Gender-Based Differences in the Effects of Valproate on Dose-Corrected Plasma Concentrations of Quetiapine and Its Metabolites: A Retrospective Cohort Study

BACKGROUND: This retrospective study aimed to investigate the effects of valproate on the concentration-to-dose (C/D) ratio of quetiapine and N-desalkylquetiapine. METHODS: Multiple linear regression analysis was used to identify independent factors influencing the C/D values of quetiapine and N-desalkylquetiapine, and the results were compared. Subgroup analyses were based on sex and age. RESULTS: Valproate independently influenced the C/D ratios of quetiapine and N-desalkylquetiapine in a multivariate linear regression model adjusted for covariates. The Mann-Whitney U test indicated that the valproate combination group experienced a 16.85% reduction in the C/D ratio for quetiapine and a 23.68% reduction in the C/D ratio for N-desalkylquetiapine compared with the nonvalproate combination group, with significant differences (P < 0.001). Plasma N-desalkylquetiapine C/D ratios were negatively correlated with valproate dose (rs = -0.151). The subgroup analysis indicated no significant interactions between age and valproate, or between sex and valproate, on the C/D ratios of N-desalkylquetiapine (P-interaction >0.05); however, a significant interaction was observed between sex and valproate on the C/D ratio of quetiapine (P-interaction = 0.007). The Mann-Whitney U test revealed that concomitant valproate use significantly reduced the C/D ratio of quetiapine in females aged <40 and ≥40 years (all P < 0.05), but not in males (all P > 0.05). CONCLUSIONS: This study presents a novel finding that valproate significantly decreases the quetiapine C/D ratio, specifically in females. Furthermore, valproate also significantly decreases the N-desalkylquetiapine C/D ratio, an effect not specific to any population.