乌鸦传媒

Study Authors: Dinah S. Reddihough, Catherine Marraffa, et al.; Bryan King

Target Audience and Goal Statement: Pediatricians, neurologists, psychiatrists

The goal of this study was to examine the efficacy of fluoxetine (Prozac) for reducing the frequency and severity of obsessive-compulsive behaviors in autism spectrum disorders (ASDs).

Question Addressed:

• Did fluoxetine, compared with placebo, reduce obsessive-compulsive behaviors among children and adolescents with ASD?

Synopsis and Perspective:

Persistent deficits in social communication and social interaction, as well as restricted, repetitive patterns of behavior, interests, and activities are characteristic of the neurodevelopmental condition known as . Converging support from genetic, biological, and neuroimaging studies have indicated that people with ASD have higher levels of serotonin than those without these conditions. Thus, the evidence suggested that selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, might play a contributory role in the pathophysiology of ASDs.

Up to 32% of children and adolescents with ASDs who are prescribed medications take SSRIs, but results from a randomized double-blind placebo-controlled suggested that fluoxetine was no better than placebo for the treatment of repetitive behaviors in youths with ASDs.

Specifically, taking fluoxetine for 16 weeks failed to significantly lower obsessive-compulsive behaviors in youths with ASDs, including Asperger's syndrome and pervasive developmental disorder (PDD), reported Dinah Reddihough, MD, of the Royal Children's Hospital in Victoria, Australia, and colleagues in .

For the study, 146 eligible participants (mean age 11.2 years; 85% boys) from three tertiary health centers across Australia were randomized to receive fluoxetine (n=75) or placebo (n=71), titrated based on weight as directed by a study physician. 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 mg/d (participants <40 kg) or 3 0mg/d (participants ≥40 kg) over 4 weeks.

Participants had ASDs such as Asperger disorder, and pervasive developmental disorder, not otherwise specified. Youths scored at ≥6 for compulsive behaviors measured with the Children's Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (). Researchers permitted medications for attention deficit-hyperactivity disorder.

The difference between groups in 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 served as the primary outcome. Possible obsessions and compulsions, rated from zero to 4 across five items, on this detailed symptom checklist focused on stereotypic and complex behaviors typically associated with ASDs (time spent on obsessions, interference, distress, resistance, and degree of control).

Secondary outcomes included the difference between groups at 16 weeks in the following scales:

• Repetitive Behavior -Revised
• Spence Children's Anxiety Scale
• Aberrant Behavior -Community Version
• Clinical Global Impression Scale-Global Improvement and Efficacy Index

Researchers also assessed the frequency and type of adverse events (AEs) that occurred during the 16 weeks, the 4 weeks of weaning, and at 2 weeks post-completion.

Only 109 participants completed the trial, with "reasons for treatment discontinuation included parent/caregiver decision to drop out of the study (20 fluoxetine, 12 placebo), adverse events (5 fluoxetine, 4 placebo), clinician decision to discontinue treatment (2 fluoxetine, 2 placebo), commencement of study-excluded medication (1 fluoxetine), and a small number with other personal reasons (3 fluoxetine, 3 placebo)," according to the researchers.

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).

The authors reported that 45% of the fluoxetine group and 42% of the placebo group experienced AEs, most commonly mood disturbance (especially irritability), gastrointestinal problems such as nausea and diarrhea, and sleep disorders. Researchers also noted that two participants in the placebo group and none in the fluoxetine group experienced serious AEs (suicidality).

The placebo group had a comparatively more severe ASD behavioral phenotype than the fluoxetine group. The researchers accounted for this baseline imbalance in their sensitivity analyses, but highlighted this important caveat as it affected the initially positive findings seen in the primary analysis.

Other study limitations included difficulties in recruitment and retention, as discontinued participation (41% in the fluoxetine group; 30% in the placebo group). The moderately high dropout rate was attributed to the perceived failure of treatment and adverse reactions being attributed to the medication despite the fact the medication may not have been responsible, the researchers noted.

Source Reference: 2019; DOI:10.1001/jama.2019.14685

Editorial: 2019; DOI:10.1001/jama.2019.11738

Study Highlights: Explanation of Findings

One in 59 children had a by the age of 8 years, according to 2014 CDC data. Boys were four times more likely to be diagnosed with ASD than girls. are central to ASD and may be linked with high levels of anxiety and self-injury. Such behaviors may functionally impair the individual and create a burden for families. Only from 3% to 10% of people with autism are able to live independently as adults. Conceptually, pharmacotherapy could aid in making individuals more responsive to educational and behavioral interventions.

When Reddihough's group first registered the trial in 2008, there was very little evidence to guide the . Use of psychotropic medications remained common in the ensuing years, despite a of nine trials, involving 320 people with ASDs, who took four SSRIs -- fluoxetine, fluvoxamine (Luvox), fenfluramine, and citalopram (Celexa) -- suggesting that there was no evidence of the effect of SSRIs in children.

While initial results showed some behavioral improvements, Reddihough said in a that additional analyses revealed no significant difference between the groups, which should be given more weight because it corrects for any imbalances in the data.

"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 stated, adding that "if parents have any concerns about the use of fluoxetine they should speak with their health professional before changing any treatment plan."

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 . But King pointed out that the study population was not enriched for children for whom repetitive behaviors were specific or significant problems.

"While arguably a strength from the standpoint of generalizing findings to clinical practice, the population with ASD is heterogeneous, and using entry criteria that did not produce a study cohort of children at greatest risk may have made it more difficult to find a therapeutic signal," he wrote.

Neither the frequency nor severity of AEs differed between groups, but 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.

"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," King concluded.