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

> **NIH NIH U01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $754,826

## Abstract

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.

## Key facts

- **NIH application ID:** 10052190
- **Project number:** 1U01MH120155-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Soonjo Hwang
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $754,826
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052190

## Citation

> US National Institutes of Health, RePORTER application 10052190, Dose-Response Relationship and Pharmacokinetics of Intranasal Oxytocin on Neural Impact in Youths with High Levels of Irritability (1U01MH120155-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10052190. Licensed CC0.

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