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; 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 PTSD的治疗（两者都来自同一药物类别，仅显示中等效应大小 FDA注册试验）。因此，许多具有PTSD的退伍军人仍然是有症状的使命。 治疗，增加接受药物治疗干预措施的可能性 很少或没有经验证据。使用新药物方法的随机对照试验（RCT）是 在伊拉克/阿富汗时代的资深人口中，急需急需，这可能会减少治疗 - 难治性（尤其是在PTSD符号开发过程中进行的治疗）。投资 因此，这位资深人士队列的有前途的药物可能不会更及时或紧急。 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。为了 例如，Allopregnanolone（一种下游的untixtolone代谢产物）具有抗焦虑，抗抑郁药 侵略性，恐惧，神经保护性，抗炎和神经发生的动作 - 这些特性可能具有PTSD的清晰的热实用程序。我们的初步数据也表明 与对照相比 参加两个独立队列的参与者。我们在多项研究中表明，imhtimentolone给药 提高下游Allopregnanolone水平5-10倍，因此可以作为前体负载 恢复PTSD中差异不足的异源水平的策略。此外，最近的神经影像学研究 证明异戊酮在与负相关的脑功能的调节中起作用 情感并增强与情绪调节过程相关的活动（Sripada，2013；优先级 沟通，生物精神病学）。此外，我们的临床前啮齿动物模型表明 捕食者压力暴露后，用imemintolone治疗可缓解啮齿动物的动画样行为。 最后，我们已经证明了轻度脑损伤的退伍军人的PTSD症状会改善 （MTBI）在Pilot RCT和MTBI较大的随访RCT中施用了Timhtolone之后。 这两项研究，随机分配给imextolone的退伍军人都显示了串行的标志性高度 治疗后的Allopregnanolone和Timhtolone水平。提高默认值的前体加载策略 因此，内源性异卵酮水平可能是PTSD的有效治疗方法。因此，我们建议： 1.）调查iNeptolone对伊拉克/阿富汗时代的PTSD的潜在有效性 进行timhtolone vs.安慰剂的RCT（主要端点CAPS-5更改； [90随机 参与者； n =每组45;] 8周的治疗时间）， 2.）确定untixtolone是否还可以改善同时发生的疼痛和抑郁症状（次要 终点简短的疼痛清单和汉密尔顿抑郁量表）， 3.）在基线和治疗后量化血清神经类固醇水平 下游神经类固醇代谢产物，例如Allopregnanolone（和其他生物标志物候选者 作为炎症标记）是治疗反应的预测指标。 拟议的RCT的结果可以为untixtolone的潜在有效性提供科学基础 在PTSD中，导致了一项关键的III期研究。临床和临床前数据支持可能的治疗 Timhtolone用于PTSD症状，疼痛障碍和抑郁症的效用，以及Timhtolone的实用性非常非常 迄今为止，资深人队的耐受性良好。因此，用Timhtolone治疗可能代表了新的承诺 在伊拉克/阿富汗时代的退伍军人中，干预PTSD的PTSD高效，廉价且安全。