Gene polymorphisms potentially related to the pharmacokinetics of clozapine: A systematic review

Clozapine is currently the ultimate effective therapy for otherwise treatment-refractory schizophrenia. However, the drug is also associated with many adverse effects, some of them potentially fatal. Thus, there is an unmet need to predict clinical response to clozapine. As the pharmacokinetics of clozapine vary considerably between and within individuals, there may be an association between genetic polymorphisms and clozapine plasma concentration and consequently, clinical response. We have reviewed studies that have investigated the association between clozapine metabolic pathways related to genes polymorphisms in relation to plasma clozapine concentration and clinical response. Overall, most of the studies reported negative results. The only gene polymorphism that has been found to be associated with clozapine plasma concentration and response was the ABCB1 gene, which codes for transmembrane transporters expressed in the bowel mucosa, blood-brain barrier, kidney and liver. More prospective longitudinal studies are needed to elucidate the possible role of the ABCB1 polymorphism and transmembrane transporters in clozapine pharmacokinetics and clinical response.