CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP

Patricia Huezo-Diaz, Nader Perroud, Edgar P Spencer, Rebecca Smith, Sarah Sim, Susanne Virding, Rudolf Uher, Cerisse Gunasinghe, Jo Gray, Desmond Campbell, Joanna Hauser, Wolfgang Maier, Andrej Marusic, Marcella Rietschel, Jorge Perez, Caterina Giovannini, Ole Mors, Julien Mendlewicz, Peter McGuffin, Anne E FarmerMagnus Ingelman-Sundberg, Ian W Craig, Katherine J Aitchison

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)398-407
Number of pages10
JournalJournal of psychopharmacology (Oxford, England)
Volume26
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • Adult
  • Aged
  • Antidepressive Agents/blood
  • Aryl Hydrocarbon Hydroxylases/genetics
  • Biotransformation
  • Citalopram/analogs & derivatives
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6/genetics
  • Depressive Disorder, Major/blood
  • Diagnostic and Statistical Manual of Mental Disorders
  • European Continental Ancestry Group
  • Female
  • Genetic Association Studies
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Serotonin Uptake Inhibitors/blood
  • Young Adult

Fingerprint

Dive into the research topics of 'CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP'. Together they form a unique fingerprint.

Cite this