6533b861fe1ef96bd12c59d5

RESEARCH PRODUCT

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

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SUMMARY Background: Venlafaxine (V) is a mixed serotoninand noradrenaline reuptake inhibitor used as afirst-line treatment of depressive disorders. It ismetabolized primarily by the highly polymorphiccytochrome P450 (CYP) enzyme CYP2D6 to yielda pharmacologically active metabolite, O-des-methylvenlafaxine (ODV), and to a lesser extentby CYP3A4, to yield N-desmethylvenlafaxine(NDV).Objectives: The aim of this study was to assesswhether the O-demethylation phenotype of V hasan impact on the pharmacokinetics and clinicaloutcome.Method: In 100 patients treated with V, serumconcentrations of V, ODV and NDV and theratios of concentrations ODV/V as a measure ofO-demethylation were determined. Individualsexhibiting abnormally high or low metabolicratios of ODV/V were selected for genotyping.Clinical effects were monitored by the ClinicalGlobal Impressions Scale and side effects by theUKU (Udvalg for Kliniske Undersogelser SideEffect Rating Scale) rating scale.Results: There was wide inter-individual variab-ility in ODV/V ratios. The median ratio ODV/Vwas 1AE8 and the 10th and 90th percentiles 0AE3 and5AE2, respectively. Individuals with ODV/V ratiosbelow 0AE3 were all identified as poor metabolizers(PM), with the genotypes *6/*4 (n = 1), *5/*4(n = 2) or *6/*6 (n = 1). Individuals with ratiosabove 5AE2 were all ultra rapid metabolizers (UM,n = 6) due to gene duplications. Five individualswith intermediate metabolic activity (ODV/V,1AE1±0AE8) were heterozygotes with the CYP2D6*4genotype, and one patient with an intermediatemetabolic ratio of 4AE8 had the genotype *4/2x*1.Clinical outcome measurements revealed thatpatients with ODV/V ratios below 0AE3 had moreside effects (P <0AE005) and reduced serum con-centrations of sodium (P <0AE05) in comparisonwith other patients. Gastrointestinal side effects,notably nausea, vomiting and diarrhoea were themost common. Differences in therapeutic efficacywere not significant between the different phe-notypes.Conclusion: The O-demethylation phenotype of Vdepends strongly on the CYP2D6 genotype. A PMphenotype of CYP2D6 increases the risk of sideeffects.Keywords: clinical response, CYP2D6, depression,molecular genetics, side effects, venlafaxine