Abstract
Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342).
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Acknowledgements
We thank Georgia Salanti for her initial help in developing the statistical method, Samantha Roberts for her help in the literature search, Magdolna Tardy, M.Sc, for her help in study selection and Marc Krause, Philipp Rothe, MD, Thomas Arndt and Matteo Rabaioli, Susanne Bächer, Natalie Peter for help in data extraction. Ole Andreassen, Guy Chouinard, Michael Jann, Herbert Meltzer, Ofer Agid, Bret Rutherford, Merck, Dainippon Sumitomo, Novartis, Sunovion, EliLilly, Johnson&Johnson and Pfizer have replied to our requests for explanations or data. We could also again use the data that authors had sent us for requests in the context of previous meta-analyses of our group.
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SL, A Chaimani, DM, and JMD were involved in designing the review. MH, MT, and SL identified and acquired reports of trials. CL, MH, BH, MS, MR, SB, MK, PR, TA, NP, and SL extracted data. SL and CL contacted authors of trials and pharmaceutical industries for additional information. SL, A Chaimani, and DM analyzed and interpreted the data. A Chaimani and JRG contributed to the interpretation of the data. SL, A Chaimani, A Cipriani, and BH drafted the manuscript and all other authors critically reviewed the manuscript for important intellectual content. All authors approved the final version.
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Leucht, S., Chaimani, A., Mavridis, D. et al. Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis. Neuropsychopharmacol. 44, 1955–1966 (2019). https://doi.org/10.1038/s41386-019-0440-6
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DOI: https://doi.org/10.1038/s41386-019-0440-6
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