Neuroactive Steroids and TBI in OEF/OIF Veterans

描述(由申请人提供)： 摘要：在持久自由行动/伊拉克自由行动(OEF/OIF)中，迫切需要有效的新疗法来治疗创伤性脑损伤(TBI)引起的认知症状退伍军人。轻度脑外伤在OEF/OIF退伍军人中非常常见，经常伴有创伤后应激障碍和抑郁症状，这两种疾病共存，导致残疾增加和生活质量下降。神经活性类固醇(NS)是治疗这些不同症状领域的有希望的靶点，因为这些分子中有许多表现出显著的神经保护和神经营养特性。生理盐水孕烯醇酮(PREG)是一个合理的治疗选择，因为它可以增强学习和记忆，也可以增加啮齿动物模型中的髓鞘形成。PRG是一种内源性化合物，在人脑中丰富，在中枢神经系统和其他组织(如肾上腺)中合成。此外，PREG的减少与抑郁症状有关，其硫酸盐衍生物增加乙酰胆碱的释放，促进神经发生。PREG也被代谢成别孕酮(Allo)，这是一种下游的抗焦虑药物NS，在创伤后应激障碍中减少。PRIG可以作为一种非处方药作为膳食补充剂，但使用这种药物治疗任何疾病的随机对照试验(RCT)非常少，到目前为止还没有在TBI中进行过。我们对OEF/OIF退伍军人进行的PREG试验性随机对照试验的初步数据表明，在执行功能(由伦敦塔测试评估)和创伤后应激障碍D群症状(如睡眠不良、易怒、愤怒爆发、难以集中、高度警惕和惊吓反应增加(由临床医生管理的创伤后应激障碍量表(CAPS)评估)方面，可能有认知改善。此外，治疗后神经类固醇的增加似乎预示着创伤后应激障碍症状的改善。因此，我们建议在OEF/OIF退伍军人中进行一项随机对照试验，以证实我们在轻度脑外伤中的初步发现。待检验的假设：1.)PREG代表了一种多目标治疗方法，它将改善患有轻度脑外伤(由伦敦塔测试评估)的OEF/OIF退伍军人的执行功能，并减少创伤后应激障碍D群症状(由CAPS评估)。2.)在患有轻度脑外伤的OEF/OIF退伍军人中使用PRIG将增加下游ALLO和其他GABA能NS水平，这代表了有助于其疗效的潜在机制和治疗反应的候选生物标志物。方法：1.)我们建议对140名患有轻度脑外伤(每组70人)的OEF/OIF退伍军人进行RCT，以伦敦塔测试(10个认知结果衡量标准)和PTSD簇D症状(10个行为结果衡量标准)来评估执行功能。2.)我们将使用最先进的基于质谱学的技术来确定基线和NS干预后的PREG和PREG代谢物水平，以评估服用PREG后NS的变化是否可以预测治疗反应，并代表这种治疗方法的潜在候选生物标记物。 公共卫生相关性： 目前，缺乏有效的药物来治疗轻度脑外伤的认知症状，这种疾病影响了大量的OEF/OIF退伍军人，并经常伴随有创伤后应激障碍和抑郁症状。如果我们的初步研究结果在拟议的随机对照试验中得到证实，那么使用神经类固醇孕烯醇酮的药物干预可能代表着一种针对这些症状的新的、有效的、耐受性良好的、可立即获得的治疗方法。一种治疗轻度脑外伤的新方法可能会改善遭受这种损伤的OEF/OIF退伍军人的功能结局和生活质量。

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. PUBLIC HEALTH RELEVANCE: There is currently a paucity of effective agents for the treatment of cognitive symptoms in mild TBI, a condition that impacts large numbers of OEF/OIF Veterans and is frequently accompanied by PTSD and depression symptoms. If our pilot study results are confirmed in the proposed randomized controlled trial, pharmacological intervention with the neurosteroid pregnenolone may represent a novel, effective, well-tolerated, and immediately accessible treatment for these symptoms. A new treatment for mild TBI could potentially lead to improved functional outcome and quality of life in OEF/OIF Veterans who have sustained this injury.