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

项目摘要/摘要： 内源性催产素(Oxt)因其在亲社会中的作用，一直是精神病学研究的重点。 对社会/情绪刺激的反应的行为和调节。尽管之前的研究结果表明 鼻腔给药OXT可以引起行为和神经的改变，令人惊讶的是 在这个问题上几乎没有明确的研究。到目前为止，大多数研究都受到缺乏严格方法论的限制 测量实际靶点参与和/或缺乏已建立的、全面的药代动力学模型。无 这些问题中的一个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。 我们建议进行一项研究，以确定OXT鼻腔内引起神经变化的程度。 对有临床意义的精神病理学的青少年进行管理。我们的目标是：(1)验证目标参与度 通过OXT鼻腔给药；(2)建立剂量-反应关系；(3)形成全面的 OXT鼻腔给药的药代动力学模型。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更大的愤怒倾向。这是最常见的 青少年接受心理健康服务的原因，以及纵向研究表明，患有慢性病的青少年 易怒在成年后会导致不良后果，包括抑郁症、焦虑症、 药物使用和犯罪行为。 作为OXT给药靶点的应激性的神经生物学机制被认为是 急性威胁反应系统(杏仁核和内侧前额叶皮质的过度活动和功能障碍 招募调节/调节皮质系统)。以前的研究已经证明了最常见的 提示OXT的作用机制是降低急性脑缺血所涉及的神经区的反应性。 威胁应对系统。我们将应用已显示的方法(任务相关和静息状态功能磁共振) 捕获核心目标机制及其响应变化的可验证和可衡量的能力 牛。我们将在安全范围内使用广泛的剂量范围(从10IU到80IU的8倍)。我们将实施 测量外周水平的方法，具有改进的、最先进的有效性和可靠性(质谱仪)。 我们将在不同的精神病学诊断中以及在每个诊断中对这种精神病理学进行维度检查 分类诊断(研究领域标准(RDoC)方法)。 该项目将在理解OXT的神经影响方面取得快速的纵向进展，OXT是一种病理生理 以及开发一种新的、潜在有效的基于机制的治疗方法来解决 这个重大问题。

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.