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: 7944190
• 负责人: Michael E Saladin
• 金额: $ 40.81万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944190
• 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; 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）：本申请题为“创伤记忆调节对 PTSD 和酒精依赖的治疗影响”，主要解决广泛的挑战领域 (15) 转化科学和具体挑战主题，15-AA-104：PTSD 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）同时发生是最常发生且使人衰弱的心理健康合并症之一。关于这些疾病之间关系的性质已经提出了几种观点，其中最广泛认可的概念之一认为，创伤后应激障碍患者经常使用酒精作为减轻与创伤后应激障碍相关的情绪困扰的一种手段。随着时间的推移，饮酒会升级为AD。从行为分析的角度来看，病理性饮酒的作用机制是逃避或避免创伤后应激障碍（PTSD）的情绪困扰。对 PTSD 和 AD 相互关系的概念性理解的一个重要含义是，有效治疗 PTSD 应该会显着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，本研究将通过检查β-肾上腺素能阻滞剂普萘洛尔对情绪困扰、渴望和对创伤和酒精相关线索的其他反应以及对饮酒和创伤后应激障碍症状的影响，进一步推动这一假设。所提出的概念验证转化研究的动力来自于基础科学和不断发展的临床科学文献，这些文献表明，在回忆起恐惧诱发事件的记忆后，战略性地施用β-肾上腺素能阻滞剂普萘洛尔可以导致负面情绪的减弱和对恐惧诱发事件的记忆的唤醒。据推测，这种效应是由于普萘洛尔能够抑制肾上腺素能活动，而肾上腺素能活动参与回忆起恐惧诱发事件后的记忆重新巩固过程。方法：本研究将雇用 50 名患有 PTSD/AD 共病的参与者来调查普萘洛尔与安慰剂的影响，在暴露于犯罪相关创伤的脚本图像后立即服用普萘洛尔，对在随后的测试过程中发生的主观、生理和压力反应产生影响，测试过程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。参与者将被随机分配接受 40 毫克普萘洛尔或安慰剂（双盲），在安排在 MUSC 临床和转化研究中心 (CTRC) 住院连续几天进行的两次创伤意象线索暴露课程中的第一次课程后，立即接受 40 毫克普萘洛尔或安慰剂（双盲）。第一个会话将作为检索会话，在此期间，创伤脚本图像提示暴露将引发参与者索引创伤记忆的检索和重新巩固；第二次会议将是一个测试会议，以检查普萘洛尔对检索期间可能引发的重新巩固记忆的潜在调节作用。假设测试过程中渴望、生理和/或压力反应性的变化将反映普萘洛尔对检索过程中创伤线索暴露引起的记忆再巩固过程的影响。主观渴望、情绪、生理唤醒（例如心率）和压力（例如皮质醇）反应性的测量将在基线、第 1 节中的创伤提示呈现期间和之后以及测试会话中的创伤和酒精提示呈现期间和之后获得。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会议中进行评估，该会议与测试会议相同。还将评估对前 14 天内饮酒和 PTSD 症状严重程度的治疗效果。意义：这项研究将通过将记忆调节的基本神经科学发现扩展到人类实验室概念验证类似物，直接解决创伤后应激障碍（PTSD）和阿尔茨海默病（AD）转化科学的挑战领域，为高危、双重折磨的人群带来巨大的潜在临床益处。积极的发现可能会激发未来的研究，以确定普萘洛尔可用于长期暴露疗法（PTSD 治疗金标准）的最佳参数，以增强减少 PTSD 相关的焦虑和饮酒。此外，通过使用普萘洛尔干扰线索->酒精关联的记忆重新巩固（促进对酒精的渴望），线索暴露疗法（即系统性地暴露于与酒精相关的线索）可能会增强AD的线索暴露疗法的临床益处。事实上，在检索创伤记忆和提示->酒精关联记忆后，策略性应用普萘洛尔可能会协同增强两种类型的暴露疗法。拟议的研究还将解决行为、行为改变和预防挑战领域内的行为改变机制这一主题领域，方法是：a) 建立文献基础，表明 PTSD 在 PTSD/AD 合并症中具有主要因果作用，因为 PTSD 是厌恶情绪/唤醒的根源，当酒精使用抑制时，它会提供负面强化，促进进一步使用和依赖风险，b) 实证评估 ¿-肾上腺素能系统在介导 PTSD 和 AD 之间界面的创伤相关记忆过程中的作用。这项创新的转化研究工作将采用既定的线索反应/暴露方法来评估未经测试且有潜力的辅助药物疗法对最普遍和最棘手的心理健康合并症之一——创伤后应激障碍（PTSD）和酒精依赖的治疗潜力。希望这一概念验证研究的结果将导致药物治疗要素的开发，该药物治疗要素将增强针对患有创伤后应激障碍和酒精依赖的个体的基于暴露的治疗的结果，并可推广到其他同时发生的物质使用障碍。