»Treatment Resistance« Enigma Resolved by Pharmacogenomics 3 A Case Study of Clozapine Therapy in Schizophrenia Translated title: Enigma »Terapo-Rezistence« Razrešena uz Pomoć Farmakogenomike – Prikaz Slučaja Terapije Klozapinom u Shizofreniji

Summary

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 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«.

Kratak sadržaj

Početak primene antipsihotika pedesetih godina prošlog veka zauvek je promenio perspektivu lečenja shizofrenije, mada značajan broj pacijenata sa ovom bolešću još uvek ne postiže funkcionalni oporavak. Klozapin, triciklični dibenzodijazepin sa kompleksnim farmakološkim profilom, koji se u tretmanu shizofrenije pokazao efikasnijim od ostalih antipsihotika, uglavnom je treća linija terapijskog izbora. Međutim, u najmanje 30% slučajeva obolelih od shizofrenije stanje se ne poboljšava ni na terapiji klozapinom, pa se zbog toga pristupa polifarmaciji i odstupa od racionalne primene psihofarmaka. Postoji velika interindividualna varijabilnost u bioraspoloživosti klozapina, stabilnoj koncentraciji u plazmi i njegovom klirensu. Klozapin se metaboliše preko sistema citohrom P450 oksidaza ( CYP450). Citohrom P450 1A2 ( CYP1A2), koji se u humanoj populaciji odlikuje genskim polimorfizmima, glavni je enzim u metabolizmu klozapina. Aktuelni prikaz slučaja ilustruje uticaj polimorfizma CYP1A2*1F na metabolizam klozapina, gde je primarni izostanak odgovora na terapiju kod mlade pacijentkinje sa shizofrenijom objašnjen povećanjem ekspresije gena kod homozigotnog genotipa *1F/*1F (povišen metabolizam klozapina), i naglašava značaj personalizacije tretmana shizofrenije uz pomoć genetike i drugih molekularnih parametara, posebno u slučajevima »terapo-rezistence«.