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Does fluoxetine compared with placebo reduce obsessive-compulsive behaviors among children and adolescents with autism spectrum disorders?
In this randomized clinical trial that involved 146 participants, mean scores for obsessive-compulsive behaviors at 16 weeks (as measured by the Children’s Yale-Brown Obsessive Compulsive Scale–Modified for Pervasive Developmental Disorders; range, 0-20 points; minimal clinically important difference, 2 points) were 9.02 points in the fluoxetine group and 10.89 points in the placebo group, a difference that was statistically significant. However, prespecified analyses that accounted for potentially confounding factors and baseline imbalances were null, with CIs that included the minimal clinically important difference.
In this preliminary study of children and adolescents with autism spectrum disorders, treatment with fluoxetine resulted in significantly lower scores for obsessive-compulsive behaviors at 16 weeks, although interpretation is limited by null findings and imprecise estimates from prespecified analyses that accounted for confounding factors and baseline imbalances.
Selective serotonin receptor inhibitors are prescribed to reduce the severity of core behaviors of autism spectrum disorders, but their efficacy remains uncertain.
To determine the efficacy of fluoxetine for reducing the frequency and severity of obsessive-compulsive behaviors in autism spectrum disorders.
Design, Setting, and Participants
Multicenter, randomized, placebo-controlled clinical trial. Participants aged 7.5-18 years with autism spectrum disorders and a total score of 6 or higher on the Children’s Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (CYBOCS-PDD) were recruited from 3 tertiary health centers across Australia. Enrollment began November 2010 and ended April 2017. Follow-up ended August 2017.
Participants were randomized to receive fluoxetine (n = 75) or placebo (n = 71). Study medication was commenced at 4 or 8 mg/d for the first week, depending on weight, and then titrated to a maximum dose of 20 or 30 mg/d over 4 weeks. Treatment duration was 16 weeks.
Main Outcomes and Measures
The primary outcome was the total score on the CYBOCS-PDD (scores range from 0-20; higher scores indicate higher levels of maladaptive behaviors; minimal clinically important difference, 2 points) at 16 weeks postrandomization, analyzed with a linear regression model adjusted for stratification factors (site, age at baseline, and intellectual disability), with an additional prespecified model that included additional adjustment for baseline score, sex, communication level, and imbalanced baseline and demographic variables.
Among the 146 participants who were randomized (85% males; mean age, 11.2 years), 109 completed the trial; 31 in the fluoxetine group and 21 in the placebo group dropped out or did not complete treatment. The mean CYBOCS-PDD score from baseline to 16 weeks decreased in the fluoxetine group from 12.80 to 9.02 points (3.72-point decrease; 95% CI, −4.85 to −2.60) and in the placebo group from 13.13 to 10.89 points (2.53-point decrease; 95% CI, −3.86 to −1.19). The between-group mean difference at 16 weeks was −2.01 (95% CI, −3.77 to −0.25; P = .03) (adjusted for stratification factors), and in the prespecified model with further adjustment, it was −1.17 (95% CI, −3.01 to 0.67; P = .21).
Conclusions and Relevance
In this preliminary study of children and adolescents with autism spectrum disorders, treatment with fluoxetine compared with placebo resulted in significantly lower scores for obsessive-compulsive behaviors at 16 weeks. Interpretation is limited by the high dropout rate, null findings of prespecified analyses that accounted for potentially confounding factors and baseline imbalances, and CIs for the treatment effect that included the minimal clinically important difference.
anzctr.org.au Identifier: ACTRN12608000173392
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Corresponding Author: Dinah S. Reddihough, MD, Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria 3052, Australia (firstname.lastname@example.org).
Accepted for Publication: August 23, 2019.
Author Contributions: Dr Reddihough had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Reddihough, Marraffa, O’Sullivan, Lee, Hazell, Wray, Dossetor, Santosh, Silove, Kohn.
Acquisition, analysis, or interpretation of data: Reddihough, Marraffa, Mouti, Lee, Orsini, Hazell, Granich, Whitehouse, Wray, Dossetor, Silove, Kohn.
Drafting of the manuscript: Reddihough, Marraffa, Lee, Orsini, Granich, Whitehouse, Wray, Kohn.
Critical revision of the manuscript for important intellectual content: Reddihough, Marraffa, Mouti, O’Sullivan, Lee, Orsini, Hazell, Whitehouse, Wray, Dossetor, Santosh, Silove, Kohn.
Statistical analysis: Lee, Orsini, Whitehouse.
Obtained funding: Reddihough, Marraffa, Hazell, Whitehouse, Kohn.
Administrative, technical, or material support: Reddihough, Mouti, O’Sullivan, Granich, Whitehouse, Dossetor, Santosh, Kohn.
Supervision: Reddihough, Marraffa, Dossetor, Kohn.
Recruitment and clinical expertise: Wray.
Ethics applications, recruiting, testing, conducting assessments and reports, monitoring participants, entering data: Mouti.
Coordination of trial at site: Granich.
Study coordination, recruitment, and database management: O’Sullivan.
Conflict of Interest Disclosures: Drs Reddihough and Lee and Ms Orsini report receiving grants from NHMRC and the Royal Children's Hospital Foundation during the conduct of the study. Dr Hazell reports that his employer has received payment from Shire for speaker’s fees. Dr Whitehouse reports receiving grants from NHMRC during the conduct of the study. Dr Santosh reports that his employer has received payment from Medice for speaker’s fees, grants from Newron Pharma for conducting clinical trials, and he is a shareholder with Health Tracker Ltd, which has no relationship with the submitted work.. No other disclosures were reported.
Funding/Support: The study was funded by the NHMRC (NHMRC project grant 607332) (Drs Reddihough, Marraffa, Hazell, Lee, Kohn, and Wray) and the Royal Children’s Hospital Foundation, Melbourne, Australia (Dr Reddihough). Infrastructure support was provided by the Victorian government’s Operational Infrastructure Support Program. The Murdoch Children’s Research Institute, Melbourne, was the sponsor for this study.
Role of the Funder/Sponsor: The agencies providing funding/support for this work had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 4.
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