Neurosteroid Intervention for PTSD in Iraq/Afghanistan-era Veterans

神经类固醇干预伊拉克/阿富汗时期退伍军人的创伤后应激障碍

• 批准号: 10417141
• 负责人: JENNIFER C NAYLOR
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 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/10417141
• 关键词: Acute; Address; Afghanistan; Aftercare; Allopregnanolone; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antidepressive Agents; Biological Psychiatry; Bipolar Depression; Brain; Brief Pain Inventory; Clinical; Clinical Data; Communication; Data; Development; Emotional; Emotions; FDA approved; Focus Groups; Foundations; Fright; Functional disorder; Hamilton Rating Scale for Depression; Intervention; Investigation; Iraq; Lead; Low Back Pain; Mass Spectrum Analysis; Mental Depression; Neurobiology; Pain; Pain Disorder; Participant; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Placebos; Play; Post-Traumatic Stress Disorders; Prediction of Response to Therapy; Pregnenolone; Process; Property; Quality of life; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Refractory; Research; Rodent; Rodent Model; Role; Serum; Stress; Symptoms; Techniques; Therapeutic; Time; Veterans; anxiety-like behavior; associated symptom; base; candidate marker; chronic pain; cohort; depressive symptoms; disabling symptom; dual diagnosis; efficacious treatment; experience; follow-up; improved; inflammatory marker; mild traumatic brain injury; military veteran; neurogenesis; neuroimaging; neurosteroids; novel therapeutics; pain reduction; pain symptom; phase 3 study; pre-clinical; primary endpoint; secondary endpoint; side effect; symptomatic improvement; treatment duration; working group

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.

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， PTSD的治疗（两者都来自同一药物类别，并且在治疗中仅显示出中等效果） 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，尽管这些 治疗，增加接受药物治疗干预的可能性， 很少或没有经验证据。使用新药物方法的随机对照试验（RCT） 因此，伊拉克/阿富汗时代的退伍军人迫切需要，这一群体可能较少治疗- 难治性（特别是如果在PTSD症状发展的早期治疗）。调查 因此，对于这一退伍军人群体来说，有希望的药理学药剂是最及时或最紧迫的。 越来越多的证据支持神经类固醇在神经生物学和PTSD治疗中的潜在作用。为 例如，别孕烯醇酮（异孕烯醇酮的下游代谢物）具有抗焦虑、抗抑郁和抗抑郁的作用。 攻击性，减少恐惧，神经保护，抗炎和神经发生增强作用-以及 这些特性对创伤后应激障碍具有明显的治疗效用。我们的初步数据还表明， 与对照组相比，PTSD患者的血清别孕烯醇酮水平显著降低 参与者分为两个独立的队列。我们在多项研究中表明， 使下游别孕烯醇酮水平提高5-10倍，因此可以潜在地用作前体负载 恢复PTSD患者异孕烯醇酮水平不足策略此外，最近的神经成像研究 表明别孕烯醇酮在与负性脑功能相关的脑功能调节中起作用， 情绪，并增强与情绪调节过程相关的活动（Sripada，2013;优先 生物心理学（Biological Psychiatry）。此外，我们的临床前啮齿动物模型表明， 用双烯醇酮治疗减轻啮齿动物在捕食者应激暴露后的焦虑样行为。 最后，我们已经证明，创伤后应激障碍症状改善退伍军人轻度创伤性脑损伤 在mTBI中的先导性RCT和较大的随访RCT中，在给予阿贝烯醇酮后，在 在这两项研究中，随机分配到阿贝烯醇酮的mTBI退伍军人显示血清中 治疗后别孕烯醇酮和双烯醇酮水平。前体加载策略，以增强缺乏 因此，内源性别孕烯醇酮水平可能是PTSD的有效治疗。因此，我们提议： 1.）的人。通过以下方法研究利凡诺龙治疗伊拉克/阿富汗时期退伍军人PTSD的潜在疗效： 进行一项随机对照试验（主要终点CAPS-5变化; [90例随机 参与者; n=45/组;] 8周治疗持续时间）， 2.）的情况。为了确定双烯醇酮是否也能改善同时发生的疼痛和抑郁症状（继发性）， 终点简明疼痛量表和汉密尔顿抑郁评定量表）， 3.）第三章定量基线和治疗后的血清神经类固醇水平，以确定是否有异烯醇酮和 下游神经类固醇代谢物如别孕烯醇酮（和其他生物标志物候选物， 作为炎症标志物）是治疗反应的预测因子。 本随机对照试验的结果为评价双烯醇酮的潜在疗效提供了科学依据 导致了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 对创伤后应激障碍症状，疼痛障碍和抑郁症的实用性，和对己烯醇酮已经非常 迄今为止在退伍军人队列中耐受良好。因此，用双烯醇酮治疗可能代表一种有前途的新方法。 创伤后应激障碍的干预是有效的，廉价的，在伊拉克/阿富汗时代的退伍军人安全。