Pharmacogenetic Biomarkers of Clozapine-Induced Sialorrhoea: A Systematic Review

INTRODUCTION. Despite the proven clozapine effectiveness in patients with treatment resistant schizophrenia, its use can cause adverse drug reactions, including clozapine-induced sialorrhea (CIS). Data on CIS pathogenesis are limited. Identifying CIS pharmacogenetic predictors will make it possible to both predict adverse drug reactions prior to therapy and specify individual pathogenetic elements. AIM. This review aimed to identify CIS predictors using systematic analysis of literature data. DISCUSSION. Research was conducted independently by two co-authors using PubMed, Google Scholar, GeneCads, and PharmGKB databases. A total of six (6) studies were selected that examined 17 candidate genes. The ADRA2A and DRD4 genes were associated with CIS. Polymorphism rs1800544 of ADRA2A gene regulates the expression of alpha-2A adrenoreceptor (ADRA2A). Alpha-2-adrenoreceptors regulate salivation, thus clozapine antagonistic effect causes CIS. Polymorphism of 120-bp DRD4 will reduce expression of type 4 dopamine receptor ( DRD4 ). In turn, this may result in CIS as clozapine increases the receptor blockade. However, the results contradicted other studies, presumably due to assessment of different polymorphisms in the above studies. Moreover, the analysed studies had a number of methodological limitations. CONCLUSIONS. The performed systematic review made it possible to identify CIS pharmacogenetic predictors. However, large multicenter studies using a strong prospective design and considering these limitations are required in order to develop a pharmacogenetic panel with high predictive accuracy for CIS. REGISTRATION. Systematic review protocol is included in the national systematic review register (PROSPERO), Registry No. CRD420251089235.