Clinical trial NCT03863288: Dose Response Relationship of Oxytocin on Irritability in Youths
Official title: Dose-Response Relationship and Pharmacokinetics of Intranasal Oxytocin on Neural Impact in Youth With High Levels of Irritability
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Irritable Mood
Keywords: oxytocin
neuroimaging
irritability
fMRI
pharmacokinetics
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2019-03-05
Enrollment: 60
Sex: ALL
Minimum age (years): 14
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 50 minutes
measure: Plasma concentrations of OXT at 10, 20, 30, 40, and 50 minutes post intranasal OXT administration, and immediately post-fMRI scanning.
timeFrame: 50 minutes and 2 hours
Secondary outcomes:
measure: 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).
timeFrame: 50 minutes
measure: The degree of functional connectivity between rmPFC and amygdala during resting-state fMRI (rs-fMRI) after intranasal administration of OXT.
timeFrame: 60 minutes
measure: 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.
timeFrame: 70 minutes
measure: 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)
timeFrame: 50 minutes and 2 hours
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center, Department of Psychiatry
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Soonjo Hwang, MD
role: PRINCIPAL_INVESTIGATOR
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