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）是战斗的普遍结果，部分由 与创伤相关的超伴和反应性，在增加的惊吓反应和睡眠受损中，结果是 来自中央和自主神经系统的改变。实际上，睡眠不安是最普遍的症状 受PTSD患者的认可，并可能在许多功能领域中衰弱（1，2）。相对 没有耻辱的症状，睡眠不足是激励退伍军人的原因也就不足为奇了。 与PTSD寻求治疗（3，4）。但是，大多数针对睡眠的药物会导致不必要的副作用， 例如第二天，会影响军事和平民生活的功能。此外，旁边 从几个仅在改善PTSD方面有效的SSRI，几乎没有取得进展 致力于推进PTSD和退伍军人的药理治疗。 临床前证据表明，Orexin神经肽系统可能是一种共同的机制 睡眠障碍和PTSD。 Orexin是参与睡眠调节的觉醒的中心启动子， 以及恐惧学习和情感记忆。双甲甲蛋白受体拮抗剂Suvorexant是A的第一个 最近，FDA批准了新的药物治疗失眠症。与前几代 用于PTSD患者使用的治疗 有望立即为紧迫的睡眠问题提供立即缓解，同时也有可能减少PTSD 通过靶向可能解释这两种情况的生物学机制的症状。而其功效 失眠症得到了临床试验（5-8）的强烈支持，这是su耐药物对创伤的潜在益处 尚未检查相关的睡眠障碍和PTSD症状，也没有对其进行评估 退伍军人的安全性和耐受性。 我们提出了一个两点平行组，随机，双盲，安慰剂对照期IV期临床试验 测试Suvorexant对创伤相关的睡眠障碍和PTSD症状的功效和安全性 退伍军人。我们将使用灵活的suvorexant剂量设计，并进行2周的滴定，然后进行为期10周 稳态期。我们预测，与安慰剂相比，Suvorexant将导致更大的减少 在为期12周的试验中，失眠严重程度指数（ISI）失眠。我们还预测，suvorexant是 与安慰剂相比，临床医生的非结肠PTSD症状会增加 在12周的试验中，DSMV（CAPS-5）的PTSD量表管理。其次，我们将检查潜力 客观测量的手腕动作法是临床改善的生物学机制， 使用匹兹堡睡眠质量指数附录对PTSD相关的噩梦的伴随影响 （PSQI-A）。在suvorexant对PTSD的显着影响之前，我们将进行探索性分析以评估 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（包括抑郁，情绪，活力，自杀性和 白天迟感，精神运动警惕和功能残疾）。这项研究的结果将提供 与这些关注点对退伍军人的治疗中使用Suvorexant的实质性理由。这项研究 将是第一个检查具有PTSD的老将样本中选择性的OREXIN受体拮抗剂的人。 Suvorexant 是一种易于使用的，污名化的药物，其使用和安全性在非精神 健康环境。它在治疗退伍军人的常见和令人痛苦的症状方面都有巨大的承诺 作为与创伤相关的睡眠障碍和PTSD的平民。