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

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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.