Uloga farmakogenetičkih varijacija u terapiji depresije [ The role of pharmacogenetic variations in the therapy of depression ]

Genetic variations of metabolic enzymes and transporter proteins are important determinants of pharmacotherapy efficacy and toxicity. In addition, interindividual, interethnic differences in the prevalence of genetic variations are signifficant. In this study, pharmacogenetic analysis was performed in Croatian healthy population and patients with depression. The influence of genetic variations of metabolic enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4 and transporter proteins: P-glycoprotein (MDR1) and serotonin transporter (SERT) on pharmacologic and toxicologic effects of major depression therapy were investigated. The study included 286 healthy subjects and 114 patients with major depression. Pharmacogenetic analyses were performed by PCR-RFLP methods. Drug concentrations were determined by GC-MS and HPLC methods. The prevalence of allelic variants and predicted genotypes in the Croatian population ranged between values for Mid-European and Mediterranean populations. The prevalence of CYP2C19 genotype with mutant alleles was higher in population with major depression than in healthy population. Frequencies of homozygous “wild type” alleles of CYP2D6 were higher in healthy population, while homozygous mutant alleles were significantly higher in patients with major depression. Frequencies of ultraextensive CYP2D6 genotype were significantly higher in non-responder than in responder group. Significantly higher requencies of mutant CYP2D6 alleles were found in patients with adverse drug reactions compared to the group without adverse reactions. G2677 allele of MDR1 gene was more frequent in non-responder than in responder group. Frequencies of SERT-LL and SERT-ss genotypes were significantly higher in the group of patients without than in the group with adverse reactions. Variable paroxetine concentrations due to different CYP2D6 genotypes were more pronounced at the beginning of therapy, while differences in steady state were diminished. The results obtained could contribute to therapy individualization