Abstract
Switching to long-acting injectable (LAI) antipsychotic therapy as compared with continuation of oral therapy after a first episode of psychosis (FEP) may reduce the risk of relapse and hospitalization, as reported in some randomized trials. However, other trials and network meta-analyses reported no risk reduction. We emulated two target trials using data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts of people with FEP. The first target trial was designed to ask a similar question as the European Long-Acting Antipsychotics in Schizophrenia Trial (EULAST) trial, which compared the 18-month hospitalization risk between patients assigned to LAI therapy (aripiprazole, risperidone or paliperidone) and those on continuation of oral therapy. We benchmarked the observational estimates to those from the actual trial. The second target trial extended the first to examine the 3-year risks of psychotic relapses and in subgroups (prior relapses, non-adherence, substance use disorder). Of 2,228 individuals with FEP, 1,067 were eligible for the benchmarking analyses. Both our target trial emulation and EULAST showed little effect of LAI therapy initiation on the 18-month hospitalization risk. In the extended analysis (1,193 individuals), the 3-year risk difference of psychotic relapse comparing LAI therapy initiation with oral continuation was –7.0% (95% CI: –12.1, –0.7). The risk difference was substantially lower in subgroups with a prior relapse (–15.5%, 95%CI: –24.1, –5.5) or prior non-adherence (–21.9, 95% CI: –41.9, –2.0). We estimated that, compared with oral therapy continuation, LAI therapy initiation reduced psychotic relapses over 3 years. LAI therapy initiation may be particularly beneficial in vulnerable subgroups.
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Data availability
Data are made available to the Coordinating Center of the FEP-CAUSAL Collaboration via data user agreements with each of the participating sites. Investigators interested in obtaining the data would need to establish similar arrangements.
Code availability
Code is available via GitHub at https://github.com/CausalInference/CAUSALab_Papers.
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Acknowledgments
This study was funded by NIMH grant P50 MH115846-06 (D.Ö. and M.A.H.) and a BBRF Young Investigator Award (A.G.S). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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A.G.S. and G.M.-A. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. A.G.S., G.M.-A., D.Ö. and M.A.H. were involved in concept and study design. Acquisition and harmonization of datasets was conducted by G.M.-A., R.L., R.J., M.F., C.K., D.F., L.E.T., S.C., CM.D.-C., V.S., L.N.Y., D.K.S., A.K.S., C.A. and J.L.S. Analysis and interpretation of data was performed by A.G.S., G.M.-A., R.L., D.Ö. and M.A.H. The drafting of the manuscript was done by A.G.S. Critical revision of the manuscript for important intellectual content involved: G.M.-A., R.L., R.J., M.F., C.K., D.F., L.E.T., S.C., C.M.D.-C., V.S., L.N.Y., D.K.S., A.K.S., C.A. and J.L.S. The statistical analysis was performed by A.G.S. and M.A.H.; and the overall supervision by M.A.H. and D.Ö.
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D.O. served on the advisory board for Rapport Therapeutics in the past 12 months. C.M.D.-C. has received honoraria from Angelini and Viatris and travel support from Janssen and Angelini. M.A.H. Serves on the advisory board of ADIA Lab. C.A. has been a consultant to or has received honoraria or grants from Abbot, Acadia, Ambrosetti, Angelini, Biogen, BMS, Boehringer, Carnot, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, Takeda and Teva. L.N.Y. reports consultant/speaker fees from Alkermes, Allergan (currently Abbvie), Intracellular Therapies, LivaNova, Merck, Newron and Sumitomo Pharma and grants from Allergan (now AbbVie), CIHR and Sumitomo Pharma, outside the submitted work, over the past 3 years. He also received grants from Janssen, BMS, Otsuka, Lundbeck, Astra Zeneca and HLS. R.J. served as speaker and member of advisory board committees for Pfizer, Janssen, BMS, Sunovian, Myelin, Otsuka, Lundbeck, shire and Perdue. The other authors declare no competing interests.
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All research complies with the Declaration of Helsinki. The study was approved by the Harvard TH Chan School of Public Health Institutional Review Board (reference number IRB20-1842).
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Szmulewicz, A.G., Martínez-Alés, G., Logan, R. et al. Comparative effectiveness of long-acting injectable versus oral antipsychotic medication after a first episode of psychosis. Nat. Mental Health 3, 421–428 (2025). https://doi.org/10.1038/s44220-025-00407-5
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DOI: https://doi.org/10.1038/s44220-025-00407-5
