Prazosin for Noncombat Trauma PTSD

描述(由申请人提供)：我们建议进行一项双盲、安慰剂对照的增强试验，对普遍可获得的α-1肾上腺素能拮抗剂哌唑嗪治疗由非战斗(平民)创伤引起的慢性创伤后应激障碍(PTSD)。尽管进行了选择性5-羟色胺再摄取抑制剂(SSRI)帕罗西汀的试验，但主要的创伤后应激障碍症状将是残余的痛苦、与创伤相关的噩梦和睡眠障碍。尽管有几种SSRI被FDA批准用于治疗创伤后应激障碍，但SSRI(和其他药物)往往对这些非常令人痛苦的夜间创伤后应激障碍症状没有帮助。对患有慢性创伤后应激障碍的老年男性退伍军人的初步研究表明，哌唑嗪(唯一可用的从血液进入大脑的α-1拮抗剂)消除或大幅减少了以前难以治疗的创伤相关噩梦和睡眠障碍，这些梦魇和睡眠障碍多年来一直令人痛苦和虚弱。哌唑嗪还降低了总体疾病严重程度和功能损害，且耐受性良好。这些有益的哌唑嗪效应与PTSD病理生理学中大脑α-1肾上腺素能受体反应性增加的参与是一致的。在这里，我们将确定这些令人鼓舞的哌唑嗪结果是否也可以在通常较年轻且以女性为主的非战斗创伤创伤后应激障碍患者中得到证实，这些人尽管接受了标准的创伤后应激障碍治疗，但仍继续遭受与创伤有关的残余痛苦、噩梦和睡眠障碍的折磨。在一项为期8周的双盲安慰剂对照平行组临床试验中，将检验以下假设：假设1：患有创伤后应激障碍的患者，表现为残余痛苦的创伤相关噩梦和睡眠。 与随机接受安慰剂强化治疗的患者相比，随机接受哌唑嗪强化治疗的患者在创伤相关噩梦和睡眠障碍方面表现出更大的减少。假设2：以残余痛苦、创伤相关噩梦和睡眠障碍(尽管接受SSRI治疗)为表现的创伤后应激障碍患者随机接受哌唑嗪强化治疗将比随机接受安慰剂强化治疗的患者在总体创伤后应激障碍的严重程度和功能上有更大的改善。假设3：研究由于不可接受的不良反应而停药(“退出”)的时间在随机接受哌唑嗪强化治疗的PTSD受试者和随机接受安慰剂强化治疗的PTSD受试者之间没有差别。主要的结果衡量标准将是临床医生实施的创伤后应激障碍量表(CAPS)、反复痛苦的梦境项目、匹兹堡睡眠质量指数和临床全球变化印象。其他结果测量将是CAPS总分，CAPS难以入睡或保持睡眠的项目，三个CAPS子量表(重新体验/侵扰， 避免/麻木和过度唤醒)、噩梦质量和频率的测量、抑郁症状和症状以及生活质量。完成研究的天数和不良事件也将在不同组之间进行比较。

DESCRIPTION (provided by applicant): We propose a double-blind placebo-controlled augmentation trial of the generically available alpha-1 adrenergic antagonist prazosin in chronic posttraumatic stress disorder (PTSD) caused by noncombat ("civilian") trauma. Primary target PTSD symptoms will be residual distressing trauma-related nightmares and sleep disturbance that persist despite a trial of the selective serotonin reuptake inhibitor (SSRI) paroxetine. Although several SSRIs are FDA-approved for PTSD, SSRIs (and other drugs) often are not helpful for these very distressing nighttime PTSD Symptoms. Preliminary studies in older male combat veterans with chronic PTSD demonstrated that prazosin (the only available alpha-1 antagonist that crosses from blood into brain) eliminated or Substantially reduced previously treatment resistant trauma-related nightmares and sleep disturbance that had been distressing and debilitating for many years. Prazosin also reduced overall illness severity and functional impairment, and was well tolerated. These beneficial prazosin effects are consistent with involvement of increased responsiveness of brain alpha-1 adrenergic receptors in PTSD pathophysiology. Here we will determine if these encouraging prazosin results also can be demonstrated in the generally younger and predominantly female population of persons with noncombat trauma PTSD who continue to suffer from residual distressing trauma related nightmares and sleep disturbance despite standard PTSD treatment. In a double-blind placebo-controlled parallel group 8-week clinical trial of prazosin augmentation (following a 12-week "lead-in" of standard SSRI plus manualized psychotherapy treatment) the following hypotheses will be tested: Hypothesis 1: Persons with PTSD manifested by residual distressing trauma-related nightmares and sleep disturbance (despite SSRI treatment) randomized to prazosin augmentation will manifest a greater reduction in trauma related nightmares and sleep disturbance than those randomized to placebo augmentation. Hypothesis 2: Persons with PTSD manifested by residual distressing trauma-related nightmares and sleep disturbance (despite SSRI treatment) randomized to prazosin augmentation will manifest greater improvement in overall global PTSD severity and function than those randomized to placebo augmentation. Hypothesis 3: The time to study discontinuation ("dropout") due to unacceptable adverse effects will not differ between PTSD subjects randomized to prazosin augmentation and those randomized to placebo augmentation. Primary outcome measures will be the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams item, the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change. Additional outcome measures will be the total CAPS score, the CAPS Difficulty Falling or Staying Asleep item, the three CAPS subscales (Reexperiencing/Intrusions, Avoidance/Numbing, and Hyperarousal), measures of nightmare quality and frequency, depressive signs and symptoms, and quality of life. Number of study days completed and adverse events also will be compared between groups.