Examining Mu Opioid Mechanisms of Ketamine's Rapid Effects in OCD

检查 Mu 阿片类药物对氯胺酮快速作用于强迫症的机制

• 批准号: 10708665
• 负责人: Carolyn I Rodriguez
• 金额: $ 73.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708665
• 关键词: Acute; Adult; Anti-Cholinergics; Childhood; Corpus striatum structure; Data; Development; Diameter; Direct Costs; Drug Exposure; Exposure to; Facilities and Administrative Costs; Functional Magnetic Resonance Imaging; Functional disorder; Funding Opportunities; Hour; Human; Hyperactivity; Inferior; Insula of Reil; Ketamine; Major Depressive Disorder; Medial; Mediating; Memantine; Midazolam; Modeling; Morbidity - disease rate; Morphine; N-Methylaspartate; NMDA receptor antagonist; Naltrexone; Obsessive-Compulsive Disorder; Opioid; Opioid Antagonist; Opioid Receptor; Opioid agonist; Oral; Participant; Pharmaceutical Preparations; Placebos; Prefrontal Cortex; Productivity; Prolactin; Property; Psychiatric therapeutic procedure; Randomized; Receptor Activation; Refractory; Reporting; Rest; Rewards; Role; Saline; Selective Serotonin Reuptake Inhibitor; Serum; Severities; Speed; Symptoms; System; Testing; Therapeutic; Time; Work; antagonist; antidepressant effect; arm; brain abnormalities; cognitive control; cohort; cost; economic cost; financial incentive; improved; mu opioid receptors; neural; neural circuit; neuroimaging; patient engagement; response

PROJECT SUMMARY Obsessive-compulsive disorder (OCD) typically starts in childhood, leads to lifelong morbidity, and costs the economy $2.1 billion (direct costs) and $6.2 billion (indirect costs such as lost productivity) annually. OCD often responds inadequately to serotonin reuptake inhibitors (SRIs). Moreover, the typical SRI response is only partial and is delayed by 2-3 months. Given the dysfunction OCD imposes on millions of U.S. adults, exploring whether SRI non-responders are helped by adding drugs with different mechanisms of action is urgently needed. Emerging data support ketamine’s rapid and sustained anti-obsessional effects in OCD. We seek to understand the mechanisms underlying ketamine’s rapid OCD effect and thereby to speed development of more effective agents for OCD. For several reasons, this proposal focuses on ketamine’s action on the mu-opioid system and OCD neural circuits. First, our prior work found that the mu-opioid receptor antagonist naltrexone blocks ketamine’s acute, dramatic antidepressant effects. Second, naltrexone also worsens OCD symptoms, while morphine (a mu-opioid receptor agonist) diminishes OCD symptoms. Third, in major depression, attempts to develop follow- on agents that work via NMDA antagonism have not been successful. One possible explanation is that NMDA antagonism may not fully explain ketamine’s rapid and enduring antidepressant effects. To assess the neural targets modulated by mu-opioid receptor antagonism, we focus on fronto-striatal cognitive control circuits which neuroimaging studies show are directly influenced by the mu-opioid system. Indeed, mu-opioid receptors are distributed throughout the fronto-striatal circuits associated with OCD. Drawing on this rationale, the proposed mechanistic trial would be the first to probe the role of ketamine’s opioid properties in modulating fronto-striatal circuitry and bringing about anti-obsessional effects in OCD. We will test, by administering pre-treatment with naltrexone, whether opioid receptor antagonism blocks ketamine’s effects on control and reward circuits and circuit connectivity. Low-cost markers of opioid system engagement that predict anti-obsessional response are needed. We will therefore explore two promising, low- cost markers of opioid system engagement in humans. The proposed projects combine experimental medication and neuroimaging approaches in order to open a new avenue for therapeutics to transform psychiatric treatments.

项目摘要 强迫症（OCD）通常从童年开始，导致终身发病率，并且 每年损失21亿美元（直接成本）和62亿美元（诸如生产率损失）的损失。 强迫症通常会对5-羟色胺再摄取抑制剂（SRIS）做出反应。此外，典型的SRI响应 仅部分延迟2-3个月。考虑到数百万美国成年人的功能障碍OCD不可能 探索是否通过添加具有不同作用机理的药物来帮助SRI非反应者是 迫切需要。新兴数据支持氯胺酮在强迫症中的快速且持续的抗痴迷效应。我们 寻求了解氯胺酮快速OCD效应的基础机制，从而加快 开发更有效的OCD代理。 由于几个原因，该提案重点介绍氯胺酮对MU-Apoid System和OCD的行动 神经回路。首先，我们先前的工作发现Mu-Apioid受体拮抗剂Naltrexone阻止了氯胺酮的 急性，戏剧性的抗抑郁作用。其次，纳曲酮也会恶化强迫症症状，而吗啡（a MU阿片受体激动剂）减轻了OCD症状。第三，在严重抑郁症中，试图发展跟进 - 关于通过NMDA拮抗作用的代理人，尚未成功。一种可能的解释是NMDA 拮抗作用可能无法完全解释氯胺酮快速而持久的抗抑郁作用。评估神经 通过MU-Apioid受体拮抗作用的靶标，我们专注于额叶认知控制电路 神经影像学研究表明，直接受MU阿片类药物系统的影响。实际上，MU-Apoid接收器 分布在与OCD相关的整个额叶纹状体中。利用这个理由， 拟议的机械试验将是第一个探测氯胺酮阿片类药物在调节中的作用的试验 额叶纹状体电路，并在强迫症中产生抗痴迷效应。 我们将通过使用纳曲酮进行预处理测试，是否是阿片受体拮抗作用 氯胺酮对控制和奖励电路以及电路连接的影响。阿片类药物系统的低成本标记 需要预测反痴迷反应的参与。因此，我们将探索两个诺言，低 - 阿片类系统参与人类的成本标记。提议的项目结合了实验 药物和神经影像学方法，以打开新的途径以改造 精神病治疗。