Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review a
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RESEARCH
Open Access
Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis Spyridon Siafis1* , Oğulcan Çıray2 , Johannes Schneider-Thoma1 , Irene Bighelli1 , Marc Krause1 , Alessandro Rodolico3 , Anna Ceraso4, Giacomo Deste4, Maximilian Huhn1,5 , David Fraguas6,7 , Dimitris Mavridis8,9 , Tony Charman10 , Declan G. Murphy11 , Mara Parellada8,9, Celso Arango8,9 and Stefan Leucht1
Abstract Background: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. Methods: We searched ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a randomeffects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317. Results: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8–12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = − 0.32, 95% CI [− 0.39, − 0.25], in repetitive behaviors − 0.23[− 0.32, − 0.15] and in scales measuring overall core symptoms − 0.36 [− 0.46, − 0.26]. Overall, 19%, 95% CI [16–22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. Limitations: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. (Continued on next page)
* Correspondence: [email protected] 1 Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675 Munich, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as l
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