Uloga farmakogenetike u terapiji depresije

professional thesis

• Author: Ana Mihelčić Šokman
• Mentor: Nada Božina (mentor)
• Committee member: Karmela Barišić (predsjednik povjerenstva)
• Committee member: Nada Božina (član povjerenstva)
• Committee member: Vesna Bačić Vrca (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; Zagreb
• Defense date and country: 2021-09-30, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Antidepresivi su jedna od najčešće propisivanih skupina lijekova. Koriste se za liječenje
depresije, anksioznosti, opsesivno-kompulzivnog poremećaja, neuropatske boli i prevenciju
migrene. Incidencija depresije u svjetskoj populaciji je oko 16 %. Antidepresivi imaju izražen
metabolizam prvog prolaza putem citokroma P450 (CYP), i to najviše putem CYP2D6,
CYP2C19, CYP3A4, CYP2C9 i CYP1A2. U terapiji depresije najznačajniji su polimorfizmi
CYP2D6 i CYP2C19 enzima jer mogu imati utjecaj na metabolizam selektivnih inhibitora
ponovnog povrata serotonina i tricikličkih antidepresiva, tj na učinkovitost i sigurnost
lijekova. Na temelju genetičkih informacija o polimorfizmima gena iz obitelji CYP-a može se
zaključiti o mogućim fenotipovima biotransformacije/metaboliziranja lijeka. Genotipovi
određuju četiri različita fenotipa. Normalni metabolizatori imaju normalnu enzimsku
aktivnost, to su prvenstveno homozigotni nositelji “divljega” alela. Intermedijarni
metabolizatori u usporedbi s normalnim metabolizmom imaju smanjenu enzimsku aktivnost
zbog prisustva odgovarajućih varijantnih alela sa smanjenom funkcijom ili gubitkom funkcije.
Spori metabolizatori imaju značajno smanjenu enzimsku aktivnost ili ona potpuno izostaje jer
su homozigotni nositelji inaktivirajućih alela/varijanti gena. Vrlo brzi metabolizatori imaju
enzimsku aktivost koja je veća od normalne, prosječne, zbog prisustva više kopija gena.
Društva poput Kliničkog konzorcija za implementaciju farmakogenetike i Nizozemske radne
grupe za farmakogenetiku izdala su smjernice za doziranje antidepresiva. Smjernice upućuju
na promjenu doze i/ili lijeka u slučaju bolesnika sa sporim, a u nekim slučajevima i
intermedijarnim metaboličkim fenotipom za CYP2C19 i/ili CYP2D6. Prilagodbom doze
prema genotipu smanjuje se učestalost nuspojava i povećava učinak terapije.
Farmakogenetički testovi trebaju biti razmotreni uz druge kliničke i biokemijske čimbenike s
posebnim naglaskom na interakcije lijekova i druge komorbiditete.

Abstract (english)

Antidepressants are one of the most commonly prescribed groups of drugs. They are used to
treat depression, anxiety, obsessive-compulsive disorder, neuropathic pain and for migraine
prevention. The incidence of depression in the world population is about 16%.
Antidepressants have a pronounced first-pass metabolism via cytochrome P450 (CYP),
mostly via CYP2D6, CYP2C19, CYP3A4, CYP2C9 and CYP1A2. The most important
polymorphisms in the treatment of depression are CYP2D6 and CYP2C19 enzymes
polymorphisms because they can affect the metabolism of selective serotonin reuptake
inhibitors and tricyclic antidepressants, i.e., drug efficacy and safety. Based on genetic
information on CYP gene polymorphism, it is possible to predict phenotypes of drug
biotransformation / metabolism. There are four different phenotypes. Normal metabolizers
have normal enzymatic activity, they are homozygous carriers of the "wild" type of alleles.
Intermediate metabolizers have reduced enzyme activity compared to normal metabolism due
to the presence of alleles with reduced or lost function. Poor metabolizers have significantly
reduced or absent enzyme activity because they are homozygous carriers of inactivating
alleles/gene variants. Ultrarapid metabolizers have a genotype with enzymatic activities that is
higher than normal due to the presence of multiple copies of the gene. Companies such as the
Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics
Working Group have issued guidelines for antidepressants dosing. The guidelines suggest
dose and / or drug variation in patients with a poor and in some cases intermediate metabolic
phenotype for CYP2C19 and/or CYP2D6. Adjusting the doses according to genotype reduces
the frequency of side effects and increases the effect of therapy. Pharmacogenetic tests should
be considered in addition to other clinical and biochemical factors with special emphasis on
drug interaction and other comorbidities.

• Keywords: antidepresivi; farmakogenetika; polimorfizmi enzima; CYP2D6; CYP2C19; genotip; fenotip
• Keywords (english): antidepressants; pharmacogenetics; enzymes polymorphisms; CYP2D6; CYP2C19; genotype; phenotype
• Language: croatian
• URN:NBN: urn:nbn:hr:163:542786
• Study programme: Title: Clinical pharmacy; Study programme type: university; Study level: postgraduate specialist; Academic / professional title: sveučilišni/a magistar/sveučilišna magistra kliničke farmacije (sveučilišni/a magistar/sveučilišna magistra kliničke farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-03-16 14:24:46