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. 2025 Sep 11.
doi: 10.1007/s40263-025-01225-0. Online ahead of print.

Impact of Long-Acting Injectable Versus Oral Antipsychotic Treatment on All-Cause Discontinuation Risk in People with Early Phase Schizophrenia and Comorbid Substance Use Disorder: A Secondary Analysis of the EULAST Randomized Trial

Matin Mortazavi #  1   2 , Zahra Aminifarsani #  3   4 , Inge Winter-van Rossum  5   6 , René S Kahn  6 , W Wolfgang Fleischhacker  7   8 , Michael Davidson  9   10 , Mark Weiser  11   12 , Dan Siskind  13   14 , Stefan Leucht  15 ; EULAST Study Group; Alkomiet Hasan #  4   16 , Elias Wagner #  3   4
Collaborators, Affiliations

Impact of Long-Acting Injectable Versus Oral Antipsychotic Treatment on All-Cause Discontinuation Risk in People with Early Phase Schizophrenia and Comorbid Substance Use Disorder: A Secondary Analysis of the EULAST Randomized Trial

Matin Mortazavi et al. CNS Drugs. .

Abstract

Background: Individuals with schizophrenia and comorbid substance use disorder (SUD) often experience poor treatment adherence, leading to worse clinical outcomes. However, high-quality evidence from randomized trials on the preferred mode of antipsychotic treatment in this population remains limited.

Aims: The aim was to examine whether long-acting injectable (LAI) antipsychotic treatment reduces the risk of all-cause discontinuation (ACD) compared with oral antipsychotics in individuals with early phase schizophrenia and comorbid SUD.

Methods: This study was a secondary analysis of the European Long-Acting Antipsychotics in Schizophrenia Trial (EULAST), a multisite, randomized, open-label trial conducted across multiple European healthcare settings. A total of 471 individuals with early phase schizophrenia were included in this secondary analysis, stratified by presence (n = 143) or absence (n = 328) of comorbid SUD. The observation period lasted 18 months. Participants were randomly assigned to second-generation LAI or oral second-generation antipsychotic treatment. The primary outcome was ACD, an indirect measure of treatment efficacy, defined as discontinuation of the initially assigned treatment for any reason. Hazard ratios (HRs) were estimated using Cox proportional hazards regression models, adjusted for relevant covariates.

Results: Among 143 individuals with schizophrenia and SUD, LAI treatment was associated with a 36% lower risk of ACD compared with oral antipsychotics (adjusted HR = 0.641; 95% CI, 0.438-0.938; P = 0.022). Kaplan-Meier curves showed longer median time to ACD for LAI treatment (158 days) versus oral antipsychotics (97 days). By contrast, among the 328 individuals without SUD, LAI treatment did not significantly reduce ACD risk (P = 0.282). Crude HRs were also assessed, replicating the adjusted hazard findings.

Conclusions: LAI antipsychotics significantly delayed treatment discontinuation compared with oral antipsychotics in participants with early phase schizophrenia and comorbid SUD but not in those without SUD. While these findings provide robust evidence supporting the use of LAIs in people with schizophrenia and comorbid SUD, future studies are needed to more precisely quantify the potential clinical benefits and tolerability of LAIs in this high-risk population. EULAST was registered at ClinicalTrials.gov (NCT02146547).

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Conflict of interest statement

Declarations. Conflicts of interest: The authors declare that there are no conflicts of interest in relation to the subject of this study. General declaration of potential conflict of interests: E.W. was invited to advisory boards from Recordati, Teva, and Boehringer Ingelheim. A.H. was and is a member of advisory boards and received paid speakership by Boehringer-Ingelheim, Lundbeck, Otsuka, Rovi, Teva (no speakership), AbbVie, Recordati, and Advanz. He is editor of the AWMF German guidelines for schizophrenia. W.W.F. has received grants from Otsuka and Lundbeck and speaker’s fees from Sumitomo Pharma. M.D. is an employee of Minerva Neurosciences, a biotech developing central nervous system drugs. In the past 3 years, S.L. has received honoraria as a consultant, adviser, or lecturer from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. D.S. has no conflicts to declare. All other authors declare no competing interests. Consent to participate: All study participants provided informed written consent for secondary data analysis. Consent for publication: All study participants provided informed written consent. Ethics approval: Relevant regulatory bodies and ethics committees in each participating country approved the study and its adherence to local regulations and the Declaration of Helsinki. The trial was overseen by the University Medical Center Utrecht in the Netherlands, following the guidelines of Good Clinical Practice and the International Conference on Harmonization. Availability of data and material: A request for receipt of the study data, the data dictionary, study protocol, and informed consent can be submitted for review and approval by the study management group. Code availability: A request for receipt of the codes (R scripts and SPSS Syntax) can be submitted for review and approval by the study management group. Author contributions: M.M., E.W., and A.H. designed the secondary analysis. M.M. and Z.A. conducted the statistical analysis. M.M., A.H., and E.W. interpreted the data and wrote the initial draft of the manuscript. A.H., E.W., and I.W.-v.R. conceptualized the study, provided supervision, and critically revised the manuscript for important intellectual content. I.W.-v.R., R.S.K., W.W.F., M.D., M.W., S.L., and the EULAST Study Group were responsible for the design and conduct of the original EULAST trial and the acquisition of the data. D.S. provided critical intellectual contributions and revisions. All authors reviewed and approved the final manuscript. M.M. and Z.A. share the first authorship; A.H. and E.W. share the last authorship.

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