Olanzapine-Associated Hepatotoxicity in Bipolar Disorder: A Multicenter Real-World Study of Prevalence, Risk Factors, and Outcomes

Background: Olanzapine, an atypical antipsychotic agent, is widely used in the treatment of bipolar disorder due to its multifaceted therapeutic effects, encompassing sedation, mood stabilization, and antidepressant activity. Nevertheless, safety concerns remain a critical consideration in clinical application. Objects: This real-world, multicenter retrospective cohort study aimed to investigate the prevalence, risk factors, clinical patterns, and outcomes of olanzapine-associated hepatotoxicity in bipolar disorder patients. Methods: We conducted a multicenter retrospective cohort study was conducted across three tertiary hospitals, enrolling bipolar disorder patients (DSM-5 criteria) treated with olanzapine between January and December 2023. Demographics, treatment details, and laboratory data were extracted from electronic records. Univariate and multivariate logistic regression analyses identified risk factors for olanzapine-associated liver injury. Results: Hepatotoxicity, defined according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria, was the primary endpoint and occurred in 118 of 487 hosptialized patients (24.2%), with the majority classified as mild (19.3%). Injury patterns were predominantly mixed in mild-to-moderate cases and hepatocellular in severe cases. Multivariate analysis identified higher daily dosage (OR: 1.070, 95%CI: 1.006– 1.138, P =0.030) and elevated gamma-glutamyl transferase (GGT) (OR: 1.022, 95%CI: 1.006– 1.139, P =0.007) as independent risk factors. Concomitant use of valproate (OR: 0.553, 95%CI: 0.347– 0.881, P =0.013) was associated with a significant reduction in hepatotoxicity risk. A favorable clinical course was observed in majority of patients after olanzapine withdrawal and conservative management with hepatoprotective agents. Conclusion: This real-world observational study demonstrates a significant association between olanzapine and hepatotoxicity in hospitalized bipolar disorder patients. Our findings highlight the importance of regular liver function monitoring during olanzapine treatment, particularly in patients receiving higher daily doses, and suggest that dose management strategies may play a key role in mitigating hepatotoxicity risk in routine clinical practice. Keywords: bipolar disorder, olanzapine, hepatotoxicity, real-world study, risk factors