International Meeting for Autism Research: A Randomized Controlled Double-Blind Trial of N-Acetylcysteine In Children with Autism

A Randomized Controlled Double-Blind Trial of N-Acetylcysteine In Children with Autism

Thursday, May 12, 2011: 3:45 PM
Elizabeth Ballroom GH (Manchester Grand Hyatt)
2:00 PM
A. Y. Hardan1, L. K. Fung2, R. A. Libove1, T. V. Obukhanych3, S. Nair4, T. W. Frazier5, L. Herzenberg3 and R. Tirouvanziam6, (1)Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, (2)Stanford University, (3)Department of Genetics, Stanford University School of Medicine, Stanford, CA, (4)Stanford University, Stanford, CA, (5)Center for Autism and Center for Pediatric Behavioral Health, Cleveland Clinic, Cleveland, OH, (6)Department of Pediatrics, Stanford University School of Medicine, Stanford, CA

Causes of autism remain elusive yet clearly combine genetic, developmental, and environmental factors. Several neurobiologic models have recently been proposed including the existence of a glutamatergic dysfunction and excessive oxidative stress. These models have sparked hope for the development of targeted therapeutic agents leading to disease-specific interventions. 


The goal of this study was to conduct a double-blind randomized controlled 12-week trial of N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant known to replete glutathione, in children with autism. Specific aims were to assess the tolerability of NAC and its effectiveness in the treatment of behavioral deficits in children with autism.  


The present investigation is a 12-week, double-blind randomized, placebo-controlled study of NAC in children with autistic disorder who are between the ages of 3 and 12 years. Randomization was based on age and gender. Subjects randomized to the active drug were initiated at the dose of 900 mg every day for the first 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks.  If subjects could not tolerate a specific dose, s/he would be maintained at the lowest tolerated dose.  Subjects were evaluated at baseline, week 4, week 8 and week 12.  The Aberrant Behavior Checklist (ABC), the Clinical Global Rating Scale (CGRS), and a side effects rating scale were obtained in each visit.  Other clinical measures, including the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale (SRS), were also obtained at baseline and at the end of the trial at week 12. Analyses were completed using a mixed effects regression model.


Thirty-three subjects representing 31 males and 2 females were included in the study. When examining all randomized participants, improvement with NAC was observed compared to placebo on the irritability subscale of the ABC (F(3,75)=5.25, p=.002) beginning in week 4 and continuing through the end of the study. The same pattern was present for ABC-Total Scores (F(3,75)=3.11, p=.031). NAC treatment improved stereotypic/repetitive behavior on the ABC (ABC-Stereotypy F(3,76)=2.87, p=.042), but these reductions were no longer significant when ABC-irritability was included as a time-varying covariate. In spite of limited scaling and sensitivity of the CGI-S, there was a trend toward improvements in global severity across the study (F(3,75)=2.47, p=.068). Improvements with NAC were observed on RBS-R and SRS but differences with placebo did not reach statistical significance. Minimal side effects were encountered with mild gastro-intestinal symptoms being reported.  


This preliminary randomized, placebo-controlled, double-blind trial provides the first evidence in the usefulness of NAC in treating irritability and disruptive behaviors in children with autism. While benefits are being observed in associated behaviors, it remains unclear if NAC is beneficial in treating the core features of autism. Although this current report has shown substantial magnitude of desirable effects, these data have to be used with caution as it represents a preliminary analysis of a relatively small study. Replication of these data in a larger study is warranted to confirm these findings.

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