Neurosteroid Intervention for PTSD in Iraq/Afghanistan-era Veterans

迫切需要开发新的有效的药理学干预措施 创伤后应激障碍(PTSD)，因为目前只有两种FDA批准的药物治疗创伤后应激障碍 治疗创伤后应激障碍(这两种药物都来自同一药物类别，在#年仅显示出中等疗效 FDA注册试验)。因此，许多患有创伤后应激障碍的退伍军人仍然有症状，尽管有这些 治疗，增加接受药物治疗干预的可能性 很少或根本没有经验证据。利用新的药物治疗方法的随机对照试验(RCT) 因此，在伊拉克/阿富汗时代的退伍军人中，迫切需要一个可能得到较少治疗的队列- 难治性(特别是如果在创伤后应激障碍症状发展的早期进行治疗)。对…的调查 因此，对于这一老兵群体来说，前景看好的药理药物再及时也没有比这更紧迫的了。 越来越多的证据支持神经类固醇在神经生物学和创伤后应激障碍治疗中的潜在作用。为 例如，别孕酮(孕烯醇酮的下游代谢物)具有抗焦虑、抗抑郁等作用。 攻击性、减少恐惧、神经保护、抗炎和增强神经再生的作用--以及 这些特性可能对创伤后应激障碍有明确的治疗作用。我们的初步数据也表明， 创伤后应激障碍患者血清别孕酮水平显著低于对照组 两个独立队列的参与者。我们已经在多项研究中表明，孕烯醇酮给药 使下游的别孕酮水平升高5-10倍，因此可以潜在地作为前体负荷 恢复创伤后应激障碍患者不良激素水平的策略。此外，最近的神经成像研究 说明别孕酮对负性脑功能的调节作用 情绪，并增强与情绪调节过程相关的活动(斯里帕达，2013；优先 通信、生物精神病学)。此外，我们的临床前啮齿动物模型表明，临床前 孕烯醇酮治疗减轻捕食者应激暴露后啮齿动物的焦虑样行为。 最后，我们证明了轻度创伤性脑损伤退伍军人的创伤后应激障碍症状有所改善。 (MTBI)在试验性随机对照试验和更大范围的后续随机对照试验中应用孕烯醇酮后。在……里面 这两项研究都显示，患有mTBI的退伍军人随机服用孕烯醇酮后血清水平显著升高。 治疗后别孕酮和孕烯醇酮水平。一种加强缺陷性的前驱加载策略 因此，内源性别孕酮水平可能是治疗创伤后应激障碍的有效方法。因此，我们建议： 1)研究孕烯醇酮治疗伊拉克/阿富汗时期退伍军人创伤后应激障碍的潜在疗效 进行孕烯醇酮与安慰剂的随机对照试验(主要终点CAPS-5改变；[90随机 参与者；每组45人；]疗程8周)， 2.)确定孕烯醇酮是否也能改善同时出现的疼痛和抑郁症状(继发性 Endpoint Brief Pain Inventory和汉密尔顿抑郁评定量表)， 3.)量化治疗前和治疗后的血清神经类固醇水平，以确定孕烯醇酮和 下游神经类固醇代谢物，如别孕酮(和其他候选生物标记物 作为炎症标志物)是治疗反应的预测因子。 随机对照试验的结果可为孕烯醇酮的潜在疗效提供科学依据。 在创伤后应激障碍中，并导致一项关键的第三阶段研究。临床和临床前数据支持可能的治疗方法 孕烯醇酮对创伤后应激障碍症状、疼痛障碍和抑郁的疗效非常显著。 到目前为止，在老兵群体中耐受性很好。因此，孕烯醇酮治疗可能代表着一种有希望的新技术 对伊拉克/阿富汗时代的退伍军人进行有效、廉价和安全的创伤后应激障碍干预。

There is an acute and urgent need to develop new and effective pharmacological interventions for posttraumatic stress disorder (PTSD), as there are currently only two FDA-approved medications for the treatment of PTSD (both of which are from the same drug class and have shown only moderate effect sizes in FDA registration trials). Many Veterans with PTSD thus remain symptomatic despite the availability of these treatments, increasing the likelihood of receiving pharmacological treatment interventions for which there is little or no empirical evidence. Randomized controlled trials (RCT) utilizing new medication approaches are thus acutely needed in the Iraq/Afghanistan-era Veteran population, a cohort that may be less treatment- refractory (particularly if treated early in the course of PTSD symptom development). The investigation of promising pharmacological agents for this Veteran cohort could thus not be more timely or urgent. Increasing evidence supports a potential role for neurosteroids in the neurobiology and treatment of PTSD. For example, allopregnanolone (a downstream metabolite of pregnenolone) has anxiolytic, antidepressant, anti- aggressive, fear-reductive, neuroprotective, anti-inflammatory, and neurogenesis-enhancing actions – and these properties could have clear therapeutic utility for PTSD. Our preliminary data also demonstrate that serum allopregnanolone levels are significantly decreased in patients with PTSD compared to control participants in two independent cohorts. We have shown in multiple studies that pregnenolone administration elevates downstream allopregnanolone levels 5-10 fold, and can thus potentially serve as a precursor loading strategy to restore deficient allopregnanolone levels in PTSD. Furthermore, recent neuroimaging studies demonstrate that allopregnanolone plays a role in the modulation of brain function associated with negative emotion, and enhances activity associated with emotional regulatory processes (Sripada, 2013; Priority Communication, Biological Psychiatry). In addition, our preclinical rodent models demonstrate that pre- treatment with pregnenolone mitigates anxiety-like behaviors in rodents following predator stress exposure. Finally, we have demonstrated that PTSD symptoms improve in Veterans with mild Traumatic Brain injury (mTBI) following administration of pregnenolone in both a pilot RCT and in a larger follow-up RCT in mTBI. In both studies, Veterans with mTBI randomized to pregnenolone showed marked elevations in serum allopregnanolone and pregnenolone levels post-treatment. A precursor loading strategy to enhance deficient levels of endogenous allopregnanolone may thus be an efficacious treatment for PTSD. We therefore propose: 1.) To investigate the potential efficacy of pregnenolone to treat PTSD in Iraq/Afghanistan-era Veterans by conducting an RCT of pregnenolone vs. placebo (primary endpoint CAPS-5 change; [90 randomized participants; n=45 per group;] 8-week duration of treatment), 2.) To determine if pregnenolone also improves co-occurring pain and depression symptoms (secondary endpoints Brief Pain Inventory and Hamilton Depression Rating Scale), 3.) To quantify serum neurosteroid levels at baseline and post-treatment to determine if pregnenolone and downstream neurosteroid metabolites such as allopregnanolone (and other biomarker candidates such as inflammatory markers) are predictors of therapeutic response. Results of the proposed RCT could provide the scientific foundation for the potential efficacy of pregnenolone in PTSD and lead to a pivotal Phase III study. Clinical and preclinical data support the possible therapeutic utility of pregnenolone for PTSD symptoms, pain disorders, and depression, and pregnenolone has been very well-tolerated in Veteran cohorts to date. Treatment with pregnenolone could thus represent a promising new intervention in PTSD that is efficacious, inexpensive, and safe in Iraq/Afghanistan-era Veterans.