The neural correlates of the effects of psilocybin in OCD: randomized controlled study

裸盖菇素对强迫症影响的神经相关性：随机对照研究

• 批准号: 10685246
• 负责人: BENJAMIN KELMENDI
• 金额: $ 18.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-07 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685246
• 关键词: Acute; Adverse effects; Affect; Aftercare; Algorithms; Anxiety; Anxiety Disorders; Behavioral; Belief; Brain; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Corpus striatum structure; Data; Dedications; Development; Development Plans; Disease; Dose; Ethics; Evaluation; Functional Magnetic Resonance Imaging; Funding; Goals; Grant; Hallucinogens; Hour; Institution; Intervention; Intoxication; Investigational Therapies; K-Series Research Career Programs; Maps; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Mood Disorders; Moods; Neurobiology; Neurons; Neurosciences; Nicotinic Acids; Obsessive-Compulsive Disorder; Paper; Participant; Patient Care; Patients; Pharmaceutical Preparations; Pharmacologic Actions; Physicians; Placebo Control; Population; Positioning Attribute; Prediction of Response to Therapy; Psilocybin; Psychiatrist; Psychiatry; Psychotherapy; Randomized; Refractory; Reporting; Research; Research Project Grants; Research Training; Residual state; Rest; Scientist; Symptoms; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Training; Work; Writing; active control; addiction; base; brain surgery; career; career development; clinical effect; clinical investigation; clinical training; clinical translation; drug development; experience; improved; individualized medicine; innovation; insight; neural; neural correlate; neuroimaging; neuropsychiatric disorder; novel; patient stratification; placebo controlled study; precision medicine; predicting response; randomized, controlled study; success; symptomatic improvement; symptomatology; translational neuroscience; treatment responders; treatment strategy

PROJECT SUMMARY/ABSTRACT This application for a K23 mentored patient-oriented research career development award will provide the applicant, a clinical neuroscientist with a broad background in translational neuroscience, with advanced training, an impactful mentored research experience, and protected research time. My long-term goal is to become an independent physician-scientist, focused on identifying neurobiological correlates and predictors of the therapeutic effects of novel treatments, especially those with acute effects. By applying such insights, I aim to develop individualized treatment strategies for mood and anxiety disorders. In line with these goals, I propose a training plan to gain expertise in translational clinical investigations and neuroimaging methods. This will be achieved through an integrated career development plan, overseen by a mentoring team with expertise in drug development, neuroimaging, and neurobiology. This proposed study will be the first to examine the neural correlates of the effects of psilocybin in obsessive- Numerous recent studies have reported acute, and sometimes persisting, clinical benefit after the administration of a single dose of psilocybin in mood and anxiety disorders, addiction, and OCD. The persistence of clinical effects long after acute intoxication has worn off implies lasting brain changes, but the mechanisms underlying these lasting therapeutic effects remain poorly understood. We propose to use connectivity analysis of resting-state functional magnetic resonance imaging (rs-fMRI) data to probe the neuronal correlates of clinical change after a single dose of psilocybin in OCD, in the context of an independently funded randomized, placebo-controlled pilot efficacy and tolerability trial that we have just begun at Yale. Consistent with the experimental therapeutics framework, we here examine the hypothesized brain effects of psilocybin; while we predict that these will be associated with symptom improvement, our analyses will be informative whether or not psilocybin proves to have a beneficial clinical effect in this controlled trial. We focus on the default mode network (DMN), a network known to be involved in the evaluation of internal states, disrupted in OCD, and affected by psilocybin in other populations. We hypothesize that psilocybin will result in increased (i.e. normalized) intra-DMN functional connectivity in OCD, and that this will correlate with any clinical change (Aim 1). Baseline DMN connectivity is anticipated to predict subsequent neural and clinical change (Aim 2). Finally, we will examine connectivity within the corticostriatal circuitry (Aim 3); while this circuitry has not previously been investigated in the context of psilocybin, it is robustly implicated in OCD. This work will shed light on the neurobiological underpinnings of lasting clinical and behavioral effects effects of psilocybin in neuropsychiatric disease, with potential implications for other rapid-acting pharmacological interventions. It will simultaneously provide an ideal vehicle for my training as I progress towards increasing independence and the development of an impactful research career in clinical neuroscience. compulsive disorder (OCD).

项目总结/摘要 K23指导的以患者为导向的研究职业发展奖的申请将提供 申请人是一名临床神经科学家，具有广泛的转化神经科学背景，接受过高级培训， 一个有影响力的指导研究经验，并保护研究时间。我的长期目标是成为一名 独立的医生科学家，专注于确定神经生物学相关因素和预测因素， 新疗法的治疗效果，特别是具有急性效应的治疗效果。通过应用这些见解，我的目标是 为情绪和焦虑症制定个性化的治疗策略。为了实现这些目标，我提出了一个 培训计划，以获得转化临床研究和神经影像学方法的专业知识。这将是 通过综合职业发展计划实现，由具有药物专业知识的指导小组监督 发育、神经影像学和神经生物学。 这项拟议的研究将是第一个研究裸盖菇素在强迫症中的神经相关作用的研究。 最近的许多研究报告了急性，有时是持续性的临床 在情绪和焦虑症、成瘾和强迫症中给予单剂量裸盖菇素后获益。 急性中毒后长期持续的临床影响意味着持久的大脑变化，但 这些持久治疗效果的机制仍然知之甚少。我们建议使用 静息态功能磁共振成像（rs-fMRI）数据的连接性分析，以探测神经元 在一项独立资助的研究中，强迫症患者单次服用裸盖菇素后临床变化的相关性 一个随机的，安慰剂对照的，初步的有效性和耐受性试验，我们刚刚在耶鲁开始。一致 在实验治疗学的框架下，我们在这里检验裸盖菇素的假设脑效应; 虽然我们预测这些将与症状改善有关，但我们的分析将提供信息 裸盖菇素是否在这个对照试验中被证明具有有益的临床效果。我们关注的是违约 模式网络（DMN），已知参与内部状态评估的网络，在OCD中被破坏，以及 受到裸盖菇素的影响我们假设裸盖菇素将导致增加（即， 正常化）的DMN内功能连接，这将与任何临床变化相关（目的 1）。预期基线DMN连接可预测随后的神经和临床变化（目标2）。最后， 我们将检查皮质纹状体回路内的连通性（目标3）;虽然这种回路以前没有被研究过， 在裸盖菇素的背景下研究，它与强迫症密切相关。 这项工作将阐明持久的临床和行为效应的神经生物学基础 裸盖菇素在神经精神疾病中的作用，对其他速效药物的潜在影响 干预措施。它将同时为我的训练提供一个理想的工具， 独立性和临床神经科学中有影响力的研究事业的发展。 强迫症（OCD）。