Differences in clozapine metabolism across geographical regions in Turkiye

Objective:The efficacy of clozapine is influenced by the pharmacogenetics of its metabolism, which can vary significantly among individuals.This study investigates regional variations in serum clozapine and norclozapine levels across Turkiye. Method:A retrospective analysis was conducted on 1,428 serum clozapine measurements from 328 patients treated at Hacettepe University Department of Psychiatry between 2014 and 2022.Patients were categorized based on their birthplaces and residential addresses into seven geographical regions of Turkiye.Serum levels of clozapine and norclozapine were measured, and clozapine/norclozapine ratios were calculated.Linear mixed models were used to assess the effects of region, age, sex, and clozapine dose on therapeutic drug monitoring outcomes.Results: Significant regional differences were observed in serum norclozapine levels, with notably lower levels in the Eastern Anatolia Region (=-179.04,SE=49.7).No significant regional differences were found in serum clozapine levels or clozapine/ norclozapine ratios.Age (p=0.004) and clozapine dose (p<0.001) were positively associated with norclozapine levels, while sex showed no significant association. Conclusion:This study highlights inter-regional differences in clozapine metabolism within Turkiye, suggesting that regional factors may play a role in clozapine pharmacokinetics.These findings indicate that clozapine metabolism is influenced not only by genetic variability but also by a complex relationship of sociocultural factors.The results support the need for more personalized approaches to clozapine dosing and monitoring to enhance treatment efficacy, safety, and tolerability.