Researchers have published results of a clinical trial providing preliminary evidence that intranasal administration of the hormone oxytocin may be effective in reducing symptoms of severe irritability in young people diagnosed with disruptive behavior disorders (DBDs) and disruptive mood dysregulation disorder (DMDD).

Irritability is one of the most common reasons children are referred for psychiatric treatment. Those with chronic irritability are at increased risk for long-lasting mental health problems, including anxiety and depressive disorders, as well as suicide and substance use disorders, according to the team that conducted the new trial.

The team was led by Soonjo Hwang, M.D., of the University of Nebraska Medical Center in Omaha. Dr. Hwang’s 2017 BBRF Young Investigator grant supported the research that culminated in the trial. BBRF Scientific Council member Ellen Leibenluft, M.D., of the National Institute of Mental Health, was among members of the team. They recently reported their results in the American Journal of Psychiatry.

Oxytocin is a neuropeptide—a chemical messenger released by neurons that can modify biological processes throughout the body. Sometimes called “the love hormone,” it plays roles in sex, love, and social bonding; but it has many other impacts in the brain and body. In addition to its role in so-called “pro-social” behaviors, it is also involved in the processing of fear and anxiety, among other emotions. Oxytocin has been tested with mixed results in treating depression and anxiety, among other psychiatric conditions. Delivered intranasally, it has been tested, for example, in young people with autism spectrum disorder, although increased irritability and aggressive behavior have been noted as adverse events in such trials. For various reasons, Dr. Hwang and colleagues think it is possible that the impact of oxytocin may differ in part depending on the diagnoses of those to whom it is given.

In their randomized and blinded trial, oxytocin delivered intranasally once daily over 3 weeks was given to 25 of 52 trial participants, with the remainder receiving placebo. The participants were between the ages of 10 and 18 (average age about 15). 41 participants were male, and between 50% and 60% had a primary diagnosis of ADHD; about a quarter of each group had a primary diagnosis of DMDD. Most participants had one or more secondary diagnoses, including oppositional defiant disorder and conduct disorder. All the participants had increased levels of irritability, measured by the Affective Reactivity Index (score higher than 4).

Decreased oxytocin levels have been reported in the saliva or urine of children with DBDs, including oppositional defiant disorder and conduct disorder. Also, lower levels of oxytocin in serum of children with ADHD have been correlated in some tests with their degree of aggressive behavior.

Among the aims of the trial was not only to test the effectiveness of oxytocin in reducing irritability and aggression; it was also to explore its impact on areas of the brain that past research has suggested are centrally engaged during irritable behavior. Functional MRI whole-brain scans were given to each of the participants before administration of oxytocin or placebo began and immediately after treatments concluded, with the team hoping to be able to observe changes of neural activation in key brain areas and to correlate these with any changes in symptoms. When the scans were made, the children were performing the “affective Stroop task,” which involves having them respond to a sequence of numbers and images displayed on a computer screen, some involving emotional stimuli and some not. The task simultaneously engages and differentially measures different domains in the brain that are engaged in processing emptions, including those directly related to irritable and aggressive behaviors.

In what may be the first study to report on the neural impact of an intranasal oxytocin intervention for youths with significant irritability in the context of disruptive mood and behavior disorders, the team found, first, that relative to controls, those who received oxytocin had significant reductions in the clinical severity of disruptive behavior and mood symptoms including irritability, as measured by two standard assessment indices. “In addition, there were greater improvements in reactive aggression, total level of aggression, and level of daily functioning in the oxytocin group,” although here the differences compared with placebo were not statistically significant. This, the team said, could be due to the short duration of the trial and small size of the participant group, and can be further evaluated in larger trials.

A second set of results had to do with the fMRI data. Youths in the oxytocin group showed greater reductions in neural activation compared with controls in parts of the brain considered central in the response to emotional stimuli: the dorsomedial prefrontal cortex (dmPFC), posterior cingulate cortex (PCC), and the fusiform gyrus. Activation in the anterior cingulate cortex (ACC) was reduced specifically in response to negative emotional stimuli.

Finally, in the children treated with oxytocin, the team found significant correlations between, on the one hand, reductions in neural activation in responses to emotional stimuli in the prefrontal cortex, the PCC and ACC, and, on the other hand, symptom improvements in irritability, reactive aggression, and the overall clinical severity of illness.

While it has been suggested that the neurobiological mechanism of irritability is shared among youths with disruptive behavior and disruptive mood disorder diagnosis, the team noted that “it is possible that the effect of intranasal oxytocin differs between youths with ADHD and irritability [on the one hand] and those with conduct disorder and irritability [on the other hand].”

In general, however, results of the present trial indicated to the team that oxytocin treatment correlated with engagement of brain areas implicated in emotional processing and that neural-level changes correlated with improvements in core DBD symptoms.

While “preliminary,” the team added, these results can guide future trials and the development of “new treatments for this challenging patient population.”