title: Genetic differences in cytochrome P450 enzymes and antidepressant treatment response.
abstract: OBJECTIVE
  Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration.
  
  
  METHODS
  In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped.
  
  
  RESULTS
  Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline:nortrip-tyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response.
  
  
  CONCLUSIONS
  While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.
authors.affiliation: 1MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Hodgson
authors.forename: Katherine
authors.initials: K
authors.lastname: Tansey
authors.forename: Mojca Zvezdana
authors.initials: MZ
authors.lastname: Dernovsek
authors.forename: Joanna
authors.initials: J
authors.lastname: Hauser
authors.forename: Neven
authors.initials: N
authors.lastname: Henigsberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.forename: Anna
authors.initials: A
authors.lastname: Placentino
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Daniel
authors.initials: D
authors.lastname: Souery
authors.forename: Rebecca
authors.initials: R
authors.lastname: Smith
authors.forename: Ian W
authors.initials: IW
authors.lastname: Craig
authors.forename: Anne E
authors.initials: AE
authors.lastname: Farmer
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Aitchison
authors.forename: Sarah
authors.initials: S
authors.lastname: Belsey
authors.forename: Sarah
authors.initials: S
authors.lastname: Belsy
authors.forename: Oliver S P
authors.initials: OS
authors.lastname: Davis
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015283:Citalopram / Q000097:blood / Q000627:therapeutic use; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009661:Nortriptyline / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; C013567:10-hydroxynortriptyline; D009661:Nortriptyline; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6
keywords: Antidepressant; cytochrome P450 enzymes; depression; drug metabolism; pharmacogenetics