title: CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.
abstract: 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).
  
  
  OBJECTIVE
  The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.
authors.affiliation: Department of Psychiatry, University of Mainz, Mainz, Germany.
authors.forename: M E E
authors.initials: ME
authors.lastname: Shams
authors.forename: B
authors.initials: B
authors.lastname: Arneth
authors.forename: C
authors.initials: C
authors.lastname: Hiemke
authors.forename: A
authors.initials: A
authors.lastname: Dragicevic
authors.forename: M J
authors.initials: MJ
authors.lastname: Müller
authors.forename: R
authors.initials: R
authors.lastname: Kaiser
authors.forename: K
authors.initials: K
authors.lastname: Lackner
authors.forename: S
authors.initials: S
authors.lastname: Härtter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D003511:Cyclohexanols / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003866:Depressive Disorder / Q000188:drug therapy*; D000069468:Desvenlafaxine Succinate; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D000069470:Venlafaxine Hydrochloride
chemical_list: D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D000069468:Desvenlafaxine Succinate