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

项目摘要/摘要 强迫症(OCD)是一种致残性疾病，目前影响着大约420万美国人。 治疗包括5-羟色胺再摄取抑制剂和暴露和反应的认知行为疗法 预防(EX/RP)将帮助不到50%的患者实现缓解。这个K23奖项的目标是 促进Kayser博士发展成为一名独立的医生-研究员，他应用了一种实验 以医学方法开发治疗强迫症等严重精神疾病的新方法。建议的活动 本文着重介绍内源性大麻素系统(ECS)作为强迫症治疗和治疗的潜在新领域。 在实验医学研究中获得经验的模型系统。临床前数据表明 强迫症相关神经认知过程(即威胁反应、5，6恐惧消退学习、7、8、17-21、9-16和 目标导向行为和习惯行为之间的平衡22，23)，这可以被大麻类药物调节以 治疗效果。作为一名T32研究员，凯瑟博士开始在初步研究中探索这一前提，显示 A)吸食大麻本身并不影响强迫症症状，b)nablone，一种FDA批准的合成药物 ∆-9-四氢大麻酚(THC，大麻的主要精神活性成分)的类似物对 但当两种治疗方法联合使用时，EX/RP的有效性增强了。 假设纳比隆可能促进了恐惧的消退，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通过调节部分脑区的活动来增强消亡学习 大脑的恐惧网络。Kayser博士的K23研究项目将使用 评价单剂纳贝隆与安慰剂对强迫症相关靶点影响的实验药物设计 在神经(如功能磁共振)、生理(如皮肤电导反应、肌电)和心理 60例未服药成人强迫症患者的行为反应水平他的K23培训计划将利用 优秀的研究环境和多学科的指导团队，使他能够发展技能 在(A)临床试验设计，(B)实验医学方法，c)翻译神经科学技术，d) 高级生物统计分析，以及e)授权写作、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 支持未来R61/R33应用的初步数据。除了扩大现有的关于 ECS在强迫症中的作用，研究结果可以为纳比隆在强迫症中的作用提供机制解释并确定 在未来的试验中用生物标记物来索引纳比隆和其他大麻素的效果。这一研究方向可能 最终产生治疗强迫症的新方法。此外，K23支持的经验将促进Kayser博士 过渡到专注于开发新颖的、掌握神经科学知识的独立研究职业 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.