因为它寻求加强和加快对早期、慢性和潜伏性创伤后应激障碍以及诸如澳门氏症等常见并存疾病的治疗研究。这项研究的结果将提供急需的经验证据，以帮助为临床实践指南提供信息，并更好地 满足美国军人、退伍军人及其家属的需求。

 DESCRIPTION (provided by applicant): Due to sustained military conflicts in Afghanistan and Iraq over the past decade, there are an increasing number of U.S. military personnel and Veterans returning home with posttraumatic stress disorder (PTSD) and comorbid alcohol use disorders (AUD). If left untreated, Veterans with co-occurring PTSD and substance use disorders are at increased risk for developing other mental health problems (e.g., depression, anxiety), suicidal ideation and attempts, physical health problems, reduced resiliency and military readiness, employment problems, violence, and family/relationship impairment. While mental health services are in place for U.S. service members, substantial gaps in the treatment of co-occurring PTSD and AUD exist and 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 doxazosin, a long-acting and selective alpha-1 adrenergic antagonist, as compared to placebo in reducing PTSD and AUD severity among U.S. military personnel who have served in Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn (OEF/OIF/OND). The most common substance use disorder among Veterans is alcohol use disorder (AUD); thus the proposed study targets Veterans with co-occurring PTSD and AUD. The medication to be investigated (doxazosin) represents a novel treatment approach for PTSD/AUD. While prazosin, also an alpha-1 adrenergic antagonist, has been shown to improve sleep and nightmares in military personnel with PTSD and may help reduce substance use severity, it has a short half-life of 2-3 hours and requires multiple doses each day, which is a significant limitation. In several pilot studies, doxazosin has shown promise in significantly reducing symptoms of PTSD and AUD and, in contrast to prazosin, it requires once per day dosing which confers a significant advantage in terms of translating positive findings into routine clinical practice. In this Stage I study, we will (1) employ a two-arm randomized, double-blind, between-groups experimental design that will consist of 12 weeks of treatment with doxazosin or placebo medication; (2) use standardized, repeated dependent measures to rigorously assess PTSD symptomatology and AUD severity at 5 time points (baseline, week 4, week 8, week 12 and 1-month follow-up); (3) measure impairment in associated mental and behavioral health problems (e.g., depression, anxiety, sleep, risky behaviors, family/social functioning); and (4) use functional magnetic resonance imaging (fMRI) to investigate the underlying pathophysiology of comorbid PTSD/AUD and identify prognostic indicators of treatment outcome. To achieve these aims, we have assembled a multidisciplinary team of investigators with nationally-recognized expertise in combat-related PTSD, substance use disorders and neuroimaging who have successfully collaborated in the past and are uniquely qualified to implement this type of investigation. The investigators represent a collaboration of faculty at the Ralph H. Johnson Veterans Affairs (VA) Medical Center and the Medical University of South Carolina (MUSC) in Charleston, SC. The proposed project is directly responsive to the mission of the Consortium to Alleviate PTSD (CAP) in that it seeks to enhance and accelerate research on the treatment of early, chronic and latent onset PTSD and common comorbidities such as AUD. The findings of this study will provide critically needed empirical evidence to help inform clinical practice guidelines and better serve the needs of U.S. service members, Veterans and their families.