Dose Response Relationship of Oxytocin on Irritability in Youths

March 12, 2025 updated by: University of Nebraska

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

The proposed study is a randomized, double-blind proof of concept (PoC) study on the neural impact of intranasal oxytocin (OXT) administration for adolescents (age 14 to 18), demonstrating a clinically significant level of irritability as defined by a score of ≥4 on the Affective Reactivity Index (ARI). Planned enrollment is 80 subjects over 3 years.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Nebraska
      • Omaha, Nebraska, United States, 61898-5581
        • University of Nebraska Medical Center, Department of Psychiatry

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

10 years to 14 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 14-18 years of age
  • current diagnosis of Attention Deficit/Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), or Disruptive Mood Dysregulation Disorder (DMDD) as determined by the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS), lifetime version;54
  • Clinically significant level of irritability as defined by a score of ≥4 on the Affective Reactivity Index (ARI)
  • If currently on medication, treatment must be stable for at least 2 weeks with stimulant medication, and at least 4 weeks with alpha 2 agonist, atomoxetine, antipsychotics, mood stabilizers, or antidepressant.

Exclusion Criteria:

  • Comorbid psychotic, tic, autism spectrum disorder, or substance use disorders, or current diagnosis of bipolar disorder; -Major medical illness that prohibits OXT administration (e.g., severe liver disease, seizure disorder, metabolic disorder)
  • Past history of allergic reaction to OXT and its intranasal product
  • History of Central Nervous System (CNS) disease (including history of seizure, epilepsy, CNS tumor, CNS hemorrhage, or serious CNS infection including meningitis or encephalitis)
  • A positive urine pregnancy test
  • A positive urine drug screen or currently active diagnosis of substance use disorder
  • Wechsler Abbreviated Scale of Intelligence (WASI-2; two subset form) scores <70
  • Metal in the body (i.e., hearing aid, cardiac pacemaker, bone plates, braces, non-removable piercing/implants, etc.), claustrophobia, or any other condition that would preclude MRI scanning.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Intranasal Spray Placebo
Nasal spray of placebo liquid solution as a single dose. fMRI scan pre and post-administration.
Drug: Placebo
Placebo intranasal spray liquid administration
Procedure: Functional MRI (fMRI)
Functional MRI (fMRI) scan with affective/cognitive tasks
Active Comparator: Oxytocin Intranasal Spray 8 International Unit (IU)
Nasal spray of Oxytocin 8 International Unit (8IU) liquid solution as a single dose. fMRI scan pre and post administration.
Procedure: Functional MRI (fMRI)
Functional MRI (fMRI) scan with affective/cognitive tasks
Drug: Oxytocin Intranasal Spray 8 International Unit (8IU)
Oxytocin intranasal spray liquid administration
Other Names:
  • Oxytocin 8IU
Active Comparator: Oxytocin Intranasal Spray 24 International Unit (IU)
Nasal spray of Oxytocin 24 International Unit (24IU) liquid solution as a single dose. fMRI scan pre and post administration.
Procedure: Functional MRI (fMRI)
Functional MRI (fMRI) scan with affective/cognitive tasks
Drug: Oxytocin intranasal spray 24 International Unit (24IU)
Oxytocin intranasal spray liquid administration
Other Names:
  • Oxytocin 24IU
Active Comparator: Oxytocin Intranasal Spray 48 International Unit (IU)
Nasal spray of Oxytocin 48 International Unit (48IU) liquid solution as a single dose. fMRI scan pre and post administration.
Procedure: Functional MRI (fMRI)
Functional MRI (fMRI) scan with affective/cognitive tasks
Drug: Oxytocin intranasal spray 48 International Unit (48IU)
Oxytocin intranasal spray liquid administration
Other Names:
  • Oxytocin 48IU
Active Comparator: Oxytocin Intranasal Spray 80 International Unit (IU)
Nasal spray of Oxytocin 80 International Unit (80IU) liquid solution as a single dose. fMRI scan pre and post-administration.
Procedure: Functional MRI (fMRI)
Functional MRI (fMRI) scan with affective/cognitive tasks
Drug: Oxytocin intranasal spray 80 International Unit (80IU)
Oxytocin intranasal spray liquid administration
Other Names:
  • Oxytocin 80IU

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma concentrations of OXT at 10, 20, 30, 40, and 50 minutes post intranasal OXT administration, and immediately post-fMRI scanning.
Time Frame: 50 minutes and 2 hours
Area under the curve (OXT dose response)
50 minutes and 2 hours
Blood Oxygen Level Dependent (BOLD) response within rostro-medial prefrontal cortex ( rmPFC) region of interest to emotional stimuli during the Affective Stroop (AS) at approximately 50 minutes after intranasal administration of OXT.
Time Frame: 50 minutes
Neural changes observable on fMRI as BOLD responses in medial prefrontal cortex. Response data will be generated for each participant for the four OXT doses (8, 24, 48 and 80 IU) and placebo.
50 minutes

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Saliva level of OXT at 10, 20, 30, 40 and 50 minutes post-administration of intranasal OXT, and immediately after fMRI scanning to calculate area under curve (AUC)
Time Frame: 50 minutes and 2 hours
Area under curve (OXT dose response)
50 minutes and 2 hours
BOLD responses within the amygdala region of interest (ROI) to emotional stimuli during the Affective Stroop (AS) task (at approximately 50 minutes after intranasal administration of OXT (placebo, 8, 24, 48, and 80 IU).
Time Frame: 50 minutes
Neural changes observable on fMRI as BOLD responses in amygdala.
50 minutes
The degree of functional connectivity between rmPFC and amygdala during resting-state fMRI (rs-fMRI) after intranasal administration of OXT.
Time Frame: 60 minutes
functional connectivity observable on rs-fMRI
60 minutes
BOLD responses within peri-aqueductal gray (PAG) and amygdala regions of interest (ROIs) to emotional stimuli during the facial expression task (at approximately 70 minutes) after intranasal administration of OXT.
Time Frame: 70 minutes
Neural changes observable on fMRI as BOLD responses in PAG and amygdala.
70 minutes

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nebraska

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Soonjo Hwang, MD, University of Nebraska

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 18, 2022

Primary Completion (Actual)

February 27, 2024

Study Completion (Actual)

February 27, 2024

Study Registration Dates

First Submitted

September 25, 2018

First Submitted That Met QC Criteria

March 4, 2019

First Posted (Actual)

March 5, 2019

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

March 12, 2025

Last Verified

March 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0219-20-FB
  • 1U01MH120155-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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