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Original Research

A Randomized Controlled Trial Investigating the Safety and Efficacy of Aripiprazole in the Long-Term Maintenance Treatment of Pediatric Patients With Irritability Associated With Autistic Disorder

Robert L. Findling, MD, MBA; Raymond Mankoski, MD, PhD; Karen Timko, MBA; Katherine Lears, BA; Theresa McCartney, BSN, MA; Robert D. McQuade, PhD; James M. Eudicone, MS, MBA; Joan Amatniek, MD, MSc; Ronald N. Marcus, MD; and John J. Sheehan, PhD

Published: January 15, 2014

Article Abstract

Objective: To evaluate the efficacy and safety of aripiprazole versus placebo in preventing relapse of irritability symptoms associated with autistic disorder in pediatric patients.

Method: This multicenter, double-blind, randomized, placebo-controlled, relapse-prevention trial enrolled patients (6-17 years) who met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR) criteria for autistic disorder and who also had serious behavioral problems (ie, tantrums, aggression, self-injurious behavior, or a combination of these behavioral problems) between March 2011 and June 2012. In phase 1, single-blind aripiprazole was flexibly dosed (2-15 mg/d) for 13-26 weeks. Patients with a stable response (≥ 25% decrease in Aberrant Behavior Checklist-irritability subscale score and a rating of “much improved” or “very much improved” on the Clinical Global Impressions-Improvement scale) for 12 consecutive weeks were randomized into phase 2 to continue aripiprazole or switch to placebo. Treatment was continued until relapse or up to 16 weeks. The primary end point was time from randomization to relapse.

Results: Eighty-five patients were randomized in phase 2. The difference in time to relapse between aripiprazole and placebo was not statistically significant (P = .097). Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo (hazard ratio [HR] = 0.57; number needed to treat [NNT] = 6). The most common adverse events during phase 1 were weight increase (25.2%), somnolence (14.8%), and vomiting (14.2%); and, during phase 2 (aripiprazole vs placebo), they were upper respiratory tract infection (10.3% vs 2.3%), constipation (5.1% vs 0%), and movement disorder (5.1% vs 0%).

Conclusions: In this study, there was no statistically significant difference between aripiprazole and placebo in time to relapse during maintenance therapy. However, the HR and NNT suggest some patients will benefit from maintenance treatment. Patients receiving aripiprazole should be periodically reassessed to determine the continued need for treatment.

Trial Registration: identifier: NCT01227668

J Clin Psychiatry 2014;75(1):22-30

Submitted: March 28, 2013; accepted November 6, 2013(doi:10.4088/JCP.13m08500).

Corresponding author: Robert L. Findling, MD, MBA, Child & Adolescent Psychiatry, Johns Hopkins Hospital, Bloomberg Children’s Center, 1800 Orleans St, Ste 12344A, Baltimore, MD 21287 (

Volume: 75

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