title: CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP.
abstract: In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.
authors.affiliation: MRC SGDP Centre, Institute of Psychiatry at King's College London, London, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Huezo-Diaz
authors.forename: Nader
authors.initials: N
authors.lastname: Perroud
authors.forename: Edgar P
authors.initials: EP
authors.lastname: Spencer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Smith
authors.forename: Sarah
authors.initials: S
authors.lastname: Sim
authors.forename: Susanne
authors.initials: S
authors.lastname: Virding
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Cerisse
authors.initials: C
authors.lastname: Gunasinghe
authors.forename: Jo
authors.initials: J
authors.lastname: Gray
authors.forename: Desmond
authors.initials: D
authors.lastname: Campbell
authors.forename: Joanna
authors.initials: J
authors.lastname: Hauser
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Andrej
authors.initials: A
authors.lastname: Marusic
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Jorge
authors.initials: J
authors.lastname: Perez
authors.forename: Caterina
authors.initials: C
authors.lastname: Giovannini
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.forename: Julien
authors.initials: J
authors.lastname: Mendlewicz
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Anne E
authors.initials: AE
authors.lastname: Farmer
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.forename: Ian W
authors.initials: IW
authors.lastname: Craig
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Aitchison
mesh_terms: D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D015283:Citalopram / Q000031:analogs & derivatives / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003865:Major Depressive Disorder / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D044465:White People; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D001189:Aryl Hydrocarbon Hydroxylases; D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D017367:Selective Serotonin Reuptake Inhibitors; C046304:desmethylcitalopram; C045793:CYP2C19 protein, human