MIFEPRISTONE AFTER TRAUMA TO ENHANCE RESILIENCE (MATTER)

创伤后米非司酮增强恢复力（物质）

• 批准号: 7953718
• 负责人: ANTONIA S NEW
• 金额: $ 0.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953718
• 关键词: Animal Model; Animals; Anxiety Disorders; Applications Grants; Arousal; Blood Pressure; Charge; Chronic; Clinical; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Disease; Distress; Dose; Emotional; Etiology; Event; Exhibits; Exposure to; Extinction (Psychology); Functional disorder; Funding; Galvanic Skin Response; Goals; Grant; Heart Rate; Human; Individual; Institution; Intervention; Measures; Memory; Mental disorders; Mifepristone; Modeling; Pathway interactions; Patients; Pharmacological Treatment; Physiological; Play; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Psychopathology; Research; Research Personnel; Resources; Role; Selective Serotonin Reuptake Inhibitor; Societies; Source; Stress; Suicide attempt; Symptoms; Testing; Therapeutic; Time; Trauma; United States National Institutes of Health; attenuation; base; clinical remission; conditioned fear; cost; design; effective therapy; improved; meetings; novel; novel therapeutic intervention; psychotic depression; resilience; response

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目的主要目标是为一项旨在探索创伤后应激障碍患者有效治疗方法的赠款提案获得试点数据。 创伤后应激障碍（PTSD）是一种慢性和常见的焦虑症，伴随着暴露于巨大的创伤事件。大多数PTSD患者也符合其他精神疾病的标准，许多人企图自杀。尽管它对社会造成了巨大的损失，但对这种疾病的病因学或病理生理学知之甚少。虽然PTSD对药物治疗（如选择性5-羟色胺再摄取抑制剂（SSRIs））有一定的反应，但反应率很少超过60%，甚至更少的患者（20-30%）达到临床缓解。一旦出现精神病理学，PTSD通常与普遍和衰弱的症状有关，尽管进行了积极的治疗干预，这些症状仍然存在。因此，显然需要开发新的和改进的PTSD治疗剂。我们建议研究一种药物干预，旨在减少创伤的侵入性不必要的记忆，这通常是PTSD症状中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需要的记忆的重新整合。我们的干预是基于PTSD的恐惧条件反射模型，该模型认为创伤的侵入性，非自愿，重复性和生动的情感记忆是PTSD发展的关键。这种记忆是健康个体和PTSD患者对创伤事件的初始反应的典型组成部分。 然而，对于健康的个体来说，这些记忆的侵入性和情感负荷往往会随着时间的推移而逐渐减少，而患有PTSD的个体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，创伤事件的记忆更不可磨灭地编码，巩固，并永远重新巩固，这被认为是抑制正常的灭绝过程在健康个体中观察到的。 假设： 我们假设米非司酮可能代表一种药物治疗，与想象暴露的记忆再激活一起使用，可以减轻PTSD的症状。 我们还假设应激调节通路是开发PTSD新疗法的一个容易获得的基本靶点。因此，在这项资助中，我们建议对PTSD患者进行一项临床试验，使用想象暴露与米非司酮给药相结合。 具体假设： 我们的主要目的是确定米非司酮是否是一种有效的治疗方法，用于创伤后应激障碍相关的侵入性不想要的记忆时，在重新激活创伤记忆的情况下，中断该记忆的重新巩固。我们相信，我们处于一个独特的位置，以研究新的治疗方法的基础上，记忆再巩固中断治疗创伤后应激障碍。在西奈山（Cristina Alberini博士的实验室）进行的动物研究的结果在设计我们的临床试验中发挥了关键作用。 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PTSD，米非司酮在人类中耐受性良好，并已被广泛用于临床环境中作为堕胎药，并已被广泛研究用于治疗精神病性抑郁症。我们特别预测，两个剂量的米非司酮治疗的患者将显示出更大的减少主观痛苦和更少的生理唤醒，如测量的心率（HR），血压（BP）和皮肤电导（SC），而听创伤脚本一周后。