The association of catechol-O -methyil transferase genetic variants with therapeutic response to antipsychotics in schizophrenia patients

Enzim katehol-o-metil transferaza (COMT) odgovoran je za degradaciju dopamina i smatra se ključnim regulatorom dopaminergičke neurotransmisije u prefrontalnom korteksu (PFC). Predmetom je istraživanja u mnogim asocijacijskim studijama koje ciljaju rasvijetliti njegov doprinos riziku razvoja shizofrenije te farmakogenetičkih istraživanja koja proučavaju mogući utjecaj COMT-a na terapijski odgovor na antipsihotike. Zbog nedostatka pouzdanih podataka u literaturi, cilj ovog diplomskog rada bio je istražiti povezanost dva polimorfizama (rs4680 i rs4818) gena COMT s odgovorom na terapiju olanzapinom, risperidonom, klozapinom i ostalim antipsihoticima u pacijenata sa shizofrenijom. Pacijenti su podijeljeni na one s boljim i lošijim odgovorom nakon 8 tjedana terapije s obzirom na 50 % pad bodova na ocjenskoj Pozitivnoj i negativnoj sindromskoj ljestvici (PANSS) i njezinim podljestvicama. Utjecaj polimorfizama COMT dodatno je provjeren usporedbom postotaka pada bodova na ljestvici PANSS i podljestvicama. Rezultati pokazuju da polimorfizam rs4680 gena COMT utječe na odgovor na terapiju nakon 8 tjedana olanzapina te da bi prisutnost alela povezanog sa smanjenom aktivnosti enzima (alel A) mogao biti prediktivni marker boljeg odgovora na terapiju nakon 8 tjedana primanja olanzapina u relativno velikom uzorku pacijenata sa shizofrenijom.Enzyme catechol-O-methyltransferase (COMT) is responsible for degradation of dopamine and is considered as the main regulator of dopaminergic neurotransmission in the prefrontal cortex (PFC). It is the subject of various association studies which aim to elucidate its possible role in the risk for schizophrenia and pharmacogenetic studies which are set out to investigate its role in response to antipsychotic therapies. Due to the lack of reliable data in literature, the aim of this thesis was to evaluate the association between two COMT gene polymorphisms (rs4680 and rs4818) and treatment response to olanzapine, risperidone, clozapine and other antipsychotics in patients with schizophrenia. Patients were subdivided into responders and non-responders according to a 50 % reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscale scores after 8 weeks of treatment. The influence of COMT polymorphisms was further investigated by comparing the percentage of the PANSS total and subscale score reductions. Results show that rs4680 COMT gene polymorphism affects therapeutic response after 8 weeks of olanzapine treatment and that the allele associated with lower enzyme activity (the allele A) could be considered as a predictive marker for good response to olanzapine treatment after 8 weeks in relatively large sample of patients with schizophrenia