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Safety and Tolerability of Aripiprazole for Irritability in Pediatric Patients With Autistic Disorder: A 52-Week, Open-Label, Multicenter Study

Ronald N. Marcus, MD; Randall Owen, MD; George Manos, PhD; Raymond Mankoski, MD, PhD; Lisa Kamen, MHA; Robert D. McQuade, PhD; William H. Carson, MD; and Robert L. Findling, MD

Published: July 26, 2011

Article Abstract

Objective: Evaluate the long-term safety and tolerability of aripiprazole in the treatment of irritability in pediatric subjects (6-17 years) with autistic disorder.

Method: A 52-week, open-label, flexibly dosed (2-15 mg/d) study of the safety and tolerability of aripiprazole in outpatients with a DSM-IV-TR diagnosis of autistic disorder who either had completed 1 of 2 antecedent, 8-week randomized trials or were enrolled de novo (ie, not treated in the randomized trials). Safety and tolerability measures included incidences of adverse events, extrapyramidal symptoms, weight, metabolic measures, vital signs, and other clinical assessments.

Results: Subjects were enrolled between September 2006 and June 2009. Three hundred thirty subjects entered the treatment phase: 86 de novo, 174 prior aripiprazole, and 70 prior placebo. A total of 199 (60.3%) subjects completed 52 weeks of treatment. Adverse events were experienced by 286/330 subjects (86.7%). Common adverse events included weight increase, vomiting, nasopharyngitis, increased appetite, pyrexia, upper respiratory tract infection, and insomnia. Discontinuations due to adverse events occurred in 35/330 randomized subjects (10.6%)—most commonly aggression and weight increase. One patient discontinued from the study due to a laboratory-related adverse event (moderately increased alanine transaminase and aspartate transaminase). Nine subjects experienced serious adverse events—most frequently aggression. Extrapyramidal symptoms-related adverse events occurred in 48/330 subjects (14.5%)—most commonly tremor (3.0%), psychomotor hyperactivity (2.7%), akathisia (2.4%), and dyskinesia (not tardive, 2.4%). At > 9 months’ aripiprazole exposure (n = 220), mean change in body weight z score was 0.33 and body mass index z score was 0.31. The percentages of subjects with clinically significant fasting metabolic abnormalities at > 9 months were 2% for glucose, 5% for total cholesterol, 7% for low-density lipoprotein cholesterol, 30% for high-density lipoprotein cholesterol, and 5% for triglycerides.

Conclusions: Aripiprazole was generally safe and well tolerated in the long-term treatment of irritability associated with autistic disorder in pediatric subjects. Weight should be proactively monitored during long-term treatment.

Trial Registration: clinical Identifier: NCT00365859

J Clin Psychiatry

Submitted: December 22, 2009; accepted January 3, 2011.

Online ahead of print: July 26, 2011 (doi:10.4088/JCP.09m05933).

Corresponding author: Ronald N. Marcus, MD, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492 (

Volume: 72

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