In the complex landscape of psychosis treatment, the decision between prescribing oral antipsychotic medications or long-acting injectable (LAI) therapies has sparked considerable debate among clinicians and researchers alike. A new extensive study published in Nature Mental Health delves deeper into this issue, probing the long-term effectiveness of LAI antipsychotics when initiated after a first episode of psychosis (FEP). By emulating two target trials with rigorous observational data, the research offers nuanced insights into how LAIs compare with traditional oral medications, particularly focusing on relapse prevention and hospitalization risks. This research challenges previous mixed findings and sheds critical light on subpopulations that might benefit most from LAI therapy.
Historically, LAIs have been touted as a promising strategy for improving medication adherence among individuals with psychotic disorders. Their design ensures a steady release of medication over weeks or months, potentially overcoming the challenges posed by irregular oral drug intake. However, despite this theoretical advantage, randomized controlled trials (RCTs) have produced conflicting results regarding whether LAIs genuinely reduce the risk of relapse or hospitalization after a first psychotic episode. While some European trials have suggested benefit, others and subsequent meta-analyses showed negligible or no reduction in adverse clinical outcomes, leaving uncertainty for mental health professionals on the frontlines.
Addressing these inconsistencies, Szmulewicz and colleagues turned to the FEP-CAUSAL Collaboration, an international consortium comprising multiple observational cohort datasets of people who have experienced a first psychotic episode. By harnessing such real-world data and employing sophisticated causal inference techniques, the researchers strategically emulated two “target trials” designed to mirror and extend key clinical questions. Their approach not only benchmarks observational estimates against results from the landmark European Long-Acting Antipsychotics in Schizophrenia Trial (EULAST) but also pushes the boundaries by exploring longer-term outcomes and subgroup-specific effects.
The first target trial specifically sought to recapitulate the 18-month hospitalization risk comparison between patients initiating LAI therapy—focusing on aripiprazole, risperidone, or paliperidone—and those continuing oral antipsychotic treatment. This benchmarking exercise revealed striking concordance: both the emulated observational study and the original EULAST trial indicated minimal differences in hospitalization rates over 18 months. This finding affirms the validity of the emulation methodology and suggests that, in the general FEP population, hospital readmission risks might not be substantially altered simply by changing the medication delivery method within this timeframe.
Yet, the researchers did not stop there. Extending their analysis to embrace a 3-year horizon, the second target trial investigated whether initiating LAI therapy could meaningfully affect the risk of psychotic relapse—a clinically critical outcome often preceding rehospitalization—and whether certain patient subgroups might derive greater benefit. This extended window revealed a modest but statistically significant reduction in relapse risk associated with LAI initiation compared to continued oral therapy. Specifically, the 3-year risk difference favored LAI therapy by approximately 7%, suggesting durable efficacy beyond the transient observation period favored by some RCTs.
What makes these findings particularly compelling are the more pronounced benefits observed within vulnerable subgroups. Patients with a history of psychological relapse prior to the first antipsychotic treatment exhibited an even greater reduction in relapse risk—over 15%—when started on LAI therapy. This suggests that those with a demonstrated proclivity for disease exacerbation could harness more pronounced advantages from sustained medication adherence afforded by injectables. Furthermore, individuals with prior non-adherence to oral regimens showed an astonishingly high risk reduction exceeding 20%, underscoring the critical role of consistent medication delivery in mitigating the cyclical nature of psychosis.
Substance use disorder, often a complicating factor in managing psychosis, was also examined as a subgroup. While the estimated risk reductions here were less emphasized in the current analysis, the implication remains that LAIs might confer differential benefits in complex clinical presentations where adherence and relapse prevention are particularly challenging. These subgroup findings advocate for a more personalized approach to antipsychotic treatment planning, moving beyond a one-size-fits-all model to consider individual histories and risk profiles.
Beyond clinical outcomes, this study exemplifies the power of leveraging observational data with careful methodological frameworks to answer pressing therapeutic questions. Emulating target trials from real-world cohorts offers an invaluable complement to controlled trials, especially when RCTs yield inconclusive or mixed results. This strategy enables researchers to examine long-term effects and heterogeneous treatment responses that are often impractical to capture in classical trials due to time, cost, or ethical constraints.
Despite the promising findings, the study also acknowledges inherent limitations. Observational data are susceptible to confounding, although extensive statistical adjustments and sensitivity analyses were employed to mitigate bias. Medication selection was not randomized, raising the possibility that unmeasured factors influenced both treatment choice and outcomes. Moreover, adherence measurement, particularly the distinction between initiation and sustained use of LAIs and oral agents, remains imperfect in observational settings.
Nonetheless, the consistency between the benchmarking target trial and the EULAST RCT bolsters confidence in the robustness of the results. It suggests that for patients after their first psychotic episode, simply switching to an LAI may not substantially lower short-term hospitalizations but could exert clinically relevant relapse prevention effects over extended follow-up. This insight challenges prevailing skepticism about LAIs and urges re-evaluation of their placement within early psychosis management paradigms.
Clinicians grappling with the challenge of improving adherence to antipsychotic therapy might view these findings as a call to action, particularly for individuals with documented prior relapse episodes or adherence difficulties. For these vulnerable patients, initiating LAI treatment soon after diagnosis could represent a targeted intervention to alter the otherwise chronic and relapsing course of psychotic illness. Health systems and policymakers could also take note, as preventing relapse translates into reduced healthcare utilization, improved quality of life, and potentially better long-term functional outcomes.
Future research directions inspired by this work include refining predictive models to identify patients most likely to benefit from LAIs, integrating digital adherence monitoring to complement injectable administration, and exploring the neurobiological underpinnings of differential response trajectories. Moreover, expanding international collaborations and data sharing can further enhance generalizability and uncover population-specific nuances in treatment effect.
This landmark study by Szmulewicz et al. marks a pivotal step in reconciling evidence gaps and guiding nuanced clinical decision-making in psychosis treatment. By marrying sophisticated epidemiological techniques with rich, longitudinal real-world data, the research paints a more hopeful picture for the role of long-acting injectable antipsychotic therapies. Ultimately, tailored therapeutic strategies emerging from such evidence hold promise for transforming outcomes in one of psychiatry’s most challenging conditions.
Subject of Research: Comparative effectiveness of long-acting injectable versus oral antipsychotic medication after a first episode of psychosis.
Article Title: Comparative effectiveness of long-acting injectable versus oral antipsychotic medication after a first episode of psychosis.
Article References:
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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