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物干预措施 创伤后应激障碍 (PTSD)，因为目前只有两种 FDA 批准的药物可用于治疗创伤后应激障碍 (PTSD) 治疗创伤后应激障碍（这两种药物都属于同一类药物，并且在治疗中仅显示出中等的效果） FDA 注册试验）因此，尽管有这些药物，但许多患有 PTSD 的退伍军人仍然存在症状。 治疗，增加接受药物治疗干预的可能性 使用新药物方法的随机对照试验（RCT）很少或没有。 因此，伊拉克/阿富汗时期的退伍军人群体急需这种药物，这一群体可能受到的治疗较少—— 难治性的（特别是在 PTSD 症状发展的早期进行治疗）。 因此，为这个有前途的退伍军人群体提供药物治疗是非常及时和紧急的。 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。 例如，四氢孕酮（孕烯醇酮的下游代谢产物）具有抗焦虑、抗抑郁、抗抑郁等作用。 积极的、减少恐惧的、神经保护的、抗炎的和增强神经发生的作用——以及 这些特性对于创伤后应激障碍（PTSD）具有明确的治疗效用，我们的初步数据也表明了这一点。 与对照组相比，PTSD 患者的血清四氢孕酮水平显着降低 我们在多项研究中表明，孕烯醇酮给药 将下游别孕酮水平提高 5-10 倍，因此可以作为前体负载 恢复创伤后应激障碍（PTSD）中缺乏的四氢孕酮水平的策略此外，最近的神经影像学研究。 证明四氢孕酮在调节与负性相关的脑功能中发挥作用 情绪，并增强与情绪调节过程相关的活动（Sripada，2013；优先 此外，我们的临床前啮齿动物模型表明， 孕烯醇酮治疗可减轻啮齿动物在捕食者压力暴露后的焦虑样行为。 最后，我们证明，患有轻度创伤性脑损伤的退伍军人的 PTSD 症状有所改善 (mTBI) 在 mTBI 的试点随机对照试验和更大的后续随机对照试验中给予孕烯醇酮后。 这两项研究中，随机接受孕烯醇酮治疗的 mTBI 退伍军人的血清水平显着升高 治疗后别孕酮和孕烯醇酮水平，以增强缺陷。 因此，提高内源性四氢孕酮水平可能是治疗 PTSD 的有效方法。 1.) 研究孕烯醇酮治疗伊拉克/阿富汗时期退伍军人 PTSD 的潜在功效 进行孕烯醇酮与安慰剂的随机对照试验（主要终点 CAPS-5 变化；[90 随机 参与者；每组 n=45；] 治疗持续时间 8 周）， 2.) 确定孕烯醇酮是否也能改善同时发生的疼痛和抑郁症状（次要 终点简要疼痛量表和汉密尔顿抑郁评定量表）， 3.) 量化基线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，例如四氢孕酮（以及其他候选生物标志物，例如 作为炎症标志物）是治疗反应的预测因子。 拟议的随机对照试验的结果可以为孕烯醇酮的潜在功效提供科学基础 PTSD 并导致一项关键的 III 期研究支持可能的治疗方法。 孕烯醇酮对于治疗创伤后应激障碍 (PTSD) 症状、疼痛障碍和抑郁症的效用非常显着。 迄今为止，孕烯醇酮治疗在退伍军人群体中具有良好的耐受性，因此可能代表一种有前途的新疗法。 对伊拉克/阿富汗时期退伍军人进行创伤后应激障碍 (PTSD) 干预是有效、廉价且安全的。