Pharmacologic Treatment of Repetitive Behaviors in Autism Spectrum Disorders: Evidence of Publication Bias

Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48109-2215, USA.
PEDIATRICS (Impact Factor: 5.47). 04/2012; 129(5):e1301-10. DOI: 10.1542/peds.2011-3285
Source: PubMed


The goal of this study was to examine the efficacy of serotonin receptor inhibitors (SRIs) for the treatment of repetitive behaviors in autism spectrum disorders (ASD).
Two reviewers searched PubMed and for randomized, double-blind, placebo-controlled trials evaluating the efficacy of SRIs for repetitive behaviors in ASD. Our primary outcome was mean improvement in ratings scales of repetitive behavior. Publication bias was assessed by using a funnel plot, the Egger's test, and a meta-regression of sample size and effect size.
Our search identified 5 published and 5 unpublished but completed trials eligible for meta-analysis. Meta-analysis of 5 published and 1 unpublished trial (which provided data) demonstrated a small but significant effect of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.22 [95% confidence interval: 0.07-0.37], z score = 2.87, P < .005). There was significant evidence of publication bias in all analyses. When Duval and Tweedie's trim and fill method was used to adjust for the effect of publication bias, there was no longer a significant benefit of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.12 [95% confidence interval: -0.02 to 0.27]). Secondary analyses demonstrated no significant effect of type of medication, patient age, method of analysis, trial design, or trial duration on reported SRI efficacy.
Meta-analysis of the published literature suggests a small but significant effect of SRI in the treatment of repetitive behaviors in ASD. This effect may be attributable to selective publication of trial results. Without timely, transparent, and complete disclosure of trial results, it remains difficult to determine the efficacy of available medications.

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    • "They found that although there was a significant treatment effect of SSRI (used for treating repetitive behaviors in ASD), these findings did not persist after they statistically adjusted for the publication bias. Meta-regression did not demonstrate a significant effect of SSRI treatment with age, although the trend among trials revealed that increased average patient age was associated with a greater treatment effect.48 A Cochrane review examined RCTs that studied the efficacy of several SSRIs (fluoxetine, fluvoxamine, fenfluramine, and citalopram) in treating ASD and reported that there was no evidence that SSRIs improved ASD symptoms, adding that it may even possibly cause harm.49 "
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    • "In ASD, however, 5-HT is thought to be the main abnormal neurotransmitter in the disorder, and there is a wealth of research supporting the presence of genetic and biochemical serotonergic abnormalities, leading to high levels of 5-HT (Piven et al. 1991; Chugani et al. 1997, 1999; Mulder et al. 2004; Murphy et al. 2006; Hranilovic et al. 2007; Makkonen et al. 2008; Zafeiriou et al. 2009; Nakamura et al. 2010), in addition to the positive effect of Fluoxetine on stereotyped behaviors (Fatemi et al. 1998; Hollander et al. 2005, 2012; Carrasco et al. 2012) and brain activation in areas related to reward reversal (Buchsbaum et al. 2001; Dichter et al. 2010) in children and adults with ASD. These differing biochemical abnormalities may have accounted for the positive upregulation effect of Fluoxetine on ASD mPFC activation and its negative downregulating effect on mPFC activation in ADHD. "
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    • "A small but significant effect in the treatment of repetitive behaviors with SSRIs is suggested in the published literature (Carrasco, Volkmar, & Bloch, 2012). However, the effect may be due to publication bias if studies that find a lack of support for SSRI therapy in ASD remain unpublished (Carrasco et al., 2012). This indicates that inhibition of SLC6A4 and the resulting increase in synaptic 5-HT is not sufficient as a treatment for ASD symptoms. "
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