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Fluoxetine (Prozac) did not significantly lower the frequency or severity of obsessive compulsive behaviors in children with autism spectrum disorders (ASD), results from a randomized trial in Australia suggested.

At 16 weeks, raw scores on an obsessive-compulsive scale were lower among children treated with fluoxetine than placebo, but a fully adjusted model that included sex, verbal ability, and baseline imbalances showed scores that were similar, reported Dinah Reddihough, MD, of the Royal Children's Hospital in Victoria, and colleagues, in .

The adjusted analysis should be given more weight because it corrects for imbalances in the study, Reddihough maintained. "While this is a study with negative findings, it is an important addition to the evidence base for deciding when and when not to prescribe psychoactive medications," she said in a statement.

The effects of ASD are "a significant health disability burden for individuals and their families," Reddihough added. "Restricted, repetitive and stereotypic behaviors frequently interfere with everyday functioning and include ritualistic behaviors, unusual sensory interests, and difficulty coping with change, which often manifests as anxiety, irritability, aggression and self-injury."

The results of this trial "will challenge the field to reconcile the limited performance of the drug with long-standing utilization patterns," observed Bryan King, MD, of the University of California San Francisco, in an . "Fluoxetine and other selective serotonin reuptake inhibitors have been among the most widely prescribed medications for individuals with ASD for well over a decade."

Selective serotonin receptor inhibitors (SSRIs) often are prescribed to reduce the severity of ASD behaviors, but a of nine SSRI trials concluded there was no evidence of effect of SSRIs for ASD in children and limited evidence in adults.

In their , Reddihough and co-authors recruited 146 children who had autism spectrum disorders -- including autism, Asperger disorder, and pervasive developmental disorder not otherwise specified -- and a total score of 6 or higher on the Children's Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder () from three tertiary centers from November 2010 to April 2017.

Participants had an average age of about 11 and 85% were boys. The fluoxetine group had a slightly higher proportion of boys and participants with a family history of ASDs. The placebo group had higher scores on the and the lethargy subscale than the fluoxetine group.

The researchers randomized 75 participants to receive fluoxetine and 71 to placebo. Depending on weight, fluoxetine started at 4 or 8 mg/day for the first week and was titrated to a maximum dose of 20 or 30 mg/day over 4 weeks. Treatment lasted 16 weeks.

The primary outcome was the total score on the CYBOCS-PDD at 16 weeks. An additional pre-specified model included additional adjustment for baseline score, sex, communication level, and imbalanced baseline and demographic variables. Scores on the CYBOCS-PDD range from 0 to 20, with higher scores indicating higher levels of maladaptive behaviors; a minimal clinically important difference is 2 points.

Only 109 participants completed the trial: 31 children in the fluoxetine group and 21 children in the placebo dropped out or stopped treatment. Parental decisions and adverse events that family members attributed to the medication contributed to the dropout rate, the researchers noted.

From baseline to 16 weeks, CYBOCS-PDD scores decreased in the fluoxetine group from 12.80 to 9.02 points and in the placebo group from 13.13 to 10.89 points in the primary analysis. The between-group mean difference was −2.01, 95% CI −3.77 to −0.25; P=0.03. When sex, verbal ability, baseline CYBOCS-PDD scores, and baseline imbalances in the Repetitive Behavior Scale and the Aberrant Behavior Checklist lethargy subscale were factored in, the mean difference became non-significant at −1.17, 95% CI −3.01 to 0.67; P=0.21.

A multiple imputation analysis to handle missing data did not show evidence of benefit of fluoxetine versus placebo, even without adjusting for the baseline imbalance (mean difference −1.82; 95% CI −3.71 to 0.06; P=0.06).

"Although cautious interpretation of the results from the primary analysis is warranted, all analyses of the primary outcome yielded 95% CIs that extended well above the minimum clinically important difference of 2 points, indicating that fluoxetine may reduce the frequency and severity of obsessive-compulsive behaviors in children and adolescents with ASDs," the researchers wrote. "Given the large amount of missing data, the study may have been underpowered to detect the minimum clinically important difference of 2 points."

Adverse events were reported in 45% of the fluoxetine group and 42% of the placebo group, most commonly mood disturbance, gastrointestinal problems, and sleep disorders. Because neither the frequency nor severity of adverse events differed between groups, the dose might have been too low, King pointed out. "Prior studies and clinical practice indicate that some children with ASD may be uniquely sensitive to behavioral activation and other adverse effects of SSRIs, and the absence of any such signal in this trial could indicate that the dosing was set too conservatively," he wrote.

Despite its limitations, the study shows results that are "consistent with similar trials and contributes new evidence that SSRIs do not add any value over placebo for repetitive behaviors in children and adolescents with ASD as captured in the CYBOCS-PDD," King noted. "Additional rigorous studies are needed, both to identify other potential treatments for core symptoms and, for SSRIs, to determine whether clinical indications other than repetitive behaviors might account for their persistent widespread use in ASD," he added.

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