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期暴露治疗，需要数周至数月才能带来有意义的 改善，让退伍军人经历长期的痛苦。一种有前途的新治疗方法， 一氧化二氮，一种吸入麻醉剂和N-甲基-D-天冬氨酸 NMDAR受体（NMDAR）调节剂，在1天内减少抑郁症状，副作用有限。如果 在创伤后应激障碍中，一氧化二氮显示出类似的效果， 在长期治疗之前迅速减轻症状。拟议的项目测试的功效 一氧化二氮在缓解退伍军人的创伤后应激障碍症状，并在平行，探讨如何一氧化二氮可能改变 认知和疼痛结果。 一氧化二氮是FDA批准用于麻醉和疼痛管理，可能是一种新的方法， 治疗创伤后应激障碍一氧化二氮有利的药代动力学（在几分钟内迅速抵消）防止了瞬态 认知和拟精神病副作用（妄想，幻觉），有时与其他NMDA一起出现 谷氨酸调节剂。一氧化二氮可能适合退伍军人，因为：1）他们的年龄较大（这带来更大的 与年龄相关的认知障碍的概率），和2）与美国相比，合并症疼痛的患病率更高 人口作为一种麻醉剂，一氧化二氮有强有力的证据表明其在疼痛中的应用上级 作为牙科手术和分娩镇痛剂的安全记录。 拟议的项目将检查一氧化二氮在缓解退伍军人创伤后应激障碍症状和 平行，探索一氧化二氮是否改善认知和疼痛结果。具体来说，我们将首先评估 一氧化二氮治疗能否在1周内改善PTSD症状。同时，我们将探讨 该治疗改善了同时存在的抑郁和疼痛。此外，我们还将探讨一氧化二氮对 PTSD相关的损害，往往被忽视-在认知控制中断，一个核心的神经生物学 这个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 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认知能力基线 控制或认知控制引起的变化。如果PTSD症状的减轻与 认知控制，这些发现将表明，认知控制可能值得在一个更大的研究， 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得到复制，它可以改变 创伤后应激障碍的心理治疗

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.