Risk of adverse events associated with co-administration of quetiapine and Bupleuri Radix: A population-based cohort study

INTRODUCTION: Bupleuri Radix is a widely used herbal medicine in Asia. Experimental studies suggest it may modulate Cytochrome P450 3A4 (CYP3A4), the primary metabolic pathway of quetiapine, which is a first-line medication for psychosis, potentially altering drug exposure and raising concerns about pharmacokinetic interactions. We examined the risk of acute adverse events associated with concomitant use of Bupleuri Radix-containing formulations and quetiapine. METHODS: We conducted a retrospective cohort study using a Japanese claims database. Individuals aged 18-75 years initiating quetiapine between 2014 and 2023 were eligible. Exposure was defined as dispensing of Bupleuri Radix-containing formulations during quetiapine use. Risk-set matching (1:4) was performed on age, sex, calendar time, duration of quetiapine exposure. The primary outcome was a composite of acute adverse events, including central nervous system (CNS) depression, orthostatic hypotension, tachycardia. Cox models with inverse probability of treatment weighting estimated hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The matched cohort included 7552 exposed individuals and 30,091 controls. Weighted incidence rate of the composite outcome was 50.59 vs 32.21 per 1000 person-years in the concomitant-use and quetiapine-only groups. Concomitant use was associated with a statistically significant increased risk of the composite outcome (weighted HR 1.28, 95% CI 1.04-1.57) and CNS depression (HR 1.35, 95% CI 1.05-1.74). CONCLUSION: Concomitant use of Bupleuri Radix-containing formulations with quetiapine was associated with increased risk of acute adverse events, the absolute rate difference approached 2 additional events per 100 person-years, entailing clinical significance. Clinicians should consider this potential risk alongside expected treatment benefits.