Efficacy and safety of long-acting injectable aripiprazole in bipolar disorder: a multinational real-world target trial emulation

Long-acting injectable (LAI) aripiprazole is approved for maintenance treatment of bipolar disorder (BD), but real-world efficacy and safety evidence remains limited. Using the TriNetX Global Collaborative Network, we conducted a target trial emulation among patients with BD who initiated oral aripiprazole between 2017 and 2023. Patients switching to LAI within one month were compared with those continuing oral therapy. After 1:1 propensity score matching on demographics, comorbidities, prior treatments, and laboratory data, hazard ratios (HRs) with 95% confidence intervals (CIs) for nine efficacy and safety outcomes were estimated using Cox proportional hazards models, with prespecified sensitivity and subgroup analyses. After matching, 1814 LAI and 1814 oral aripiprazole users were followed for a mean of 1.6 years. LAI use was associated with reduced all-cause hospitalization (HR 0.77, 95%CI 0.69–0.85) and emergency department visits (0.88, 0.79–0.98), with no difference in suicidal ideation or behavior (0.90, 0.75–1.08) or all-cause mortality (0.86, 0.55–1.37). Risks were higher for obesity (1.17, 1.06–1.29) and extrapyramidal symptoms (2.20, 1.38–3.50), but lower for major adverse cardiovascular events (0.73, 0.55–0.95) and hyperlipidemia (0.83, 0.72–0.97). Efficacy benefits were most pronounced in females and middle-aged or older adults; in adolescents, suicidal ideation or behavior was markedly reduced (0.49, 0.35–0.68). Sensitivity analyses showed similar trends. In BD, LAI aripiprazole was associated with better clinical outcomes without increased mortality compared with continued oral aripiprazole. The favorable benefit–risk profile supports broader consideration of LAI in maintenance care, with active monitoring of obesity and extrapyramidal symptoms.