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. 2024 Feb 15;10(1):17.
doi: 10.1038/s41537-024-00442-8.

Are the results of open randomised controlled trials comparing antipsychotic drugs in schizophrenia biased? Exploratory meta- and subgroup analysis

Stefan Leucht #  1   2 , Spyridon Siafis #  3   4 , Johannes Schneider-Thoma  3   4 , Aran Tajika  5 , Josef Priller  3   4 , John M Davis  6   7 , Toshi A Furukawa  5
Affiliations

Are the results of open randomised controlled trials comparing antipsychotic drugs in schizophrenia biased? Exploratory meta- and subgroup analysis

Stefan Leucht et al. Schizophrenia (Heidelb). .

Abstract

A recent meta-epidemiological study did not reveal major differences between the results of blinded and open randomised-controlled trials (RCTs). Fewer patients may consent to double-blind RCTs than to open RCTs, compromising generalisability, making this question very important. However, the issue has not been addressed in schizophrenia. We used a database of randomised, acute-phase antipsychotic drug trials. Whenever at least one open and one blinded RCT was available for a comparison of two drugs, we contrasted the results by random-effects meta-analysis with subgroup tests. The primary outcome was overall symptoms as measured by the Positive and Negative Syndrome Scale, supplemented by seven secondary efficacy and side-effect outcomes. We also examined whether open RCTs were biased in favour of more recently introduced antipsychotics, less efficacious or more prone to side-effects antipsychotics, and pharmaceutical sponsors. 183 RCTs (155 blinded and 28 open) with 34715 participants comparing two active drugs were available. The results did not suggest general differences between open and blinded RCTs, which examined two active drugs. Only 12 out of 122 subgroup tests had a p-value below 0.1, four below 0.05, and if a Bonferroni correction for multiple tests had been applied, only one would have been significant. There were some exceptions which, however, did not always confirm the originally hypothesized direction of bias. Due to the relatively small number of open RCTs, our analysis is exploratory, but this fundamental question should be given more scientific attention. Currently, open RCTs should be excluded from meta-analyses, at least in sensitivity analyses.

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Conflict of interest statement

In the last 3 years, S.L. has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Otsuka, NovoNordisk, Recordati, Rovi, Teva, A.T. received lecture fees from Sumitomo Dainippon Pharma, Eisai, Janssen Pharmaceutical, Meiji-Seika Pharma, Mitsubishi Tanabe Pharma, Otsuka and Takeda Pharmaceutical. TAF reports personal fees from Boehringer-Ingelheim, DT Axis, Kyoto University Original, Shionogi, SONY and UpToDate, and a grant from Shionogi. In addition, T.A.F. has patents 2020-548587 and 2022-082495 pending and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Overall efficacy, blinded versus open RCTs.
a The more recently licensed antipsychotic is the intervention. b The less efficacious antipsychotic is the intervention.
Fig. 2
Fig. 2
Overall efficacy of sponsored versus non-sponsored antipsychotics in blinded and open RCTs.
See this image and copyright information in PMC

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