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

目前迫切需要基于机制的新型药理学方法来治疗创伤相关的 创伤后应激障碍（PTSD），因为40-60%的患者对目前的治疗没有反应。 药理学或行为疗法。创伤后应激障碍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了改变负效价加工与反应唤醒 对情感刺激（AS）和条件性恐惧刺激（CFS）的反应被认为是多层次的翻译 NIMH研究领域标准（RDoC）中与创伤和其他压力相关的过程- 相关疾病。在调节AS的大脑系统的功能中已经观察到可靠的中断 和CFS的反应性。一类作用于内源性大麻素系统的药物， 脂肪酸酰胺水解酶（FAAHi）抑制剂的假设，基于大量的临床前研究， 研究，以调节AS和CFS监管系统的活动（例如，恐惧灭绝（fear extinction）FAAHi 因此，可能为PTSD患者提供临床益处，并对其他焦虑症进行跨诊断， 与压力有关的条件--这些回路表现出持续的功能障碍。拟议项目评估 由Janssen开发和表征的FAAHi，JNJ-42165279， 调节AS（例如，情绪面部处理期间的杏仁核激活;主要目标）和CFS（例如，恐惧 消退;次要目标），以减少过度觉醒（主要临床结局）和再觉醒（主要临床结局）。 出现症状（次要结局）。该项目的目标得到了广泛的初步数据的支持， 表明JNJ-42165279剂量依赖性抑制FAAH，如剂量- 血浆大麻素依赖性增加; FAAH的饱和（>80%）在剂量下达到， 在人体中具有临床显著的不良反应;一旦达到稳态，AS和CFS反应性 减弱的基于这些观察，我们提出了一个两个地点，随机双盲固定剂量（25 mg 在N=150例PTSD患者中开展的JNJ-42165279安慰剂对照试验。目标1寻求确认目标 通过减少AS处理期间杏仁核激活（主要目标）以及减少杏仁核激活来参与 在创伤叙述和恐惧消退回忆中的生理和主观CFS反应 （次要目标）从基线至稳态（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至第5天的减弱将与 从基线至第8周的症状变化。我们将探讨二级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 8周后再次出现症状。如果这些预测得到证实，该项目将支持未来 FAAHi（和其他具有类似作用机制的药物）在确定性、较大随机对照 创伤后应激障碍和其他焦虑和压力相关的条件与AS和CFS领域的功能障碍的试验。

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.