Comparative Risk of Metabolic Adverse Outcomes in Patients with Schizophrenia Spectrum Disorder Treated with Aripiprazole Versus Olanzapine: A Retrospective Cohort Study Using the Global TriNetX Network

Abstract

Introduction: Second-generation antipsychotics manage schizophrenia spectrum disorders but carry metabolic risks. Olanzapine is associated with greater metabolic liability, while aripiprazole is considered more metabolically neutral. This study compares the risk of developing hyperlipidemia, diabetes mellitus, and pancreatitis among adults prescribed aripiprazole versus olanzapine using electronic health record data. Methods: A retrospective cohort study was performed using the TriNetX Research Network. Adults ages 18-80 years with schizophrenia spectrum disorders (ICD-10: F20-F29) were included. Cohorts consisted of patients prescribed aripiprazole (n=94,759) and patients prescribed olanzapine (n=1,716,356). After 1:1 propensity-score matching by age, sex, race, and ethnicity, each cohort included 94,125 patients. Incidence of the composite metabolic outcome was compared using risk estimates, Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards modeling. Results: The metabolic outcome occurred in 27.7% of aripiprazole patients and 20.1% of olanzapine patients. Aripiprazole was associated with higher metabolic risk: risk difference 0.076 (95% CI:0.073-0.080; p<0.001), risk ratio 1.380 (95% CI:1.358-1.403), and odds ratio 1.526 (95% CI:1.494-1.559). Kaplan-Meier analysis demonstrated lower event-free survival for aripiprazole (60.87%) versus olanzapine (68.93%) (log-rank χ²= 875.280; p<0.001). The hazard ratio was 1.33 (95% CI:1.300-1.350), and the proportional hazards assumption was met (p=0.791). Conclusion: In this large real-world analysis, aripiprazole was unexpectedly associated with higher incidence of metabolic complications than olanzapine, challenging assumptions regarding aripiprazole’s metabolic advantage and highlighting the need for ongoing metabolic monitoring.