Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders

Abstract

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and by repetitive behaviors and interests. Irritability/aggression is a significant comorbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability/aggression in children and adolescents with ASD. This was a 12-week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. A total of 55 subjects gavetheir consent and 27 were randomized in a 1 : 1 manner (mean age 9.46+/-2.46, mean nonverbal IQ 63.3+/-23.9). Two subjects from the active group and one subject from the placebo group discontinued the study because of either a lack of efficacy or side effects (increased irritability). Primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, which focused on irritability. Overall, 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGI-irritability OR: 16.7, Fisher's exact p=0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale (p=0.048). There was a trend for responders to have higher valproate blood levels compared with nonresponders. This study suggests the efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.

Figure 1

Consort diagram. ^*One subject withdrew because of side effects, one subject withdrew for nonefficacy. ^**One subject withdrew because of side effects.

Figure 2

Improvements in ABC-Irritability subscale in divalproex vs placebo-randomized subjects over 12 weeks. There is a significant weeks x condition interaction (t=−2.09, df=22.71, p=0.048), suggesting that the active group showed a drop of more than 0.53 points per week compared with the placebo group. Note that the scatter plot includes all subjects, but the symbols correspond to ABC values. Some subjects had identical scores and are therefore reflected in a single overlapping symbol.