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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要强迫症（OCD）通常始于童年，导致终生发病，并且每年给经济造成 21 亿美元（直接成本）和 62 亿美元（间接成本，如生产力损失）的损失。强迫症通常对血清素再摄取抑制剂 (SRI) 反应不足，而且典型的 SRI 反应也不佳。考虑到数百万美国成年人患有强迫症，这只是部分的，并且延迟了 2-3 个月。探索添加具有不同作用机制的药物是否可以帮助 SRI 无反应者迫切需要新的数据支持氯胺酮对强迫症的快速和持续的抗强迫作用。寻求了解氯胺酮快速强迫症作用的机制，从而加速开发更有效的强迫症药物。出于多种原因，该提案重点关注氯胺酮对 mu-阿片类药物系统和强迫症的作用首先，我们之前的工作发现 mu-阿片受体拮抗剂纳曲酮可以阻断氯胺酮的作用。其次，纳曲酮也会加重强迫症症状，而吗啡（一种） mu-阿片受体激动剂）可减轻强迫症症状第三，在重度抑郁症中，尝试发展后续症状。一种可能的解释是，通过 NMDA 拮抗剂发挥作用的药物尚未成功。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。 mu-阿片受体拮抗作用调节的目标，我们关注额纹状体认知控制回路神经影像学研究表明，μ-阿片受体直接受到 mu-阿片系统的影响。分布在与强迫症相关的额纹状体回路中。拟议的机械试验将是第一个探讨氯胺酮的阿片类药物特性在调节中的作用的试验额纹状体电路并在强迫症中产生反强迫效应。我们将通过纳曲酮预处理来测试阿片受体拮抗作用是否会阻断氯胺酮对阿片类药物系统的控制和奖励回路以及回路连接的影响。因此，我们需要探索两种有希望的、低-强迫反应的参与。拟议的项目结合了实验性的阿片类药物系统参与人类的成本标记。药物和神经影像学方法，为治疗方法的转变开辟新途径精神科治疗。