»Treatment Resistance« Enigma Resolved by Pharmacogenomics − A Case Study of Clozapine Therapy in Schizophrenia / Enigma »Terapo-Rezistence« Razrešena Uz Pomoć Farmakogenomike - Prikaz Slućaja Terapije Klozapinom U Shizofreniji

Abstract

SummaryThe introduction of antipsychotic medication in the 1950s forever changed the outlook on the treatment of schizophrenia, although there is still a large proportion of patients who do not reach functional recovery. At least 30% of patients do not respond to clozapine, the tricyclic dibenzodiazepine with complex pharmacological actions, which was proven to be more effective than any other antipsychotic in the treatment of schizophrenia. According to most of the therapeutic guidelines for schizophrenia, clozapine is the third line therapy for patients who did not respond to other antipsychotics. Large inter-individual variability exists for clozapine bioavailability and plasma steady-state concentrations and clearance. Clozapine is metabolized by the cytochrome P450 oxidase enzyme family (CYP450). Cytochrome P450 1A2 (CYP1A2), which is polymorphically expressed in humans, is the main enzyme of clozapine metabolism. This case report addresses the influence of CYP1A2*1F genetic polymorphism on clozapine metabolism, explains the primary non-response of a young patient with schizophrenia due to increased gene expression in homozygous genotype *1F/*1F (increased metabolism of clozapine) and underlies the importance of personalizing schizophrenia treatment by means of genetic and other molecular tools, at least in the cases of »treatment resistance«.

PharmGKB summary

“…In patients receiving clozapine, CYP1A2*1F has been associated with treatment non-response requiring higher doses [17–19,72]. Homozygotes of CYP1A2 *1F (rs762551 AA) who are smokers have lower plasma clozapine, higher metabolite concentrations and faster clearance than non-smokers.…”

A novel biomarker renalase and its relationship with its substrates in schizophrenia

“…This theory suggests an overactive state in dopaminergic stimulation in certain brain regions of patients (2, 4). The dopamine theory of schizophrenia is the principal basis of antipsychotic drug treatment (5, 6, 7). On the other hand, it has been argued that genes involved in the dopaminergic system have effects on neurocognitive dysfunction in schizophrenia (8).…”