Comparing Metabolic Outcomes Associated with Aripiprazole and Olanzapine in Schizophrenia Spectrum Disorder: Insights from a Large Real-World Cohort Using TriNetX | Chapter 8 | Medical Science: Updates and Prospects Vol. 4

 

Background: 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. Although multiple randomised controlled trials and meta-analyses have compared these agents, results have varied depending on duration, dosage, and population characteristics. Also, only a few large-scale real-world studies have examined these associations across diverse populations using harmonised electronic health records.

 

Aims: 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 aged 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 modelling.

 

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).

 

Discussion: Patients treated with aripiprazole demonstrated a higher observed incidence of the combined metabolic outcome compared with those receiving olanzapine. These findings are counter to the conventional expectation that olanzapine carries greater metabolic risk, suggesting that the established metabolic advantage of aripiprazole may not always hold in usual clinical practice. This observation may reflect residual confounding, differential monitoring frequency, prescribing bias, and effects of high statistical power rather than a clinically large difference. From a clinical perspective, these results underscore the importance of individualised antipsychotic selection and routine metabolic surveillance regardless of a medication’s perceived safety profile.

 

Conclusion: In this large real-world analysis, aripiprazole was unexpectedly associated with a higher incidence of metabolic complications than olanzapine, challenging assumptions regarding aripiprazole’s metabolic advantage and highlighting the need for ongoing metabolic monitoring.

 

 

Author(s) Details

Cameron Asay
Drexel University College of Medicine, USA.

 

Kypros Dereschuk
Drexel University College of Medicine, USA.

 

Eduardo Espiridion
Drexel University College of Medicine, USA.

 

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