Neuroactive Steroids and TBI in OEF/OIF Veterans

描述（由申请人提供）： 总结：迫切需要有效的新疗法来治疗持久自由行动/伊拉克自由行动（OEF/OIF）退伍军人中创伤性脑损伤（TBI）引起的认知症状。轻度TBI在OEF/OIF退伍军人中非常常见，经常伴有PTSD和抑郁症状，这些并发症导致残疾增加和生活质量下降。神经活性类固醇（NS）是这些不同症状领域干预的有希望的靶点，因为许多这些分子表现出明显的神经保护和神经营养特性。NS双烯醇酮（PREG）是一种合乎逻辑的治疗选择，因为它可以增强学习和记忆，并增加啮齿动物模型中的髓鞘形成。PREG是一种内源性化合物，在人脑中富集，在中枢神经系统以及其他组织如肾上腺中合成。此外，PREG的减少与抑郁症状有关，其硫酸化衍生物增加乙酰胆碱释放并增强神经发生。PREG还代谢为别孕烯醇酮（allopregnanolone，ALLO），一种在PTSD中减少的抗焦虑下游NS。PREG可作为膳食补充剂在非处方药中使用，但使用这种药物的任何疾病的随机对照试验（RCT）非常少，迄今为止还没有在TBI中进行过。我们的初步数据来自PREG试点RCT，用于OEF/OIF退伍军人中轻度TBI，表明执行功能（通过伦敦塔测试评估）和PTSD D类症状（如睡眠不良、易怒、愤怒爆发、难以集中注意力、过度警惕和惊吓反应增加）（通过临床医生-管理员PTSD量表（CAPS）评估）可能有认知改善。此外，治疗后神经类固醇的增加似乎可以预测PTSD症状的改善。因此，我们建议在OEF/OIF退伍军人中进行RCT，以确认我们在轻度TBI中的初步发现。1.第一章：PREG代表了一种多靶向治疗方法，将改善OEF/OIF退伍军人轻度TBI的执行功能（由伦敦塔测试评估），并减少PTSD D组症状（由CAPS评估）。2.）的情况。在患有轻度TBI的OEF/OIF退伍军人中给予PREG将增加下游ALLO和其他GABA能NS水平，这代表了有助于其治疗疗效的潜在机制和治疗反应的候选生物标志物。方法：1.）我们提出了一项随机对照试验，在140名OEF/OIF退伍军人轻度TBI（每组70人），目标是执行功能评估的伦敦塔测试（10个认知结果测量）和PTSD D组症状（10个行为结果测量）。2.）的情况。我们将使用最先进的基于质谱的技术来确定基线时和NS干预后的PREG和PREG代谢物水平，以评估PREG给药后的NS变化是否预测治疗反应并代表这种治疗方法的潜在候选生物标志物。

DESCRIPTION (provided by applicant): SUMMARY: Effective new treatments for cognitive symptoms resulting from traumatic brain injury (TBI) in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans are urgently needed. Mild TBI is extremely common among OEF/OIF Veterans and frequently accompanied by PTSD and depression symptoms, co-occurring disorders that contribute to increased disability and decreased quality of life. Neuroactive steroids (NS) represent promising targets for intervention for these diverse symptom domains, since a number of these molecules demonstrate pronounced neuroprotective and neurotrophic properties. The NS pregnenolone (PREG) is a logical therapeutic option, since it enhances learning and memory and also increases myelination in rodent models. PREG is an endogenous compound that is enriched in human brain and synthesized in the central nervous system, as well as in other tissues such as the adrenal. Furthermore, decreases in PREG have been associated with depressive symptoms, and its sulfated derivative increases acetylcholine release and enhances neurogenesis. PREG is also metabolized to allopregnanolone (ALLO), an anxiolytic downstream NS that is decreased in PTSD. PREG is available over-the-counter as a dietary supplement, yet randomized controlled trials (RCT) for any disorder utilizing this agent are exceedingly few and none have been conducted in TBI to date. Our preliminary data from a PREG pilot RCT for mild TBI in OEF/OIF Veterans suggest possible cognitive improvement in executive functioning (as assessed by the Tower of London test) and PTSD Cluster D symptoms such as poor sleep, irritability, anger outbursts, difficulty concentrating, hypervigilance, and increased startle response (as assessed by the Clinician-Administered PTSD Scale, CAPS). Further, neurosteroid increases post-treatment appear to predict improvements in PTSD symptoms. We thus propose an RCT in OEF/OIF veterans to confirm our initial findings in mild TBI. HYPOTHESES TO BE TESTED: 1.) PREG represents a multi-targeted treatment approach that will improve executive functioning in OEF/OIF veterans with mild TBI (as assessed by the Tower of London test) and reduce PTSD Cluster D symptoms (as assessed by the CAPS). 2.) PREG administration in OEF/OIF veterans with mild TBI will increase downstream ALLO and other GABAergic NS levels, representing potential mechanisms contributing to its therapeutic efficacy and candidate biomarkers for treatment response. METHODS: 1.) We propose an RCT of adjunctive PREG in 140 OEF/OIF veterans with mild TBI (70 per group) targeting executive functioning as assessed by the Tower of London test (10 cognitive outcome measure) and PTSD Cluster D symptoms (10 behavioral outcome measure). 2.) We will use state-of-the art mass spectrometry-based techniques to determine PREG and PREG metabolite levels at baseline and following this NS intervention, to assess if NS alterations following PREG administration predict treatment response and represent potential candidate biomarkers for this therapeutic approach.