Multimodal Assessment of Cannabinoid Target Engagement in Adults with Obsessive-Compulsive Disorder

项目总结/摘要 强迫症（OCD）是一种致残性疾病，影响着约420万美国人， 治疗包括5-羟色胺再摄取抑制剂和认知行为疗法， 预防（EX/RP）将帮助不到50%的患者获得缓解。K23奖的目标是 促进Kayser博士发展成为一名独立的医生调查员， 医学的方法来开发新的治疗严重的精神疾病，如强迫症。提议的活动 本文重点关注内源性大麻素系统（ECS）作为开发OCD治疗的潜在新领域， 一个模型系统，从中获得实验医学研究的经验。临床前数据表明， OCD相关神经认知过程中的ECS（即，威胁反应，5，6恐惧消退学习，7，8，17- 21，9 -16和 目标导向和习惯行为之间的平衡22，23），这可以通过大麻素调节， 治疗益处。作为一名T32研究员，凯泽博士开始在初步研究中探索这一前提， a）单独吸食大麻不会影响强迫症症状，B）nabilone，一种FDA批准的合成药物， 类似物的β-9-四氢大麻酚（THC，大麻的主要精神活性成分），没有效果， 但当两种治疗联合使用时，EX/RP的有效性增强。 假设nabilone可能促进了恐惧消退，这被认为发生在EX/RP期间，因为 对健康成年人的成像研究表明，THC通过调节大脑皮层部分区域的活动， 16，17，21，24 Kayser博士的K23研究项目将使用一个 评价单剂量nabilone与安慰剂如何影响OCD相关靶点的实验医学设计 在神经（如功能磁共振成像），生理（如皮肤电导反应，肌电图），和心理 (e.g.行为反应）水平。他的K23训练计划将利用 出色的研究环境和多学科导师团队，使他能够发展技能 在（a）临床试验设计，（B）实验医学方法，c）转化神经科学技术，d） 先进的生物统计学分析，和e）资助写作，研究报告，和手稿准备。 设计和实施研究的实践经验将支持上述培训目标，并提供 初步数据，以支持未来的R61/R33应用。除了扩大现有的知识， ECS在强迫症中的作用，研究结果可能为纳比隆治疗强迫症提供机制解释， 生物标志物，以在未来的试验中指示nabilone和其他大麻素的作用。该研究方向可 最终为强迫症提供新的治疗方法。此外，K23支持的经验将促进Kayser博士的 过渡到独立研究生涯，专注于开发新颖的、具有神经科学知识的研究 强迫症和其他严重精神疾病患者的治疗。

PROJECT SUMMARY/ABSTRACT Obsessive-compulsive disorder (OCD) is a disabling illness affecting about 4.2 million Americans,4 and current treatments including serotonin reuptake inhibitors and cognitive behavioral therapy with exposure and response prevention (EX/RP) will help fewer than 50% of patients achieve remission. This goal of this K23 Award is to promote Dr. Kayser’s development into an independent physician-investigator who applies an experimental medicine approach to develop new treatments for severe mental illnesses like OCD. The activities proposed herein focus on the endocannabinoid system (ECS) as a potential new area for developing OCD treatments and a model system from which to gain experience in experimental medicine research. Preclinical data implicate the ECS in OCD-relevant neurocognitive processes (i.e., threat response,5,6 fear extinction learning,7,8,17–21,9–16 and the balance between goal-directed and habitual behavior22,23), which could be modulated by cannabinoids to therapeutic benefit. As a T32 fellow, Dr. Kayser began to explore this premise in preliminary studies, showing that a) smoked cannabis alone did not affect OCD symptoms and b) nabilone, an FDA-approved synthetic analogue of ∆-9-tetrahydrocannabinol (THC, the primary psychoactive component of cannabis), had no effect as monotherapy but enhanced the effectiveness of EX/RP when both treatments were combined.3 This leads to the hypothesis that nabilone may have facilitated fear extinction, which is thought to occur during EX/RP, since imaging studies of healthy adults show that THC enhances extinction learning by modulating activity in parts of the brain’s fear network.16,17,21,24 Dr. Kayser’s K23 research project will test this hypothesis using an experimental medicine design to evaluate how a single dose of nabilone vs. placebo affects OCD-relevant targets at the neural (e.g. fMRI), physiological (e.g. skin conductance response, electromyography), and psychological (e.g. behavioral response) level in 60 unmedicated adults with OCD. His K23 training plan will capitalize on an outstanding research environment and multidisciplinary mentorship team and enable him to develop skills in (a) clinical trial design, (b) experimental medicine methods, c) translational neuroscience techniques, d) advanced biostatistical analyses, and e) grantwriting, research presentation, and manuscript preparation. Hands-on experience from designing and conducting the study will support the above training goals and provide preliminary data to support a future R61/R33 application. In addition to expanding current knowledge of the ECS’ role in OCD, study results could provide a mechanistic explanation for nabilone’s effects in OCD and identify biomarkers to index the effects of nabilone and other cannabinoids in future trials. This research direction may ultimately yield new treatments for OCD. Moreover, the experiences this K23 supports will foster Dr. Kayser’s transition to an independent research career focused on developing novel, neuroscientifically-informed treatments for patients with OCD and other severe psychiatric illnesses.