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)是战斗的一种常见后果，部分表现为 与创伤相关的过度觉醒和反应，表现为惊吓反应增加和由此导致的睡眠受损 中枢神经系统和自主神经系统的改变。事实上，睡眠障碍是最常见的症状。 由创伤后应激障碍患者认可，并在许多功能领域潜在地削弱(1，2)。作为一种相对的 非耻辱性症状，毫不奇怪，睡眠障碍往往是激励退伍军人的原因 伴创伤后应激障碍寻求治疗(3例，4例)。然而，大多数针对睡眠的药物都会产生不想要的副作用， 例如第二天的嗜睡，这可能会影响军事和平民生活的功能。此外，抛开 从几种在改善创伤后应激障碍方面只有适度有效的SSRI来看，进展甚微 推动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同的机制，解释 睡眠障碍和创伤后应激障碍。食欲素是参与睡眠调节的清醒的中心推动者， 以及恐惧学习和情绪记忆。双重增食欲素受体拮抗剂Suvorexant是第一个 最近FDA批准的治疗失眠的新型药物。与前几代 用于创伤后应激障碍患者的治疗，可提供延迟且往往不充分的症状缓解，Suvorexant 有希望立即缓解紧迫的睡眠问题，同时潜在地减少创伤后应激障碍 通过针对一种可能解释这两种情况的生物机制来解决症状。虽然它对 失眠已经得到了临床试验(5-8项)的大力支持，Suvorexant对创伤的潜在好处- 没有对相关的睡眠障碍和创伤后应激障碍症状进行检查，也没有对其进行评估 退伍军人的安全性和耐受性。 我们提出了一项两点平行分组、随机、双盲、安慰剂对照的IV期临床试验 检测舒乐宁对创伤后睡眠障碍和创伤后应激障碍症状的疗效和安全性 退伍军人。我们将使用灵活的剂量设计，先滴定2周，然后再滴定10周 稳定剂量阶段。我们预测，与安慰剂相比，Suvorexant将导致更大的降幅 在为期12周的试验中，失眠对失眠严重程度指数(ISI)的影响。我们还预测Suvorexant，因为 与安慰剂相比，临床医生的非睡眠创伤后应激障碍症状将得到更大程度的缓解 在为期12周的试验中，对DSMV(CAPS-5)实施创伤后应激障碍量表(PTSD)。其次，我们将研究潜在的 客观测量腕关节活动描记作为临床改善的生物学机制 匹兹堡睡眠质量指数-创伤后应激障碍附录对创伤后应激障碍相关噩梦的伴随效应 (PSQI-A)。在Suvorexant对创伤后应激障碍有显著疗效之前，我们将进行探索性分析以评估 睡眠改善是否介导亚复氧对创伤后应激障碍症状的影响。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 日间嗜睡、精神运动警觉和功能残疾)。这项研究的结果将提供 在有这些担忧的退伍军人治疗中使用Suvorexant的实质性理由。本研究 将首次在患有创伤后应激障碍的老兵样本中检测选择性食欲素受体拮抗剂。复活剂 是一种可获得的、非污名化的药物，其使用和安全性在非精神疾病中已得到很好的证实 运行状况设置。它在治疗退伍军人常见的和令人痛苦的症状方面也有突出的前景 作为患有创伤相关睡眠障碍和创伤后应激障碍的平民。