RRBs constitute a core feature of ASD. In the past decade, a flurry of research activity has allowed for the better understanding of RRB subtyping and the development of better tools for diagnosing and measuring RRBs. Unfortunately, a gap continues to exist in the literature with regard to the effective pharmacologic treatment of RRBs in children and adults diagnosed with this disorder.54
Addressing this question remains of utmost importance, given that RRBs continue to be a major barrier toward learning and social adaptation in both children and adults with ASD.
Initial results showed a small effect of SRIs for the treatment of repetitive behaviors in autism, including obsessions and compulsions. However, a closer look at the trials included in this meta-analysis demonstrated significant evidence of heterogeneity and publication bias. It is noteworthy that, after adjusting for publication bias in the literature, the effect of SRI medications in ASD was no longer significant.
As part of this meta-analysis, we also evaluated a number of indicators of publication bias, including funnel plots, adjusted effect sizes after publication had been taken into account using Duval and Tweedie's procedure, and tests for the symmetry of the funnel plots by using Egger’s linear regression method. This research made it clear that the effects of SRI treatment in ASD are considerably overrated because of publication bias. In addition, our search strategy uncovered as many completed SRI trials in ASD with unpublished results as have been published, further supporting the influence of potential publication bias on effect estimates.
Publication bias has been demonstrated previously to influence the estimates of many other interventions in child psychiatry and medicine. The potential efficacy of antidepressant agents has been particularly influenced by this phenomenon. For example, previous research found that only 51% of the antidepressant trials registered with the US Food and Drug Administration reported positive results. By contrast, as many as 94% of trials published in the peer-reviewed literature evaluating antidepressant agents reported positive results.55
A particularly influential meta-analysis published in 2004 suggested that published trials of antidepressant agents in children demonstrated greater evidence of efficacy and a more benign risk/benefit profile than those trials that were not published but submitted to regulatory agencies.56
A time-lag bias in the pediatric antidepressant literature whereby negative trials have a longer time to publication than positive trials has also been demonstrated.57
Regardless of whether frank publication bias or time-lag bias is the cause of the large unpublished available literature in SRI trials for the treatment of repetitive behaviors in autism, there is a strong possibility that publication has distorted the perception (and evidence) of how effective these medications likely are.
Our meta-analysis is not without limitations. Our analyses were limited by the reduced number of published, randomized, placebo-controlled trials of SRIs in ASD that are currently available and were bound to whichever rating scales the authors used to study RRB outcomes. Unfortunately, in most studies included in this meta-analysis, changes in RRBs were quantified by using a number of scales that were originally written for quantifying obsessions and compulsions in OCD (eg, Children’s Yale-Brown Obsessive-Compulsive Scale). The overall lack of specific assessments to better quantify RRBs in autism clinical trials is an ongoing issue in the field and one that complicates meta-analysis research.
When making a decision regarding whether to initiate a medication, it is important to weigh the potential benefits against potential risks. All articles included in this meta-analysis provided data on the adverse events associated with the use of SRIs versus placebo in patients with ASD.46–50
In general, the adverse event profile of medications was very similar to that observed in the general population. Clomipramine, a tricyclic antidepressant, was poorly tolerated by subjects, with a substantially increased number of dropouts due to adverse effects in the treatment compared with placebo groups. Increased rates of sedation, insomnia, and cardiovascular adverse events were observed with clomipramine compared with placebo. Although SRIs were better tolerated than clomipramine, increased rates of gastrointestinal adverse events were observed compared with placebo. Finally, although perhaps not effective in the treatment of RRBs, there is some evidence to suggest that SRIs may be helpful for the proper management of comorbid anxiety in ASD, and therefore its therapeutic use in ASD should not be completely dismissed.58