Extinction of Fear Memories with Glucocorticoids in Veterans with PTSD

描述（由申请人提供）： 摘要有很少系统的研究，对人类的重点是改变潜在的创伤记忆，一旦创伤后应激障碍已经建立。拟议的项目是一个翻译研究的基础上，我们的工作与动物模型的创伤后应激障碍，其中coricosterone增强灭绝的背景恐惧记忆。该研究设计是一项双盲随机对照临床试验，涉及88名OEF/OIF退伍军人与战斗相关的PTSD。我们计划将多种恐惧记忆再激活与口服糖皮质激素或安慰剂配对，使用脚本化的图像技术。参与者将在干预后1个月、3个月和6个月接受随访，以测量预期效果的持续时间。结果测量将包括PTSD症状严重程度、抑郁症状严重程度和生理测量。具体目标/假设：目标1：研究创伤记忆再激活后糖皮质激素给药对患有战斗相关PTSD的退伍军人精神症状的影响。 具体的假设进行测试：（A）受试者接受外源性糖皮质激素创伤记忆再激活后将表现出较少的PTSD和抑郁症状一周后，相比那些谁接受安慰剂创伤记忆再激活后。 (B)糖皮质激素减少效应将是累积的;也就是说，减少将持续，并且进一步的再活化后糖皮质激素施用将进一步减少症状。 (C)与接受安慰剂的受试者相比，接受外源性糖皮质激素的受试者的PTSD和抑郁症状的减轻将持续1、3和6个月。目标二：检验创伤记忆再激活后糖皮质激素给药对退伍军人个人战斗记忆的生理反应的影响。 (D)与创伤记忆再激活后接受安慰剂的受试者相比，在创伤记忆再激活后接受外源性糖皮质激素的受试者将在一周后表现出降低的生理反应。 (E)与心理测量一样，生理测量的抑制将表现出随时间的持续性和随后的再活化后糖皮质激素给药的累积。 公共卫生相关性： 由于持久自由行动/伊拉克自由行动（OEF/OIF）的部署，与战斗有关的创伤后应激障碍（PTSD）的患病率正在增加，OEF/OIF服务的PTSD的估计风险为11%至18%。创伤后应激障碍的特征是由于暴露于创伤事件而以不想要的图像、噩梦和闪回的形式出现的侵入性记忆。这些记忆与强烈的痛苦有关，涉及对创伤相关刺激的过度生理和心理反应。目前的研究工作集中在探索与PTSD相关的潜在神经化学变化，以预防或治疗相关的创伤记忆。到目前为止，很少有系统的研究集中在一旦PTSD建立后改变潜在的创伤记忆。记忆可以以各种方式改变，包括干扰已建立的恐惧记忆的重新巩固或通过消失，其中与创伤相关的新记忆形成。传统的行为疗法称为暴露疗法，使用了我们在拟议研究中使用的相同的灭绝过程。虽然有效，但由于治疗提供者和接受者所感知的障碍，这种疗法没有被广泛使用。这项研究是一种治疗创伤后应激障碍的新方法，将恐惧记忆消退的动物模型应用于人类，通过将创伤记忆的重新激活与糖皮质激素配对来增强与战斗相关的潜在创伤记忆的消退。我们将通过观察退伍军人的生理反应以及自我报告的创伤后应激障碍和抑郁症的精神症状以及临床医生对创伤后应激障碍的评估来衡量他们对自己战斗创伤剧本的反应。这项研究的结果可能提供一种独特，廉价和快速的方法来治疗创伤后应激障碍，并为开发其他专门针对消除与战斗有关的恐惧记忆的药物奠定基础。虽然我们不是在开发一种新型的暴露疗法，因为我们使用的是与传统暴露疗法相同的消光原理，但这项研究提供的信息将为未来结合药物疗法和行为疗法的研究奠定基础。从这项研究中获得的信息不仅适用于患有与战斗有关的创伤后应激障碍的退伍军人，而且适用于任何遭受任何类型创伤的侵入性记忆的人。

DESCRIPTION (provided by applicant): Abstract There are very few systematic studies on humans that focus on changing the underlying traumatic memory once PTSD has been established. The proposed project is a translational study based on our work with animal models of PTSD in which coricosterone augmented extinction of contextual fear memories. The study design is a double-blind randomized controlled clinical trial involving eighty-eight OEF/OIF veterans with combat-related PTSD. We plan to pair multiple fear memory reactivations, using a scripted imagery technique, with an oral glucocorticoid or placebo. Participants will be followed at 1, 3, and 6 months post intervention to measure the longevity of the expected effect. Outcome measures will include PTSD symptom severity, depression symptoms severity, and physiological measures. Specific Aims/Hypothesis: Aim 1: Examine the effects of glucocorticoid administration following traumatic memory reactivation on psychiatric symptoms in veterans with combat-related PTSD. Specific hypotheses to be tested: (A) Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate fewer PTSD and depression symptoms one week later, compared to those who receive a placebo after traumatic memory reactivation. (B) The glucocorticoid reduction effects will be cumulative; that is, reduction will persist, and further post- reactivation glucocorticoid administration will further reduce symptoms. (C) Decreases in PTSD and depression symptoms will persist at 1, 3, and 6 months for subjects receiving an exogenous glucocorticoid compared to those subjects receiving placebo. Aim 2: Examine the effects of glucocorticoid administration following traumatic memory reactivation on physiological responses to veteran's personal combat memories. (D) Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate decreased physiological responses one week later, compared to those who receive a placebo after traumatic memory reactivation. (E) As with the psychological measures, suppression of the physiological measures will demonstrate both persistence over time and accumulation with subsequent post-reactivation glucocorticoid administration. PUBLIC HEALTH RELEVANCE: Project Narrative Prevalence rates of combat-related post-traumatic stress disorder (PTSD) are increasing because of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) deployments, with the estimated risk for PTSD from OEF/OIF service ranging from 11% to 18%. PTSD is characterized by intrusive memories in the form of unwanted images, nightmares, and flashbacks as the result of being exposed to a traumatic event. These memories are associated with intense distress and involve excessive physiological and psychological responses to trauma related stimuli. Current research efforts are focused on exploring the underlying neurochemical changes associated with PTSD in an effort to prevent or treat associated traumatic memories. To date, there have been very few systematic studies on humans that focus on changing the underlying traumatic memories once PTSD has been established. Memory can be changed in various ways including interference with reconsolidation of an established fear memory or by extinction, in which new memories associated with the trauma are formed. A traditional behavior therapy called exposure therapy uses the same process of extinction that we are using in the proposed study. Although effective, this therapy is not widely used because of barriers perceived by the providers of therapy as well as the recipients. The proposed study is a novel approach to treatment for established PTSD, applying an animal model of fear memory extinction to humans, to augment the extinction of underlying traumatic memories related to combat by pairing reactivation of a traumatic memory with a glucocorticoid. We will measure veterans' responses to scripts of their own combat traumas by looking at their physiological responses as well as self-reported psychiatric symptoms of PTSD and depression as well as clinician rated assessments of PTSD. The results of this study may offer a unique, inexpensive, and rapid method to treat PTSD, as well as lay the groundwork for the development of other pharmacotherapeutic agents that specifically target the extinction of combat-related fear memories. Although we are not developing a new type of exposure therapy, because we are using the same extinction principles as traditional exposure therapy uses, the information provided by this study will lay the groundwork for future studies combining pharmacotherapy and behavior therapy. The information gained from this study will be applicable not only to veterans who have combat-related PTSD, but to any individual with suffering intrusive memories from any type of trauma.