Impact of Long-Acting Injectable Versus Oral Antipsychotic Treatment on All-Cause Discontinuation Risk

Sep 29, 2026

Background individuals with schizophrenia and comorbid substance use disorder (SUD) often show poor adherence, worsening clinical outcomes, yet randomized-trial evidence comparing preferred antipsychotic delivery modes in this group remains limited. This secondary analysis evaluates whether long-acting injectable (LAI) antipsychotics reduce all-cause discontinuation (ACD) versus oral antipsychotics in early-phase schizophrenia with comorbid SUD. Data from the EULAST randomized trial (N=471, 18 months) used Cox models to estimate adjusted hazard ratios for ACD defined as discontinuation of the assigned treatment for any reason.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

Background

Aims

Methods

Results

Conclusions

Key Points

Introduction

CNS Drugs (2026) 40:99–109 [https://doi.org/10.1007/s40263-025-01225-0](https://doi.org/10.1007/s40263-025-01225-0) 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 Mortazavi1,2 · Zahra Aminifarsani1,2 · Inge Winter‑van Rossum3,4 · René S. Kahn4 · W. Wolfgang Fleischhacker5,13 · Michael Davidson6,14 · Mark Weiser7,8 · Dan Siskind9,10 · Stefan Leucht11 · EULAST Study Group · Alkomiet Hasan2,12 · Elias Wagner1,2 Received: 16 May 2025 / Accepted: 26 August 2025 / Published online: 11 September 2025 © The Author(s) 2025 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](registered at ClinicalTrials.gov) (NCT02146547). | Matin Mortazavi and Zahra Aminifarsani have shared first authorship. | | --- | | Alkomiet Hasan and Elias Wagner have shared last authorship. | | Members of EULAST Study Group are listed in the
acknowledgements section. | Extended author information available on the last page of the article 1 Introduction Schizophrenia is a serious mental disorder with a lifetime prevalence of about 0.5–1% and accounts for a substantial healthcare burden [1]. There is a large body of evidence on the association between schizophrenia and unhealthy lifestyle, including sedentary behavior, unhealthy diet, smoking, and substance abuse, which contribute to increased risk of cardiovascular disease, and related death [2] . Schizophrenia is often associated with comorbid substance use disorders Key Points In participants with

FAQs

What question does the study address about antipsychotic treatment?

The study examines whether long-acting injectable (LAI) antipsychotics reduce all-cause discontinuation risk compared with oral antipsychotics in people with early phase schizophrenia and comorbid substance use disorder (SUD).

How was all-cause discontinuation (ACD) defined and analyzed?

ACD was defined as discontinuation of the initially assigned treatment for any reason. Hazard ratios were estimated using Cox proportional hazards regression models adjusted for relevant covariates.

What were the main findings for participants with and without comorbid SUD?

Among participants with comorbid SUD (n=143), LAI was associated with a 36% lower risk of ACD versus oral antipsychotics. Among participants without SUD (n=328), LAI did not significantly reduce ACD risk.

Sep 29, 2026

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