Author/Editor | Serretti, Alessandro; Olgiati, Paolo | |
Title | Pharmacogenetics of antidepressants | |
Translated title | Farmakogenetika antidepresivov | |
Type | članek | |
Source | Zdrav Vestn | |
Vol. and No. | Letnik 76, št. Suppl 2 | |
Publication year | 2007 | |
Volume | str. II-13-24 | |
Language | eng | |
Abstract | Background Antidepressant drug therapy is characterised by a high rate of therapeutic failure, which can not be predicted in advance. Pharmacogenetic studies in mood disorders aim to the identification of gene polymorphisms associated with therapeutic efficacy and side effects of antidepressants. During the recent years the possible influence of a set of candidate genes in the pharmacodynamic pathway as possible genetic predictors of antidepressant response efficacy were investigated and will be reviewed here. The functional polymorphism in the upstream regulatory region of the serotonin trarcsporter gene (5-HTTLPR), the A218C gene variant on the tryptophan hydroxylase gene (TPH), the 102TC variant in the 5HT2A receptor, the G-protein beta3-subunit(Gbeta3) C825T gene variant, the glucocorticoid receptor-regulating cochaperone (FKBPS) and the Circadian Locomotor Output Cycles Kaput (CLOCK) genes variants were independently associated with short term SSRls antidepressant efficacy. Cytochromes P450 appear so be the most important determinant of the pharmacokinetics of antidepressants, especially polymorphic CYP2D6 that metabolizes most of the selective serotonin reuptake inhibitors (SSRI). Also polymorphic MDR2 gene coding for Pglycoprotein (ABCBI), a brain-to-blood efflux drug transporter, seems to be can important cleteminant of antidepressant efficacy. Conclusions Although in its preliminary phase, the results obtained in the pharmacogenetics of antidepressants are promising for an individualized therapy. Pharmacogenetic testing could help to identify the most effective treatment, improve the quality of life of affected persons and reduce the health-care costs. | |
Summary | Izhodišča Pri zdravljenju z antidepresivi velik problem predstavlja neodzivnost na zdravljenje, ki je ni mogoče vnaprej napovedati, pojavi pa se kar pri tretjini bolnikov. S farmakogenetskim pristopom so v zadnjih letih odkrili številne genetske polimofizme, ki so povezani z učinkovitostjo zdravljenja z antidepresivi in/ali z neželenimi učinki teh zdravil. Prispevek prinaša pregled genetskih dejavnikov, ki lahko vplivajo na farmakodinamiko in farmakokinetiko antidepresivov. Med najpomembnejšimi polimorfizmi, ki vplivajo na farmakodinamiko in na kratkoročno učinkovitost zdravljenja z antidepresivi, so: polimorfizem (insercija/delecija 44bp) v promoterju gena za serotoninski transporter (SERTPR), ki vpliva na hitrost prepisovanja; polimorfizem A218C gena za triptofan hidroksilazo (TPH), polimorfizem T102C gena za serotoninski receptor 2A (5HT2A, polimorfizem C825T gena za beta3-podenoto Gproteina (Gbeta3), ko-šaperon, ki uravnava glukokortikoidni receptor (FKBP5) in polimorfizmi gena, ki uravnava cirkadiano aktivnost (Circadian Locomotor Output Cycles Kaput - CLOCK). Na famakokinetiko antidepresivov pa najpomembneje vplivajo citokromi P450, zlasti CYP2D6 preko katerega se presnavlja večina selektivnih zaviralcev prevzema serotonina (SSRI). Na učinkovitost zdravljenja z antidepresivi pa vpliva tudi polimorfizem gena za p-glikoprotein (MDR1 oz. ABCB1), ki transportira antidepresive preko hematoencefalne bariere. Zaključki Čeprav so farmakogenetske raziskave zdravljenja z antidepresivi še v začetni fazi, so rezultati obetavni in kažejo, da farmakogenetsko testiranje lahko pripomore k individualiziranemu in bolj racionalnemu zdravljenju z antidepresivi in k boljši kvaliteti življenja bolnikov. | |
Descriptors | PHARMACOGENETICS ANTIDEPRESSIVE AGENTS POLYMORPHISM (GENETICS) TRYPTOPHAN HYDROXYLASE SEROTONIN MONOAMINE OXIDASE GTP-BINDING PROTEINS INTERLEUKIN-1 CYTOCHROME P-450 |