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

Endogenous oxytocin (OXT) has been a focus of prior psychiatric research due to its role in pro-social behavior, and modulation of response to social/emotional stimuli. Although many studies argue that the intranasal administration of OXT can produce behavioral as well as neural changes, there is surprisingly little comprehensive research on this issue. Most of the previous studies are limited by using a single dose of intranasal OXT in small samples, and there is no current consensus regarding appropriate dosage and very little data on neural impact as a function of dose. There has been little consideration of the relation between pharmacokinetics (peripheral level of OXT after administration) and the degree of induced neural changes. None of these issues have been studied in a pediatric population with clinically significant psychopathology. This study is proposed to determine the extent to which neural changes are induced by OXT intranasal administration, by examining the dose-response relationship (the degree of neural changes induced by various doses of OXT) and the correlation of pharmacokinetics (peripheral level of OXT after administration and the induced neural changes) in youths with clinically significant psychopathology. The form of psychopathology targeted is irritability: the increased propensity to exhibit anger relative to peers.One of the neurobiological mechanisms of irritability implicates dysfunction in the acute threat response system. OXT, with its most commonly proposed mechanism being reduction of hyperactivity in the acute threat response system, is a potentially promising agent to induce neural changes in the target brain areas of the acute threat response system for youths with high levels of irritability. The study aims to quantify the extent to which different doses of OXT will reduce the activation of the acute threat response system to emotional stimuli in youths with high levels of irritability. Both resting state and task-based functional MRI will be used , using affective-cognitive tasks (to obtain the primary aim will begin after the clinician scan) with demonstrated test-retest reliability and capability of capturing the core target areas of OXT administration in the acute threat response system. Pharmacokinetics (plasma and saliva level) after OXT administration will be examined to determine correlation with the induced neural changes in the target areas.