People with bipolar disorder who switched from oral aripiprazole to its long-acting injectable form experienced fewer hospitalizations and fewer emergency department visits than those who stayed on the oral medication, according to a multinational real-world study published in Translational Psychiatry. The analysis also found no increase in all-cause mortality, while flagging higher risks of obesity and movement-related side effects that the authors say warrant active monitoring.
Long-acting injectable aripiprazole is already approved for the maintenance treatment of bipolar disorder, but real-world evidence on its effectiveness and safety has remained limited. To address this gap, the research team used the TriNetX Global Collaborative Network to emulate a target trial among patients with bipolar disorder who initiated oral aripiprazole between 2017 and 2023. Patients who switched to the injectable formulation within one month were compared with patients who continued oral therapy.
To reduce the influence of differences between the two groups, the researchers applied 1:1 propensity score matching on demographics, comorbidities, prior treatments and laboratory data. After matching, the study included 1814 injectable aripiprazole users and 1814 oral aripiprazole users, who were followed for a mean of 1.6 years. Hazard ratios for nine efficacy and safety outcomes were estimated using Cox proportional hazards models, with prespecified sensitivity and subgroup analyses.
The injectable formulation was associated with a reduced risk of all-cause hospitalization, with a hazard ratio of 0.77 (95% confidence interval 0.69–0.85), and of emergency department visits, with a hazard ratio of 0.88 (95% CI 0.79–0.98). There was no statistically significant difference between the groups in suicidal ideation or behavior (hazard ratio 0.90, 95% CI 0.75–1.08) or in all-cause mortality (hazard ratio 0.86, 95% CI 0.55–1.37).
The safety picture was mixed. Risks were higher among injectable users for obesity (hazard ratio 1.17, 95% CI 1.06–1.29) and for extrapyramidal symptoms, the movement-related side effects typically associated with antipsychotic treatment, which showed a hazard ratio of 2.20 (95% CI 1.38–3.50). At the same time, risks were lower for major adverse cardiovascular events (hazard ratio 0.73, 95% CI 0.55–0.95) and for hyperlipidemia (hazard ratio 0.83, 95% CI 0.72–0.97).
Subgroup analyses suggested that the efficacy benefits were most pronounced in females and in middle-aged or older adults. In adolescents, suicidal ideation or behavior was markedly reduced, with a hazard ratio of 0.49 (95% CI 0.35–0.68). The authors note that sensitivity analyses showed similar trends to the main findings.
Because the study is a target trial emulation based on observational data rather than a randomized controlled trial, the results describe associations between treatment choice and outcomes rather than proven causal effects. The matched design and propensity scoring are intended to balance the groups, but unmeasured differences between patients who switch to an injectable formulation and those who continue oral therapy could still influence the results. The findings are also specific to patients who had already started oral aripiprazole, so they may not apply to treatment initiation with the injectable form directly.
Overall, the study concluded that in bipolar disorder, long-acting injectable aripiprazole was associated with better clinical outcomes without increased mortality compared with continued oral aripiprazole. The authors describe the favorable benefit–risk profile as supporting broader consideration of the injectable formulation in maintenance care, with active monitoring for obesity and extrapyramidal symptoms.
Subject of Research: Real-world effectiveness and safety of long-acting injectable aripiprazole in bipolar disorder
Article Title: Efficacy and safety of long-acting injectable aripiprazole in bipolar disorder: a multinational real-world target trial emulation
Article References: Hsu, C.-W., Hung, K.-C., Carvalho, A. F., Berk, M., Tseng, P.-T., Lai, Y.-C., Lin, Y.-H., Liang, C.-S., & Chen, Y.-C. B. (2026). Efficacy and safety of long-acting injectable aripiprazole in bipolar disorder: a multinational real-world target trial emulation. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04513-5
Image Credits: AI Generated
DOI: 10.1038/s41398-026-04513-5
Keywords: bipolar disorder, aripiprazole, long-acting injectable antipsychotics, target trial emulation, hospitalization, extrapyramidal symptoms, obesity, suicidal ideation, drug safety, propensity score matching, Translational Psychiatry, maintenance treatment
News Source: Scienmag.
