Riluzole as an adjunctive therapy to risperidone for the treatment of irritability in children with autistic disorder: A double-blind, placebo-controlled, randomized trial

Background: A hyperglutamatergic state has been shown to play a possible role in the pathophysiology of autistic disorders. Riluzole is a glutamate-modulating agent with neuroprotective properties, which has been shown to have positive effects in many neuropsychiatric disorders. Objective: The aim of this study was to assess the efficacy and tolerability of riluzole as an adjunctive to risperidone in the treatment of irritability in autistic children who were not optimally responding to previous medications. Study Design: This was a 10-week, randomized, double-blind, parallel-group, placebo-controlled trial. Participants: The study enrolled male and female outpatients aged 5-12 years with a diagnosis of autistic disorder based on the DSM-IV-TR criteria and a score of ≥12 on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale who had discontinued other medications because of a lack of efficacy. Interventions: Subjects received riluzole (titrated to 50 or 100 mg/day based on bodyweight) or placebo in addition to risperidone (titrated up to 2 or 3 mg/day based on bodyweight) for 10 weeks. Outcome: Patients were assessed at baseline, week 5, and week 10. The primary outcome measure was the difference in the change in the ABC-C irritability subscale score from baseline to week 10 between the two groups. We also compared changes in other ABC-C subscale scores and Clinical Global Impressions-Improvement (CGI-I) scale scores between the two groups. Results: Forty-nine patients were enrolled in the study, and forty children completed the trial (dropouts: placebo = 4, riluzole = 5). A significantly greater improvement in the study primary outcome (the ABC-C irritability subscale score) was achieved by the riluzole-treated children compared with the placebo group (P = 0.03). Patients in the riluzole group also showed significantly greater improvement on the lethargy/social withdrawal (P = 0.02), stereotypic behavior (P = 0.03), and hyperactivity/non-compliance subscales (P = 0.005), but not on the inappropriate speech subscale (P = 0.20) than patients in the placebo group. Eleven patients in the riluzole group and five patients in the placebo group were classified as responders based on their CGI-I scores [χ²(1) = 3.750, P = 0.05]. Children in the riluzole group experienced significantly more increases in their appetite and bodyweight than children in the placebo group by the end of the study. Conclusion: Riluzole add-on therapy shows several therapeutic outcomes, particularly for improving irritability, in children with autism. However, its add-on to risperidone also results in significantly increased appetite and weight gain.