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， 血清素再摄取抑制剂或长期暴露疗法需要数周至数月才能带来有意义的结果 改善，让退伍军人经历长期的痛苦。一种有前景的新治疗方法 快速减轻 PTSD 症状的是一氧化二氮、一种吸入麻醉剂和推定的 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，并且副作用有限。如果 一氧化二氮被证明对治疗创伤后应激障碍（PTSD）同样有效，它可以通过以下方式显着增加我们的治疗装备： 在长期治疗生效之前使症状迅速减轻。拟建项目检验功效 一氧化二氮在缓解退伍军人的创伤后应激障碍症状方面的作用，同时探索一氧化二氮如何改变 认知和疼痛结果。 一氧化二氮已获得 FDA 批准用于麻醉和疼痛管理，并且可能是一种新方法 管理创伤后应激障碍。一氧化二氮有利的药代动力学（几分钟内快速抵消）可防止短暂的 其他 NMDA 有时会出现认知和拟精神病副作用（妄想、幻觉） 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（这会带来更大的 与年龄相关的认知障碍的可能性），以及 2）共病疼痛的患病率高于美国 人口。作为一种麻醉剂，一氧化二氮在疼痛方面的应用有强有力的证据，并且具有优越的效果 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治疗中的功效。 同时，探索一氧化二氮是否可以改善认知和疼痛结果。具体来说，我们首先会评估 一氧化二氮治疗是否能在 1 周内改善 PTSD 症状。与此同时，我们将探讨是否 该治疗可改善共存的抑郁和疼痛。此外，我们还将探讨一氧化二氮对 经常被忽视的 PTSD 相关损伤——认知控制的破坏，这是一个核心神经生物学 对于调节思想和成功的日常运作至关重要的过程。我们将测试幅度是否 一氧化二氮对 PTSD 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 PTSD 症状的减轻与以下方面的变化有关： 认知控制，这些发现表明认知控制可能值得在更大规模的研究中进行检验 作用机制。综上所述，如果发现一氧化二氮能够迅速缓解退伍军人的 PTSD 症状，并且 改变认知和疼痛结果，并且这些结果在更大的研究中得到复制，它可以改变 PTSD 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.