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

成人强迫症患者大麻素目标参与度的多模式评估

基本信息

批准号：
10664901
负责人：
Reilly Reyns Kayser
金额：
$ 17.07万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664901
关键词：
Acute Adult Affect Agonist American Amygdaloid structure Anxiety Area Attenuated Behavior Behavioral Biological Markers Biological Models Biometry Blinking Brain CNR1 gene Cannabidiol Cannabinoids Cannabis Clinical Data Clinical Trials Design Cognitive Therapy Data Development Disease remission Dose Effectiveness Electromyography Environment Equilibrium Expectancy Extinction FDA approved Fellowship Fostering Fright Functional Magnetic Resonance Imaging Future Galvanic Skin Response Goals Habits Hippocampus Human Impairment Internet Knowledge Laboratory Study Light Link Manuscripts Measures Medicine Mental disorders Mentored Patient-Oriented Research Career Development Award Mentorship Methods Nabilone Neurocognitive Obsession Obsessive-Compulsive Disorder Oral Outcome Participant Patients Pharmaceutical Preparations Physicians Physiological Placebo Control Placebos Postdoctoral Fellow Prefrontal Cortex Preparation Prevention Process Psychophysiology Randomized Randomized, Controlled Trials Recurrence Reporting Research Research Design Research Personnel Research Project Grants Rodent Rodent Model Role Selective Serotonin Reuptake Inhibitor Smoke Stimulus Surveys Symptoms Techniques Testing Tetrahydrocannabinol Therapeutic Therapeutic Effect Thinking Time Training analog behavioral response biomarker identification career compulsion conditioned fear design endogenous cannabinoid system experience functional MRI scan human subject imaging study improved indexing learning extinction marijuana use multidisciplinary multimodality neural neural correlate neuroimaging novel novel therapeutic intervention pre-clinical psychologic repetitive behavior response severe mental illness skills therapy development translational neuroscience treatment strategy virtual reality

项目摘要

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.

项目概要/摘要强迫症 (OCD) 是一种致残疾病，影响约 420 万美国人4，目前治疗方法包括血清素再摄取抑制剂和认知行为疗法（暴露和反应）预防 (EX/RP) 将帮助不到 50% 的患者获得缓解。该 K23 奖的目标是：促进 Kayser 博士发展成为一名独立的医师研究员，应用实验提议的活动旨在开发针对强迫症等严重精神疾病的新疗法。本文重点关注内源性大麻素系统（ECS）作为开发强迫症治疗的潜在新领域从中获得实验医学研究经验的模型系统意味着强迫症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 和目标导向行为和习惯行为之间的平衡22,23)，可以通过大麻素调节作为一名 T32 研究员，Kayser 博士开始在初步研究中探索这一前提，并表明了这一点。 a) 单独吸食大麻不会影响强迫症症状 b) 大麻隆，一种 FDA 批准的合成药物 Δ-9-四氢大麻酚（THC，大麻的主要精神活性成分）的类似物，没有影响单一疗法，但当两种疗法联合使用时，增强了 EX/RP 的有效性。3 这导致假设大麻隆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 通过调节部分脑部活动来增强消退学习。大脑的恐惧网络。16,17,21,24 Kayser 博士的 K23 研究项目将使用实验医学设计，以评估单剂量大麻隆与安慰剂如何影响强迫症相关目标在神经（例如功能磁共振成像）、生理（例如皮肤电导反应、肌电图）和心理方面他的 K23 培训计划将利用 60 名未接受药物治疗的强迫症成年人的（例如行为反应）水平。优秀的研究环境和多学科的导师团队使他能够发展技能 (a) 临床试验设计，(b) 实验医学方法，c) 转化神经科学技术，d) 高级生物统计分析，以及 e) 资助写作、研究演示和手稿准备。设计和进行研究的实践经验将支持上述培训目标并提供除了扩展当前的知识之外，还支持未来 R61/R33 应用的初步数据。 ECS 在强迫症中的作用，研究结果可以为大麻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，可以用生物标志物来指示大麻隆和其他大麻素的作用。最终产生强迫症的新疗法此外，K23 支持的经验将促进 Kayser 博士的治疗。过渡到专注于开发新颖的、神经科学知识的独立研究生涯强迫症和其他严重精神疾病患者的治疗。