Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance inPosttraumatic Stress

Suvorexant：一种双重食欲素受体拮抗剂，用于治疗创伤后应激障碍的睡眠障碍

• 批准号: 9565433
• 负责人: SABRA INSLICHT
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9565433
• 关键词: Accounting; Addendum; Adverse effects; Arousal; Autonomic nervous system; Biological; Cardiovascular Diseases; Clinical; Clinical Trials; DSM-V; Distress; Dose; Double-Blind Method; Drops; Drowsiness; Drug Targeting; Emotional; FDA approved; Fright; Generations; Impairment; Inflammation; Interview; Lead; Learning; Life; Measures; Mediating; Mediator of activation protein; Memory; Mental Depression; Metabolic syndrome; Military Personnel; Moods; Neuropeptides; Nightmare; Patient Self-Report; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Phase IV Clinical Trials; Pittsburgh Sleep Quality Index; Placebos; Post-Traumatic Stress Disorders; Quality of life; Randomized; Reporting; Safety; Sampling; Selective Serotonin Reuptake Inhibitor; Severities; Site; Sleep; Sleep disturbances; Sleeplessness; Startle Reaction; Stress; Suicide; Symptoms; System; Testing; Time; Titrations; Trauma; Veterans; Wakefulness; Wrist; actigraphy; combat; design; efficacy testing; falls; flexibility; functional disability; hypocretin; improved; improvement on sleep; indexing; learning extinction; physical conditioning; pre-clinical; primary outcome; promoter; receptor; reduce symptoms; secondary outcome; side effect; sleep onset; sleep regulation; stress reactivity; stress related disorder; vigilance; week trial

Posttraumatic stress disorder (PTSD) is a common consequence of combat that is manifested in part by trauma-related hyperarousal and reactivity, seen in increased startle responses and impaired sleep that result from central and autonomic nervous system alterations. In fact, disturbed sleep is the most prevalent symptom endorsed by PTSD patients and is potentially debilitating in many domains of functioning (1, 2). As a relatively non-stigmatizing symptom, it is no surprise that disturbed sleep is often the reason that motivates Veterans with PTSD to seek treatment (3, 4). However, most drugs that target sleep result in unwanted side effects, such as next day somnolence, which can impact functioning in both military and civilian life. Furthermore, aside from several SSRI's that are only moderately effective in improving PTSD, little progress has been made toward advancing pharmacological treatments for PTSD and in Veterans. Preclinical evidence suggests that the orexin neuropeptide system may be a shared mechanism accounting for both sleep disturbance and PTSD. Orexin is a central promoter of wakefulness involved in regulation of sleep, and in fear learning and emotional memory. The dual orexin receptor antagonist, suvorexant, is the first of a new class of medications recently FDA-approved to treat insomnia. In contrast to previous generations of treatments used for patients with PTSD that provide delayed and often inadequate symptom relief, suvorexant holds promise of delivering immediate relief for pressing sleep concerns while also potentially reducing PTSD symptoms by targeting a biological mechanism that may account for both conditions. While its efficacy for insomnia has been strongly supported by clinical trials (5-8), the potential benefit of suvorexant on trauma- related sleep disturbance and on PTSD symptoms has not been examined, nor has it been evaluated for safety and tolerability in Veterans. We propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IV clinical trial to test the efficacy and safety of suvorexant on trauma-related sleep disturbance and PTSD symptoms in Veterans. We will use a flexible dose design of suvorexant with a 2-week titration followed by a 10-week steady-dose phase. We predict that suvorexant, as compared to placebo, will result in a greater decrease in insomnia on the Insomnia Severity Index (ISI) over the 12-week trial. We also predict that suvorexant, as compared to placebo, will result in a greater reduction in non-sleep PTSD symptoms in the Clinician Administered PTSD Scale for DSMV (CAPS-5) over the 12-week trial. Secondarily, we will examine potential objectively measured wrist actigraphy as a biological mechanism of clinical improvement with as well as concomitant effects on PTSD-related nightmares using the Pittsburgh Sleep Quality Index-PTSD addendum (PSQI-A). Pending a significant effect of suvorexant on PTSD, we will perform exploratory analyses to evaluate whether sleep improvement mediates the effect of suvorexant on PTSD symptoms. We will also examine safety and tolerability of suvorexant compared to placebo (including depression, mood, vigor, suicidality, and daytime somnolence, psychomotor vigilance, and functional disability). Results from this study will provide substantive rationale for the use of Suvorexant in the treatment of Veterans with these concerns. This study will be the first to examine a selective orexin-receptor antagonist in a Veteran sample with PTSD. Suvorexant is an accessible, non-stigmatized medication whose use and safety has been well-established in non-mental- health settings. It has outstanding promise for treating common and distressing symptoms in Veterans as well as civilians with trauma-related sleep disturbance and PTSD.

创伤后应激障碍 (PTSD) 是战斗的常见后果，部分表现为 与创伤相关的过度警觉和反应性，表现为惊吓反应增加和睡眠受损 来自中枢和自主神经系统的改变。事实上，睡眠障碍是最常见的症状 受到 PTSD 患者的认可，并且可能会削弱许多功能领域 (1, 2)。作为一个相对 非耻辱性症状，毫不奇怪，睡眠障碍往往是退伍军人的动力 患有 PTSD 寻求治疗 (3, 4)。然而，大多数针对睡眠的药物都会导致不良副作用， 例如第二天的嗜睡，这会影响军事和平民生活的功能。此外，除了 几种 SSRI 在改善 PTSD 方面效果有限，但进展甚微 致力于推进创伤后应激障碍和退伍军人的药物治疗。 临床前证据表明食欲素神经肽系统可能是一个共享机制 睡眠障碍和创伤后应激障碍（PTSD）。食欲素是觉醒的主要促进剂，参与睡眠调节， 以及恐惧学习和情感记忆。双重食欲素受体拮抗剂 suvorexant 是第一个 FDA 最近批准了一种治疗失眠的新型药物。与前几代相比 suvorexant 用于治疗 PTSD 患者的症状缓解延迟且通常不充分的治疗 有望立即缓解紧迫的睡眠问题，同时还可能减少创伤后应激障碍 (PTSD) 通过针对可能解释这两种情况的生物机制来治疗症状。虽然其功效为 失眠已得到临床试验的大力支持 (5-8)，suvorexant 对创伤的潜在益处 尚未对相关睡眠障碍和 PTSD 症状进行检查，也未对其进行评估 退伍军人的安全性和耐受性。 我们提出了一项两中心平行组、随机、双盲、安慰剂对照的 IV 期临床试验，以 测试 suvorexant 对创伤相关睡眠障碍和 PTSD 症状的疗效和安全性 退伍军人。我们将使用 suvorexant 的灵活剂量设计，先进行 2 周滴定，然后进行 10 周调整 稳定剂量阶段。我们预测，与安慰剂相比，suvorexant 将导致 在为期 12 周的试验中，失眠严重程度指数 (ISI) 的变化情况。我们还预测 suvorexant，如 与安慰剂相比，临床医生的非睡眠 PTSD 症状将得到更大程度的减少 在为期 12 周的试验中使用 DSMV PTSD 量表 (CAPS-5)。其次，我们将考察潜力 客观测量腕部活动记录仪作为临床改善的生物学机制 使用匹兹堡睡眠质量指数-PTSD 附录对 PTSD 相关噩梦的伴随影响 （PSQI-A）。在 suvorexant 对 PTSD 产生显着效果之前，我们将进行探索性分析来评估 睡眠改善是否介导 suvorexant 对 PTSD 症状的影响。我们还将检查 与安慰剂相比，suvorexant 的安全性和耐受性（包括抑郁、情绪、活力、自杀倾向和 白天嗜睡、精神运动警惕性和功能障碍）。这项研究的结果将提供 使用 Suvorexant 治疗有这些担忧的退伍军人的实质性理由。这项研究 将是第一个在患有 PTSD 的退伍军人样本中检查选择性食欲素受体拮抗剂的人。苏沃克生 是一种易于使用、不受​​歧视的药物，其使用和安全性已在非精神疾病领域得到充分证实。 健康设置。它对于治疗退伍军人的常见和令人痛苦的症状也具有出色的前景 患有与创伤相关的睡眠障碍和创伤后应激障碍 (PTSD) 的平民。