A Randomised Placebo-Controlled Trial to Determine If Fluoxetine Is Effective for Improving Autistic Behaviours

Background: Selective Serotonin Receptor Inhibitors (SSRIs) are often used to reduce the severity of core behaviours of Autism Spectrum Disorders (ASD) but their efficacy remains uncertain. This study was a multi-centre randomized, placebo-controlled trial examining the efficacy and tolerability of fluoxetine, a commonly prescribed SSRI, for reducing the frequency and severity of restricted, repetitive and stereotypic behaviours in ASD. Methods: Participants were aged 7·5-18 years with ASD, who were randomised to receive fluoxetine or placebo. Study medication was commenced at 4 or 8mg/day for the first week (4mg if <40Kg; 8mg if ≥40Kg), then titrated up to a maximum dose of 20mg/day for participants <40kg and 30mg/day for participants ≥40kg, over 4 weeks. Participants remained on the medication for a total of 16 weeks. The primary outcome was the total score on the Children's Yale-Brown Obsessive Compulsion Scale - Modified for Pervasive Developmental Disorders at 16 weeks. A range of secondary outcomes were also examined, measuring anxiety, repetitive and challenging behaviours at 16 weeks. Findings: 146 participants (124 male, 85%) were enrolled in the trial (75 fluoxetine, 71 placebo). The mean age of study participants was 11·2 (standard deviation 2·9) years, and 30% (n = 44) had an intellectual disability. There was little evidence that fluoxetine reduced obsessivecompulsive behaviours at 16 weeks compared with placebo (mean difference -1·62 (CI -3·57; 0·33), p = 0·10), with little evidence of group differences in any of the secondary outcomes (all p>0.07). Adverse events were similar in the two groups. Interpretation: This randomised placebo-controlled trial did not demonstrate that fluoxetine reduced the restricted and repetitive behaviours associated with ASD compared with placebo. Fluoxetine is therefore not recommended in the routine treatment of ASD symptoms. Trail Registration Number: Australian and New Zealand Clinical Trials Registry (ACTRN12608000173392). Funding Statement: The study was funded by the National Health and Medical Research Council of Australia (NHMRC project grant number 607332) and the Royal Children’s Hospital Foundation, Melbourne, Australia. Infrastructure support was provided by the Victorian Government’s Operational Infrastructure Support Program. Declaration of Interests: Dinah Reddihough, Catherine Marraffa, Anissa Mouti, Molly O’Sullivan, Katherine Lee, Francesca Orsini, Joanna Granich, Andrew Whitehouse, John Wray, David Dossetor, Natalie Silove and Michael Kohn all have no conflicts of interest to declare. Philip Hazell’s employer has received payment from Shire for speaker fees. Paramala Santosh’s employer has received payment from Medice for speaker fees and from Newron Pharma for conducting clinical trials. Ethics Approval Statement: The study was approved by Human Research Ethics Committees (HRECs) at each site: The Royal Children’s Hospital Human Research Ethics Committee (EC00238) for the site in Victoria, the Sydney West Area Health Service Human Research Ethics Committee, Westmead Campus (EC00152) for the site in New South Wales and the Princess Margaret Hospital for Children Ethics Committee (EC00268) for the site in Western Australia.