Nitrous Oxide for Posttraumatic Stress Disorder (PTSD): A Phase IIa Trial

创伤后应激障碍(PTSD)严重扰乱了许多退伍军人的生活。目前的一线治疗， 5-羟色胺再摄取抑制剂或长时间暴露治疗，需要几周到几个月的时间才能带来有意义的 改善，让退伍军人经历长期的痛苦。一种有希望的新治疗方法 快速减轻创伤后应激障碍症状的药物是一氧化二氮、一种吸入麻醉剂和可能的N-甲基-D-天冬氨酸 受体(NMDAR)调节剂，可在1天内减轻抑郁症状，副作用有限。如果 在创伤后应激障碍中显示出类似的效果，一氧化二氮可以显著增加我们的治疗设施，通过 在长期治疗站稳脚跟之前，症状迅速减少。拟议的项目检验了效果。 一氧化二氮在缓解退伍军人创伤后应激障碍症状中的作用，同时探索一氧化二氮如何改变 认知和疼痛结果。 一氧化二氮被FDA批准用于麻醉和疼痛治疗，可能是一种新的治疗方法 管理创伤后应激障碍。一氧化二氮良好的药代动力学(在几分钟内快速抵消)防止了短暂的 认知和拟精神分裂的副作用(妄想、幻觉)有时见于其他NMDA 谷氨酸调节剂。一氧化二氮可能适合退伍军人，因为：1)他们年龄较大(这带来了更大的 年龄相关认知障碍的概率)，以及2)合并疼痛的患病率比美国更高 人口。作为一种麻醉剂，一氧化二氮有强有力的证据表明它在疼痛中的应用，而且 作为牙科手术和分娩的止痛剂的安全记录。 拟议的项目将检验一氧化二氮在缓解退伍军人创伤后应激障碍症状和 同时，探索一氧化二氮是否可以改善认知和疼痛结果。具体地说，我们将首先评估 一氧化二氮治疗1周内是否改善创伤后应激障碍症状。同时，我们将探索是否 这种治疗可以改善同时存在的抑郁和疼痛。此外，我们还将探讨一氧化二氮对 经常被忽视的创伤后应激障碍相关损害--认知控制障碍，这是一种核心的神经生物学 这一过程对于调节思想和成功的日常运作至关重要。我们将测试震级是否 一氧化二氮对创伤后应激障碍症状或疼痛的影响取决于退伍军人的基线认知能力 控制或认知控制引起的变化。如果创伤后应激障碍症状的减轻与 认知控制，这些发现表明，认知控制可能值得在一项更大的研究中进行检查 作用机制。综上所述，如果一氧化二氮被发现可以迅速缓解退伍军人的创伤后应激障碍症状， 改变认知和疼痛结果，这些结果在一项更大的研究中重复，它可能会改变 创伤后应激障碍的精神治疗。

Post-traumatic stress disorder (PTSD) seriously disrupts the lives of many Veterans. Current first-line treatments, serotonin reuptake inhibitors or prolonged exposure therapy, take weeks to months to bring meaningful improvement, leaving Veterans experiencing prolonged suffering. A promising new treatment approach for rapidly reducing PTSD symptoms is nitrous oxide, an inhalation anesthetic and putative N-methyl-D-aspartate receptor (NMDAR) modulator that diminishes depression symptoms within 1 day and has limited side effects. If shown to be similarly effective in PTSD, nitrous oxide may add dramatically to our treatment armamentarium by bringing rapid symptom decrease before longer-term therapies take hold. The proposed projects test the efficacy of nitrous oxide in relieving Veteran’s PTSD symptoms and, in parallel, explore how nitrous oxide may modify cognitive and pain outcomes. Nitrous oxide is FDA-approved for use in anesthesia and pain management, and may be a new approach for managing PTSD. Nitrous oxide’s favorable pharmacokinetics (rapid offset in minutes) prevent the transient cognitive and psychotomimetic side effects (delusions, hallucinations) sometimes seen with other NMDA glutamate modulators. Nitrous oxide may be suited to Veterans in view of: 1) their older age (which brings greater probability of age-associated cognitive impairments), and 2) higher prevalence of co-morbid pain than in the US population. As an anesthetic, nitrous oxide has robust evidence regarding its application in pain, and a superior safety record as an analgesic for dental procedures and childbirth. The proposed projects will examine the efficacy of nitrous oxide in relieving Veteran’s PTSD symptoms and in parallel, explore whether nitrous oxide improves cognitive and pain outcomes. Specifically, we will first assess whether nitrous oxide treatment improves PTSD symptoms within 1 week. In parallel, we will explore whether the treatment improves co-existing depression and pain. In addition, we will explore nitrous oxide’s effects on a PTSD-associated impairment that is often overlooked - disruption in cognitive control, a core neurobiological process critical for regulating thoughts and for successful daily functioning. We will test whether the magnitude of nitrous oxide’s effect on PTSD symptoms or pain depends on the Veteran’s baseline capacity for cognitive control or on changes induced in cognitive control. If diminished PTSD symptoms are related to changes in cognitive control, these findings would signal that cognitive control may merit examination in a larger study of mechanism of action. Taken together, if nitrous oxide is found to rapidly relieve Veterans’ PTSD symptoms and modify cognitive and pain outcomes, and these results are replicated in a larger study, it could transform psychiatric treatment of PTSD.