Target Engagement and Clinical Symptom Change with a FAAH Inhibitor for Posttraumatic Stress Disorder

FAAH 抑制剂治疗创伤后应激障碍的目标参与度和临床症状变化

• 批准号: 10356333
• 负责人: MARTIN P. PAULUS
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2022-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356333
• 关键词: Adverse effects; Affect; Affective; Amygdaloid structure; Anger; Anti-Anxiety Agents; Anxiety; Arousal; Attenuated; Behavior Therapy; Behavioral; Brain; Brain region; Clinical; Clinical Trials; Cues; Data; Diagnostic; Disease; Dose; Double-Blind Method; Drug usage; Emotions; Endocannabinoids; Exposure to; Extinction (Psychology); FAAH inhibitor; Face Processing; Fright; Functional disorder; Future; Goals; Heterogeneity; Human; Image; Individual; Intervention; Laboratories; Link; Measures; Mental disorders; Modeling; Motivation; National Institute of Mental Health; Negative Valence; Neurobiology; Outcome; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Placebos; Plasma; Post-Traumatic Stress Disorders; Process; Randomized; Randomized Controlled Trials; Research Domain Criteria; Role; Safety; Sampling; Services; Signal Transduction; Site; Social Anxiety Disorder; Standardization; Stimulus; Stress; Symptoms; System; Testing; Therapeutic; Trauma; anandamide; attenuation; base; biological adaptation to stress; clinically significant; conditioned fear; disorder control; effective therapy; endogenous cannabinoid system; executive function; experience; fatty acid amide hydrolase; healthy volunteer; neural circuit; novel; placebo controlled trial; post-traumatic symptoms; pre-clinical research; primary endpoint; primary outcome; relating to nervous system; response; secondary outcome; stimulus processing; stress related disorder; stressor; tool; treatment duration

There is an urgent need for mechanism-based novel pharmacological approaches to treat trauma-related disorders such as posttraumatic stress disorder (PTSD), as 40-60% of patients do not respond to current pharmacological or behavioral therapies. High heterogeneity of symptom patterns and trajectories in PTSD suggests alterations in multiple neurobiological systems. Negative valence processing and arousal in response to affective stimuli (AS) and conditioned fear stimuli (CFS) have been proposed as translational multi-level processes within the NIMH Research Domain Criteria (RDoC) that are relevant to trauma and other stress- related disorders. Reliable disruptions have been observed in the functioning of brain systems that regulate AS and CFS reactivity in individuals with PTSD. A class of medications acting on the endocannabinoid system, inhibitors of fatty acid amide hydrolase (FAAHi) are hypothesized, based on a large body of preclinical research, to modulate activity in AS and CFS regulatory systems (e.g., enhancement of fear extinction). FAAHi may therefore offer clinical benefit for patients with PTSD—and trans-diagnostically for other anxiety and stressor-related conditions—who show consistent dysfunction in those circuits. The proposed project evaluates the ability of a FAAHi developed and characterized by Janssen, JNJ-42165279, to engage systems that regulate AS (e.g., amygdala activation during emotion face processing; primary target) and CFS (e.g., fear extinction; secondary target) in the service of reducing hyperarousal (primary clinical outcome) and re- experiencing symptoms (secondary outcome). The project aims are supported by extensive preliminary data in healthy humans indicating that JNJ-42165279 dose-dependently inhibits FAAH as evidenced by dose- dependent increases in plasma anandamide; saturation of FAAH (>80%) is achieved at doses that have no clinically significant adverse effects in humans; and once steady state is achieved, AS and CFS reactivity is attenuated. Based on these observations, we propose a two-site, randomized double-blind fixed dose (25 mg BID) placebo-controlled trial of JNJ-42165279 in N=150 patients with PTSD. Aim 1 seeks to confirm target engagement through reduced amygdala activation during AS processing (primary target) as well as reduced physiological and subjective CFS reactivity during exposure to a trauma narrative and fear extinction recall (secondary targets) from baseline to steady state (5 days of treatment). Aim 2 will test the hypothesis that attenuation of amygdala reactivity from baseline to Day 5 in the JNJ-42165279 group will be associated with symptom change from baseline to week 8. We will explore links between changes in secondary measures of target engagement (trauma-specific arousal reactivity and fear extinction recall) and changes in hyperarousal and re-experiencing symptoms at 8 weeks. If these predictions are confirmed, this project will support future studies of FAAHi (and other drugs with similar mechanisms of action) in definitive, larger randomized controlled trials for PTSD and other anxiety and stressor-related conditions with dysfunction in AS and CFS domains.

迫切需要基于机制的新药理学方法来治疗创伤相关的 创伤后应激障碍 (PTSD) 等疾病，因为 40-60% 的患者对当前治疗没有反应 药物或行为疗法。 PTSD 症状模式和轨迹的高度异质性 表明多个神经生物系统发生改变。负价处理和唤醒反应 情感刺激（AS）和条件性恐惧刺激（CFS）被提议作为转化多层次 NIMH 研究领域标准 (RDoC) 内与创伤和其他压力相关的流程 相关疾病。在调节 AS 的大脑系统的功能中观察到了可靠的破坏 PTSD 患者的 CFS 反应性。一类作用于内源性大麻素系统的药物， 基于大量临床前研究，假设脂肪酸酰胺水解酶 (FAAHi) 抑制剂 研究，调节 AS 和 CFS 监管系统的活动（例如，增强恐惧消退）。美国联邦航空管理局 因此，可能为 PTSD 患者提供临床益处，并为其他焦虑症和抑郁症患者提供跨诊断的帮助。 与压力源相关的病症——这些回路表现出持续的功能障碍。拟议项目评估 由 Janssen JNJ-42165279 开发和表征的 FAAHi 能够参与以下系统： 调节 AS（例如，情绪面部处理过程中杏仁核的激活；主要目标）和 CFS（例如，恐惧） 灭绝；次要目标）以减少过度警觉（主要临床结果）并重新 出现症状（次要结果）。该项目的目标得到了广泛的初步数据的支持 健康人表明 JNJ-42165279 剂量依赖性地抑制 FAAH，如剂量所证明的 血浆anandamide的依赖性增加； FAAH 饱和 (>80%) 是在没有剂量的情况下实现的 对人类产生临床上显着的不良影响；一旦达到稳定状态，AS 和 CFS 反应性就会 减弱了。基于这些观察，我们提出了一个两中心、随机双盲固定剂量（25 mg BID）在 N=150 名 PTSD 患者中进行的 JNJ-42165279 安慰剂对照试验。目标 1 寻求确认目标 通过减少 AS 处理过程中杏仁核的激活（主要目标）以及减少 暴露于创伤叙述和恐惧消退回忆期间的生理和主观 CFS 反应 （次要目标）从基线到稳定状态（治疗 5 天）。目标 2 将检验以下假设： JNJ-42165279 组中杏仁核反应性从基线到第 5 天的减弱将与 从基线到第 8 周的症状变化。我们将探讨次要指标变化之间的联系 目标参与（创伤特异性唤醒反应和恐惧消退回忆）和过度唤醒的变化 并在 8 周时再次出现症状。如果这些预测得到证实，该项目将支持未来 FAAHi（以及具有类似作用机制的其他药物）的明确、大规模随机对照研究 针对 PTSD 以及其他伴有 AS 和 CFS 领域功能障碍的焦虑和压力源相关病症的试验。