Role of Naltrexone in Management of Behavioral Outbursts in an Adolescent Male Diagnosed with Disruptive Mood Dysregulation Disorder

To The Editor:

Disruptive mood dysregulation disorder (DMDD) is a new Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnosis under the category of mood disorders (American Psychiatric Association 2013). Behavioral outburst is one of the most impairing symptoms of DMDD. Several medications, mostly atypical antipsychotics, have been suggested in the treatment of such outbursts, but none are yet approved by the Food and Drug Administration (FDA). As a clinician, it is important to weigh the risks versus the benefits of using atypical antipsychotics, as their overenthusiastic use can lead to unwanted metabolic and other side effects. There is a growing need for medications to control aggression that are safer for long-term use in children and adolescents. We present a case of a 15-year-old male whose behavioral outbursts, associated with DMDD, improved significantly with the use of naltrexone, a competitive opioid antagonist.

Case Report

X was a 15-year-old Caucasian male who had been previously diagnosed with attention-deficit/hyperactivity disorder (ADHD) and mood disorder not otherwise specified as per Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria (American Psychiatric Association 2000). He presented to the outpatient psychiatry clinic with frequent anger outbursts and mood instability. These symptoms were impairing his functionality both at school and at home. As per the new DSM-V, he met criteria for ADHD and DMDD. There were no significant social or environmental stressors that contributed to the worsening of his mood. Symptoms of ADHD were fairly controlled on methylphenidate and guanfacine extended release (ER). He had had no previous psychiatric hospitalizations, and risperidone had been tried in the past without much benefit.

At the initial clinic visit, he was started on oral aripiprazole at 5 mg once daily to address mood instability and aggressive behavior. However, at the 2 week follow-up appointment, his behavioral problems persisted and continued to affect functionality. The dose of aripiprazole was gradually titrated to 15 mg within the next 2 weeks. Despite these measures, X failed to show any behavioral improvement. At this point, a decision to start the patient on naltrexone was made. Naltrexone has been extensively used off-label to control agitation and aggression in children with mental retardation (MR) and pervasive developmental disorder (PDD). Although this patient did not have these diagnoses, a trial of naltrexone was considered, based on the clinician's prior experience with this medication in similar cases. The patient was started on oral naltrexone 50 mg once daily at the next clinic visit.

Over the course of the next two follow-up appointments, the patient's aggressive outbursts improved significantly along with improvement in functioning both at school and at home. However, he started reporting an increase in daytime sedation that was prominent within 2 hours after taking the morning dose of naltrexone. The sedation continued over the next few weeks and interfered with his academic performance, which warranted its discontinuation. Furthermore, lack of evidence supporting long-term naltrexone use in this population justified the decision to stop the drug. The patient was monitored closely thereafter for any mood changes or relapse of symptoms. At the next follow-up appointment, the parents stated that patient's aggressive symptoms reappeared within 1 week of discontinuation of the naltrexone and they had started him back on naltrexone 25 mg once daily for the past week. Even with this lower dose, the patient's aggressive outbursts had shown considerable improvement. He re-experienced the side effect of sedation at a lower degree, which resolved within the next couple of weeks. The patient continued to do well on naltrexone 25 mg once daily over the next 3 months, with resolution of the behavioral outbursts associated with DMDD.

Discussion

Endogenous opiates such as β-endorphins, either directly or by modifying dopaminergic pathways, play a major role in repetitive self-injurious behaviors and addiction (Stanley et al. 2010). Similarly, these reward pathways may be involved in aggressive behaviors associated with MR, PDD, and mood disorders such as DMDD. Naltrexone, a competitive opioid antagonist, blocks the effects of opioids by binding to these receptor sites. By doing so, it interrupts these reward pathways and may help remove the “rush” associated with repetitive aggressive behaviors and angry outbursts.

At low doses, naltrexone preliminarily binds to μ receptors, which is vital for blocking dopaminergic pathways. At higher doses, it binds to κ and δ opioid receptors which in turn modify μ receptors, decreasing or abolishing its effect (White and Schultz, 2000). Herman et al. described a U-shaped dose-dependent curve with a diminishing effect on self-injurious behaviors once the dose exceeded 1.5 mg/kg/day, which coincides with the dose range of 0.5–2.0 mg/kg/day suggested by other studies (Herman et al. 1987; Symons et al. 2004). The case presented here suggests that in controlling aggressive behavior, naltrexone is equally efficacious at lower doses as well. The most serious side effect associated with naltrexone use is hepatic toxicity, which is dose dependent and reversible on discontinuation of the drug (Yen et al. 2006). This supports that naltrexone can be a safer alternative to treat behavioral outbursts associated with DMDD. There is not much research evidence available supporting this treatment approach in DMDD, and hence it requires further investigation.