Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis
Open accessAbstract
Large placebo responses in many clinical trials limit our capacity to identify effective therapeutics. Although it is often assumed that core behaviors in children with autism spectrum disorders (ASDs) rarely remit spontaneously, there has been limited investigation of the size of the placebo response in relevant clinical trials. These trials also rely on caregiver and clinical observer reports as outcome measures. The objectives of this meta-analysis are to identify the pooled placebo response and the predictors of placebo response in pharmacological and dietary supplement treatment trials for participants with a diagnosis of ASD. Randomized controlled trials (RCTs) in pediatric ASD, conducted between 1980 and August 2014, were identified through a search of Medline, EMBASE, Web of Science, Cochrane Database of Systematic Reviews and clinicaltrials.gov. RCTs of at least 14 days duration, comparing the treatment response for an oral active agent and placebo using at least one of the common outcome measures, were included. Analysis of 25 data sets (1315 participants) revealed a moderate effect size for overall placebo response (Hedges’ g=0.45, 95% confidence interval (0.34–0.56), P<0.001). Five factors were associated with an increase in response to placebo, namely: an increased response to the active intervention; outcome ratings by clinicians (as compared with caregivers); trials of pharmacological and adjunctive interventions; and trials located in Iran. There is a clear need for the identification of objective measures of change in clinical trials for ASD, such as evaluation of biological activity or markers, and for consideration of how best to deal with placebo response effects in trial design and analyses.
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One explanation for unspecific effects in OT trials may be the presence of a placebo response, which has been shown to occur frequently in pediatric autism pharmacological and dietary placebo-controlled trials.
“As suggested by Yatawara et al. (2016), one explanation for these unspecific effects may be the presence of a placebo response which has been shown to occur frequently in pediatric autism pharmacological and dietary placebo-controlled trials [37].”
From Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up (2020) · cites this paper as [37]
Studies examining CSF levels of oxytocin after intranasal administration have shown small CSF increases in animal models at around 40 minutes to 1 hour post-administration.
“Studies that have examined CSF levels of oxytocin after intranasal administration have shown small CSF increases in animal models at around 40 minutes to 1 hour post-administration, 78,79”
From Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder (2017) · cites this paper as [78]
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- Authors
- Masi, A., Lampit, A., Glozier, N., Hickie, I. B., & Guastella, A. J.
- Affiliations
- The University of Sydney (AU)
- Corresponding author
- Guastella, A J
- Venue
- Translational Psychiatry
- Published
- 2015-09-22
- Volume
- 5
- Issue
- 9
- Pages
- e640-e640
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5068810
- OpenAlex
- W2190639827
- Cited by
- 78
- References
- 65
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 19 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 2 · 2017: 11 · 2016: 5 · 2015: 1
- FWCI
- 0.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- National Health and Medical Research Council (1046899, 1084880, 1043664, 1061922)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- placebo response, autism spectrum disorder, children with autism, predictors of placebo response, dietary supplements, pharmacotherapy, clinical trial outcome measures, adjunctive intervention, trial design
- MeSH terms
- Autism Spectrum Disorder, Child, Humans, Prognosis, Psychotropic Drugs, Placebo Effect, Randomized Controlled Trials as Topic, Outcome Assessment, Health Care, Dietary Supplements
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