MIFEPRISTONE AFTER TRAUMA TO ENHANCE RESILIENCE (MATTER)

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的主要目标是为一项赠款提案获得试点数据，该提案旨在探索对患有创伤后应激障碍的个人进行有效治疗。创伤后应激障碍(PTSD)是一种慢性和常见的焦虑症，发生在巨大的创伤事件之后。大多数PTSD患者也符合其他精神障碍的标准，许多人试图自杀。尽管它给社会带来了巨大的代价，但人们对这种疾病的病因或病理生理学知之甚少。虽然创伤后应激障碍对选择性5-羟色胺再摄取抑制剂(SSRIs)等药物治疗有一定的反应，但应答率很少超过60%，更少的患者(20%-30%)获得临床缓解。一旦出现精神病理学，创伤后应激障碍通常与普遍和虚弱的症状有关，尽管进行了积极的治疗干预，这些症状仍然存在。因此，显然有必要开发新的和改进的疗法来治疗创伤后应激障碍。我们建议研究一种药物干预措施，旨在减少创伤的侵入性有害记忆，这通常是创伤后应激障碍症状最严重和最令人不安的组成部分。我们建议通过使用米非司酮来中断不想要的记忆的重新巩固来做到这一点。我们的干预是基于创伤后应激障碍的恐惧条件作用模型，该模型认为侵入性的、非自愿的、重复的、生动的、充满情感负担的创伤记忆是创伤后应激障碍发展的关键。无论是健康人还是创伤后应激障碍患者，这种记忆都是创伤事件初始反应的典型组成部分。然而，对于健康的人来说，这些记忆的侵入性和情感电荷往往会随着时间的推移而逐渐减少，而患有创伤后应激障碍的人则不会表现出任何症状的减弱。创伤记忆持续存在的一个潜在原因可能是，在脆弱的个体中，创伤事件的记忆更难以消除地编码、巩固和永久地重新巩固，这被认为抑制了在健康个体中观察到的正常的灭绝过程。 假设： 我们推测，米非司酮可能代表了一种药物治疗，与记忆重新激活和想象暴露一起使用，可能会缓解创伤后应激障碍的症状。我们还假设，压力调节通路是发展创伤后应激障碍新治疗方法的一个容易获得的基本靶点。因此，在这笔赠款中，我们建议对PTSD患者进行一项临床试验，在服用米非司酮的同时，使用想象暴露。 具体假设： 我们的主要目标是确定米非司酮是否是一种有效的治疗PTSD相关的侵入性有害记忆的方法，当用于重新激活创伤性记忆以中断该记忆的重新巩固时。我们相信，我们处于一个独特的位置，可以研究基于记忆再巩固中断的治疗PTSD的新的治疗方法。西奈山(克里斯蒂娜·阿尔贝里尼博士的实验室)正在进行的动物研究的结果对我们的临床试验的设计起到了关键作用。 临床试验： 假设1：米非司酮在动物模型中破坏创伤记忆的重新巩固，因此，我们将测试米非司酮是否有效治疗创伤后应激障碍。米非司酮是一种在人类中耐受性很好的药物，已在临床环境中广泛用作人工流产剂，并已被广泛研究用于治疗精神病性抑郁症。我们特别预测，接受两种剂量米非司酮治疗的患者在一周后听取创伤脚本时，主观痛苦的下降幅度更大，生理唤醒程度更低，这是通过心率(HR)、血压(BP)和皮肤电导(SC)来衡量的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The principal goal of this project is to obtain pilot data for a grant proposal aimed at exploring effective treatments for individuals suffering from PTSD. Post-traumatic stress disorder (PTSD) is a chronic and common anxiety disorder that follows exposure to an overwhelming traumatic event. The majority of patients with PTSD also meet criteria for other psychiatric disorders and many attempt suicide. Despite its substantial costs to society, little is known about the etiology or pathophysiology of this disorder. While PTSD is somewhat responsive to pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs), response rates rarely exceed 60%, and even fewer patients (20-30%) achieve clinical remission. Once psychopathology emerges, PTSD is often associated with pervasive and debilitating symptoms that persist despite aggressive treatment interventions. Thus, there is a clear need to develop novel and improved therapeutics for PTSD. We propose to study a pharmacological intervention that aims to decrease the intrusive unwanted memories of the trauma, which are often the most severe and troubling component of PTSD symptoms. We propose to do this by using mifepristone to interrupt reconsolidation of the unwanted memories. Our intervention is based on the fear-conditioning model of PTSD that considers intrusive, involuntary, repetitive, and vivid emotionally-laden memories of a trauma as pivotal to the development of PTSD. Such memories are a typical component of the initial response to traumatic events in both healthy individuals and patients with PTSD. For healthy individuals, however, the intrusive quality and emotional charge of these memories tends to gradually diminish over time, whereas individuals with PTSD do not exhibit any attenuation in symptoms. One potential reason for the persistence of traumatic memories may be that in vulnerable individuals, memories of traumatic events are more indelibly encoded, consolidated, and perpetually reconsolidated, which is thought to inhibit the normal process of extinction observed in healthy individuals. Hypothesis: We hypothesize that mifepristone may represent a pharmacological treatment that, used in tandem with memory reactivation with imaginal exposure, may alleviate symptoms of PTSD. We also hypothesize that the stress modulatory pathway is an easily accessible and fundamental target for the development of new treatments for PTSD. Therefore, in this grant, we propose to conduct a clinical trials of PTSD patients using imaginal exposure in tandem with mifepristone administration. Specific hypotheses: Our primary objective is to determine if mifepristone is an effective treatment for the intrusive unwanted memories associated with PTSD when used in the context of reactivating a traumatic memory to interrupt reconsolidation of that memory. We believe that we are in a unique position to investigate novel therapeutic approaches based on memory reconsolidation disruption for the treatment of PTSD. The results from animal studies underway at Mount Sinai (In Dr. Cristina Alberini's lab) played a critical role in designing our clinical trial. Clinical Trial: Hypothesis 1: Mifepristone disrupts the reconsolidation of traumatic memories in an animal model, therefore, we will test whether mifepristone, which is a well tolerated in humans and have been extensively used in clinical settings as an abortofacient, and has been studied extensively in the treatment of psychotic depression, is effective in treating PTSD. We specifically predict that patients treated with two doses of mifepristone will show a greater decrease in subjective distress and less physiological arousal as measured by heart rate (HR), blood pressure (BP) and skin conductance (SC) while the listening to the trauma scripts one week later.