title: »Treatment Resistance« Enigma Resolved by Pharmacogenomics - A Case Study of Clozapine Therapy in Schizophrenia.
abstract: The 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 ofCYP1A2*1Fgenetic 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«.
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia; Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia.
authors.forename: Nadja P
authors.initials: NP
authors.lastname: Marić
authors.affiliation: Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia.
authors.forename: Slobodanka Pejović
authors.initials: SP
authors.lastname: Nikolić
authors.affiliation: Department of Human Genetics and Prenatal Diagnostics, University Medical Hospital Zvezdara, Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Buzadžić
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Jovičić
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Andrić
authors.affiliation: Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia.
authors.forename: Marina
authors.initials: M
authors.lastname: Mihaljević
authors.affiliation: Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia.
authors.forename: Zorana
authors.initials: Z
authors.lastname: Pavlović
keywords: CYP1A2; clozapine; personalized medicine; pharmacogenomics; schizophrenia