Efficacy and Safety of Aripiprazole for the Treatment of Irritability Associated with Autistic Disorder in Children and Adolescents (6–17 Years): Results from Two 8-Week, Randomized, Double-Blind, Placebo-Controlled Trials

Background: Many individuals with autistic disorder also experience problematic behaviors including irritability, aggression, tantrums, rapidly changing moods, and self-injurious behavior. Atypical antipsychotics may be useful for the treatment of these behaviors in the context of a comprehensive treatment program.

Objectives: Evaluate the short-term efficacy and safety of aripiprazole in the treatment of irritability associated with autistic disorder 

Methods: Two 8-week, randomized, double-blind, parallel-group trials evaluated the efficacy of aripiprazole (flexible dose [2–15 mg] and fixed dose [5, 10 and 15 mg/day]) versus placebo using the caregiver-rated Aberrant Behavior Checklist Irritability Subscale (ABC-I, which measures symptoms of aggression, tantrums, and self-injurious behavior) as the primary endpoint. Secondary efficacy measures, as well as safety and tolerability, were also assessed.

Results: Ninety-eight patients were randomized in the flexible dose trial, 218 patients in the fixed dose trial. Statistically significant greater improvement was seen with aripiprazole in both trials on the ABC-I at endpoint (Week 8 [LOCF] p<0.05). Secondary results favoring aripiprazole over placebo (p≤0.05 at endpoint [LOCF]) included the Clinical Global Impression – Improvement and the ABC Hyperactivity and Stereotypy Subscales (2–15; 5, 10, 15 mg); Clinical Global Impression – Severity of Illness (2–15; 10, 15 mg only); Children’s Yale-Brown Obsessive Compulsive Scale (modified), Inappropriate Speech Subscale (2–15; 15 mg only); and Response Rate (2–15mg; 5 mg only). Discontinuation rates due to adverse events (AEs) were: flexible dose: placebo 6%, aripiprazole 11%;  fixed dose: placebo 8%, aripiprazole – 5 mg 9%, 10 mg 14%, and 15 mg 7%. Adverse events (sedation, drooling, tremor, fatigue) were similar between the trials. There were two serious AEs: presyncope (5 mg) and aggression (10 mg) in the fixed dose trial. Mean weight gain at week 8 (p<0.05 for each vs. placebo) was – flexible dose 1.9 kg (2–15 mg) and 0.5 kg (placebo) and fixed dose 1.5 kg (5 mg), 1.4 kg (10 mg), 1.6 kg (15 mg), and 0.4 kg (placebo).

Conclusions: Aripiprazole was efficacious in the treatment of irritability in children and adolescents with autistic disorder and was generally safe and well-tolerated in two short-term trials, although significant weight gain was observed in some subjects.