Treatment Implications of Trauma Memory Modulation for PTSD & Alcohol Dependence

创伤记忆调节对 PTSD 的治疗意义

• 批准号: 7816357
• 负责人: Michael E Saladin
• 金额: $ 39.04万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7816357
• 关键词: Address; Adrenergic Agents; Adrenergic Antagonists; Aftercare; Alcohol consumption; Alcohol dependence; Alcoholic Beverages; Alcohols; Amylases; Anti-Anxiety Agents; Anxiety; Area; Arousal; Basic Science; Behavior; Behavioral; Center for Translational Science Activities; Classification; Clinical; Clinical Sciences; Clinical Trials; Comorbidity; Consumption; Crime; Cues; Dependence; Development; Disease; Distress; Double-Blind Method; Elements; Emotional; Emotions; Event; Exposure to; Fright; Future; Gold; Heart Rate; Human; Hydrocortisone; Imagery; Individual; Inpatients; Intervention; Investigation; Laboratories; Lead; Link; Literature; Measures; Mediating; Medical; Memory; Mental Health; Methodology; Motivation; Nature; Negative Reinforcements; Neurosciences; Outcome; Participant; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Physiological; Placebos; Population; Post-Traumatic Stress Disorders; Prevention; Procedures; Process; Propranolol; RNA Interference; Randomized; Reporting; Research; Retrieval; Risk; Role; Salivary; Schedule; Self Medication; Severities; Smell Perception; Source; South Carolina; Staging; Stress; Substance Use Disorder; Symptoms; System; Testing; Therapeutic; Therapeutic Effect; Time; Translational Research; Trauma; Treatment outcome; Universities; Vision; adrenergic; alcohol craving; alcohol cue; alcohol exposure; alcohol misuse; alcoholism therapy; analog; attenuation; base; behavior change; biological adaptation to stress; craving; cue reactivity; drinking; drinking behavior; dual diagnosis; effective therapy; emotional distress; follow-up; indexing; innovation; member; memory process; memory recall; memory retrieval; psychosocial; response; treatment effect

DESCRIPTION (provided by applicant): This application, titled "Treatment Implications of Trauma Memory Modulation for PTSD & Alcohol Dependence", primarily addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-AA-104: PTSD and Alcohol Dependence; it secondarily addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-AA-105: Mechanisms of Behavior Change. Introduction: The co-occurrence of posttraumatic stress disorder (PTSD) and alcohol dependence (AD) is one of the most frequently occurring and debilitating mental health comorbidities. Several perspectives on the nature of the relationship between these disorders have been forwarded and one of the most widely recognized conceptualizations holds that PTSD sufferers often use alcohol as a means of dampening the emotional distress associated with PTSD. Over time, the alcohol use escalates into AD. From a behavior analytic perspective, the mechanism of action for the development of pathological drinking is the escape or avoidance it provides from the emotional distress of PTSD. An important implication of this conceptual understanding of the PTSD and AD interrelationship is that effective treatment of PTSD should yield significant reductions in motivation to drink and drinking behavior. There is a developing clinical literature that supports this assumption and the present study will contribute further to it by examining the impact of the ¿-adrenergic blocker propranolol on emotional distress, craving and other responses to trauma- and alcohol-related cues and on alcohol use and PTSD symptoms. The impetus for the proposed proof-of-concept translational research comes from both basic science and a developing clinical science literature that suggests the strategic administration of the ¿-adrenergic blocker propranolol after recalling the memory of a fear-inducing event(s) can result in an attenuation of the negative emotion and arousal of memories for the fear-inducing events. This effect is presumed to result from propranolol's ability to quell the adrenergic activity involved in the reconsolidation of memories for the fear-inducing event(s) after they are recalled. Approach: This study will employ 50 PTSD/AD comorbid participants to investigate the effects of propranolol vs. placebo, administered immediately after exposure to scripted imagery of a crime-related trauma, on the subjective, physiological and stress responses occurring during a subsequent test session consisting of exposure to the trauma scripted imagery and also the sight and smell of the participant's preferred alcoholic beverage. Participants will be randomly assigned to receive either 40 mg of propranolol or placebo (double-blinded) immediately after the first of two trauma-imagery cue exposure sessions scheduled to occur on consecutive days of an inpatient stay at MUSC's Clinical and Translational Research Center (CTRC). The first session will serve as a retrieval session during which trauma script-imagery cue exposure will elicit retrieval and reconsolidation of memories of the participant's index trauma; the second session will be a test session to examine the potential modulatory role of propranolol on the reconsolidated memories putatively elicited during the retrieval session. It is posited that changes in craving, physiological and/or stress reactivity during the test session will reflect propranolol's effects on memory reconsolidation processes elicited by trauma cue exposure in the retrieval session. Measures of subjective craving, emotion, physiological arousal (e.g., heart rate) and stress (e.g., cortisol) reactivity will be obtained at baseline, during and after the trauma cue presentation in session 1 and the trauma and alcohol cue presentations in the test session. The durability of any observed treatment effects will be assessed in a follow-up laboratory session performed 14 days following discharge from the inpatient stay and which will be identical to the test session. Treatment effects on both alcohol use during preceding 14 days and severity of PTSD symptoms will also be assessed. Implications: This research will directly address the challenge area of translational science in PTSD and AD by extending basic neuroscience findings on memory modulation to a human laboratory proof-of-concept analog with substantial potential clinical benefit for members of this at risk, dually afflicted population. Positive findings could energize future studies to define the optimal parameters under which propranolol could be used in prolonged exposure therapy (PTSD treatment gold standard) to enhance reduction of both PTSD-related anxiety and drinking. Additionally, the clinical benefits of cue exposure therapy for AD (i.e., systematic exposure to alcohol-related cues) might be enhanced by using propranolol to interfere with memory reconsolidation of the cue->alcohol associations that subserve craving for alcohol. In fact, both types of exposure therapy might be synergistically enhanced by strategic application of propranolol following retrieval of both trauma-memories and memories for cue->alcohol associations. The proposed research will also address the topic area of mechanisms of behavior change within the challenge area of behavior, behavioral change, and prevention by a) contributing to a literature base that suggests PTSD has a primary causal role in PTSD/AD comorbidity because PTSD is the source of the aversive emotion/arousal which, when dampened by alcohol use, provides the negative reinforcement that promotes further use and risk of dependence, and b) empirically assessing the role of the ¿-adrenergic system in the trauma-related memory processes that mediate the interface between PTSD and AD. This innovative translational research endeavor will employ an established cue reactivity/exposure methodology to assess the therapeutic potential of an untested and potentially promising adjunctive pharmacotherapy for one of the most prevalent and intractable mental health comorbidities, PTSD and alcohol dependence. It is hoped the results of this proof-of-concept investigation will lead to the development of a pharmacological treatment element that will enhance the outcomes of exposure-based treatment for individuals with PTSD and alcohol dependence and be generalizable to other co-occurring substance use disorders.

描述（由申请人提供）：该申请题为“创伤记忆调节对创伤后应激障碍和酒精依赖的治疗意义”，主要涉及广泛的挑战领域（15）转化科学和具体挑战主题，15- aa -104：创伤后应激障碍和酒精依赖；其次，它涉及广泛的挑战领域（01）行为，行为改变和预防以及具体的挑战主题，01- aa -105：行为改变的机制。简介：创伤后应激障碍（PTSD）和酒精依赖（AD）的共存是最常见和最衰弱的精神健康合并症之一。关于这些疾病之间关系的本质已经提出了几个观点，其中一个最广泛认可的概念认为，PTSD患者经常使用酒精作为抑制与PTSD相关的情绪困扰的一种手段。随着时间的推移，酒精的使用升级为阿尔茨海默病。从行为分析的角度来看，病理性饮酒发展的作用机制是其提供了对PTSD情绪困扰的逃避或回避。这种对PTSD和AD相互关系的概念性理解的一个重要含义是，PTSD的有效治疗应该显著减少饮酒动机和饮酒行为。有越来越多的临床文献支持这一假设，本研究将进一步研究肾上腺素受体阻滞剂心得安对情绪困扰、渴望和其他创伤和酒精相关线索的反应的影响，以及对酒精使用和创伤后应激障碍症状的影响。提出的概念验证转化研究的动力来自基础科学和发展中的临床科学文献，这些文献表明，在回忆引起恐惧的事件的记忆后，策略性地使用肾上腺素受体阻滞剂心得安可以导致负面情绪的衰减和对引起恐惧的事件的记忆的唤醒。这种效果被认为是由于心得安能够抑制在回忆起引起恐惧的事件后重新巩固记忆的肾上腺素能活动。方法：本研究将采用50名PTSD/AD共病参与者，调查在接触与犯罪相关的创伤脚本图像后立即给予心得安与安慰剂，对随后的测试过程中发生的主观、生理和应激反应的影响，包括暴露于创伤脚本图像以及参与者喜欢的酒精饮料的视觉和气味。在连续几天的MUSC临床与转化研究中心（CTRC）的住院治疗中，参与者将被随机分配接受40毫克心得安或安慰剂（双盲）。第一阶段为记忆提取阶段，在此阶段，创伤脚本-意象提示暴露将诱发被试对创伤索引记忆的提取和再巩固；第二部分将是一个测试部分，研究心得安对提取过程中推断的重新巩固记忆的潜在调节作用。我们假设，在测试过程中，渴望、生理和/或应激反应的变化将反映心得安对检索过程中创伤线索暴露引发的记忆再巩固过程的影响。主观渴望、情绪、生理唤醒（如心率）和压力（如皮质醇）反应性的测量将在基线、在第1阶段的创伤提示呈现期间和之后以及在测试阶段的创伤和酒精提示呈现期间进行。任何观察到的治疗效果的持久性将在出院后14天进行的后续实验室测试中进行评估，该测试将与测试相同。还将评估治疗对前14天酒精使用和创伤后应激障碍症状严重程度的影响。意义：本研究通过将记忆调节的基础神经科学发现扩展到人类实验室概念验证模拟，将直接解决创伤后应激障碍和阿尔茨海默氏症转化科学的挑战领域，为这些处于危险中的双重折磨人群提供巨大的潜在临床益处。积极的研究结果可以为未来的研究提供动力，以确定最佳参数，在此参数下，心得安可以用于延长暴露治疗（PTSD治疗金标准），以增强减少PTSD相关焦虑和饮酒。此外，提示暴露治疗AD（即系统暴露于酒精相关提示）的临床益处可能会通过使用心得安来干扰诱发酒精渴望的提示->酒精关联的记忆再巩固而得到增强。事实上，这两种暴露疗法都可以通过在创伤记忆和cue- bbb -酒精关联的记忆检索后策略性地应用心得安来协同增强。拟议的研究还将在行为、行为改变和预防的挑战领域内解决行为改变机制的主题领域，通过a)提供文献基础，表明PTSD在PTSD/AD合并症中具有主要的因果作用，因为PTSD是厌恶情绪/觉醒的来源，当酒精使用抑制时，提供负面强化，促进进一步使用和依赖风险；b)实证评估肾上腺素能系统在创伤相关记忆过程中的作用，该过程介导PTSD和AD之间的界面。这项创新的转化研究努力将采用一种已建立的线索反应/暴露方法来评估一种未经测试但有潜力的辅助药物治疗对最普遍和最棘手的精神健康合并症之一PTSD和酒精依赖的治疗潜力。希望这项概念验证调查的结果将导致药理学治疗元素的发展，从而提高PTSD和酒精依赖个体的暴露治疗结果，并推广到其他共同发生的物质使用障碍。