title: Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.
abstract: OBJECTIVE
  Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT.
  
  
  METHODS
  Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects.
  
  
  RESULTS
  Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation.
  
  
  CONCLUSIONS
  In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.
authors: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors: Yuan
authors: Y
authors: Ji
authors: Daniel J
authors: DJ
authors: Schaid
authors: Zeruesenay
authors: Z
authors: Desta
authors: Michiaki
authors: M
authors: Kubo
authors: Anthony J
authors: AJ
authors: Batzler
authors: Karen
authors: K
authors: Snyder
authors: Taisei
authors: T
authors: Mushiroda
authors: Naoyuki
authors: N
authors: Kamatani
authors: Evan
authors: E
authors: Ogburn
authors: Daniel
authors: D
authors: Hall-Flavin
authors: David
authors: D
authors: Flockhart
authors: Yusuke
authors: Y
authors: Nakamura
authors: David A
authors: DA
authors: Mrazek
authors: Richard M
authors: RM
authors: Weinshilboum
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001711:Biotransformation; D015283:Citalopram / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human
keywords: citalopram; escitalopram; genome-wide association study; major depressive disorder; plasma drug concentration; selective serotonin reuptake inhibitor