Mohamed Shams and Borros Arneth contributed equally to this article.
CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine
Version of Record online: 30 AUG 2006
Journal of Clinical Pharmacy and Therapeutics
Volume 31, Issue 5, pages 493–502, October 2006
How to Cite
Shams, M. E. E., Arneth, B., Hiemke, C., Dragicevic, A., Müller, M. J., Kaiser, R., Lackner, K. and Härtter, S. (2006), CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. Journal of Clinical Pharmacy and Therapeutics, 31: 493–502. doi: 10.1111/j.1365-2710.2006.00763.x
- Issue online: 30 AUG 2006
- Version of Record online: 30 AUG 2006
- Received 1 March 2006, Accepted 8 June 2006
- clinical response;
- molecular genetics;
- side effects;
Background: Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O-desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N-desmethylvenlafaxine (NDV).
Objectives: The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome.
Method: In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale.
Results: There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1·8 and the 10th and 90th percentiles 0·3 and 5·2, respectively. Individuals with ODV/V ratios below 0·3 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 ratios above 5·2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1·1 ± 0·8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4·8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0·3 had more side effects (P < 0·005) and reduced serum concentrations of sodium (P < 0·05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes.
Conclusion: The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.