Dose-Response Relationship and Pharmacokinetics of Intranasal Oxytocin on Neural Impact in Youths with High Levels of Irritability

项目总结/摘要： 内源性催产素（OXT）在亲社会性神经元中的作用已成为精神病学研究的热点。 行为和对社会/情绪刺激的反应调节。尽管先前的研究结果表明 鼻内施用OXT可以产生行为以及神经变化，令人惊讶的是， 关于这个问题的研究很少。迄今为止，大多数研究都受到缺乏严格方法的限制， 测量实际靶点参与和/或缺乏已建立的综合药代动力学模型。没有一 这些问题已经在具有临床意义的精神病理学的儿科人群中进行了研究。 我们提出了一项研究，以确定在何种程度上引起的神经变化的OXT鼻内 在具有临床显著精神病理学的青年中给药。我们的目标是：（1）验证目标接合 通过OXT鼻内给药;（2）建立剂量-反应关系;和（3）形成全面的 鼻内OXT的药代动力学模型。我们在这项研究中选择的精神病理学目标是易怒。 易怒被定义为相对于同龄人表现出愤怒的倾向增加。它是最常见的 原因青年目前的精神卫生服务，纵向研究表明，青年与慢性 易怒在成年期有不良后果，包括抑郁症，焦虑症， 物质使用和犯罪行为 提出的作为OXT给药目标的易怒神经生物学机制是脑功能障碍 急性威胁反应系统（杏仁核和内侧前额叶皮质过度活跃， 调节/调节皮质系统的募集）。先前的研究表明， 提示OXT的作用机制是降低急性脑缺血相关神经区域的反应性。 威胁应对系统我们将应用已经证明的方法（任务相关和静息状态功能性MRI） 一种可验证和可测量的能力，以捕捉核心目标机制及其变化， OXT。我们将在安全范围内使用广泛的剂量范围（从10 IU到80 IU的8倍）。落实 具有改进的、最先进的有效性和可靠性的测量外周水平的方法（质谱法）。 我们将在各种精神病诊断中以及在每一个 分类诊断（研究领域标准（RDoC）方法）。 该项目将导致在理解OXT的神经影响，病理生理学， 以及开发一种新的和潜在有效的基于机制的治疗方法，以解决 这个重大的问题。

PROJECT SUMMARY/ABSTRACT: Endogenous oxytocin (OXT) has been a focus of prior psychiatric research based upon its role in pro-social behavior and modulation of response to social/emotional stimuli. Although findings from prior studies suggest that intranasal administration of OXT can produce behavioral as well as neural changes, there is surprisingly little definitive research on this issue. Most studies to date are limited by a lack of rigorous methodology to measure actual target engagement and/or lack of an established, comprehensive pharmacokinetic model. None of these issues have been studied in a pediatric population with clinically significant psychopathology. We propose a study to determine the extent to which neural changes are induced by OXT intranasal administration in youths with clinically significant psychopathology. We aim to: (1) verify the target engagement by OXT intranasal administration; (2) establish a dose-response relationship; and (3) form a comprehensive pharmacokinetics model for intranasal OXT. The psychopathology we select to target in this study is irritability. Irritability is defined as the increased propensity to exhibit anger relative to peers. It is one of the most common reasons youth present for mental health services, and longitudinal studies demonstrate that youth with chronic irritability have poor outcomes in adulthood, including increased incidences of depression, anxiety disorders, substance use, and criminal behavior. The proposed neurobiological mechanisms of irritability as the target of OXT administration is dysfunction in the acute threat response system (hyperactivity in the amygdala and medial pre-frontal cortex and dysfunctional recruitment of regulatory/modulatory cortical systems). Previous studies have demonstrated the most commonly suggested mechanism of action of OXT was reduction in reactivity of the neural areas implicated in the acute threat response system. We will apply methods (task-related and resting-state functional MRI) that have shown a verifiable and measureable ability to capture the core target mechanism as well as its changes in response to OXT. We will use a wide range of dosing (8-fold from 10 IU to 80 IU) within safe margins. We will implement methods of measuring peripheral levels with improved, state-of-the-art validity and reliability (mass spectrometry). We will examine this psychopathology dimensionally across various psychiatric diagnoses as well as in each categorical diagnosis (Research Domain Criteria (RDoC) approach). This project will lead to rapid vertical progress in understanding the neural impact of OXT, the pathophysiology of irritability, and the development of a new and potentially efficacious mechanism-based treatment to address this significant problem.