Citalopram and escitalopram plasma drug and metabolite concentrations: genome‐wide associations. (August 2014)

• Record Type: Journal Article
• Authors: Ji, Yuan; Schaid, Daniel J.; Desta, Zeruesenay; Kubo, Michiaki; Batzler, Anthony J.; Snyder, Karen; Mushiroda, Taisei; Kamatani, Naoyuki; Ogburn, Evan; Hall‐Flavin, Daniel; Flockhart, David; Nakamura, Yusuke; Mrazek, David A.; Weinshilboum, Richard M.
• Is Part Of: British journal of clinical pharmacology. Volume 78:Number 2(2014:Aug.)
• Page Start: 373
• Page End: 383
• Publication Date: 2014-08
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12348
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12348-sec-0001" sec-type="section"> <title>Aims</title> <p>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.</p> </sec> <sec id="bcp12348-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="bcp12348-sec-0003" sec-type="section"> <title>Results</title> <p>Genome‐wide significant associations were observed for S‐CT concentration with SNPs in or near the <italic>CYP2C19</italic> gene on chromosome 10 (rs1074145, <italic>P</italic> = 4.1 × 10<sup>−9</sup>) and with <italic>S</italic>‐didesmethylcitalopram concentration for SNPs near the <italic>CYP2D6</italic> locus on chromosome 22 (rs1065852, <italic>P</italic> = 2.0 × 10<sup>−16</sup>), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of <italic>CYP2C19</italic> functional alleles, the analyses also identified novel loci that will require future replication and functional validation.</p> </sec> <sec id="bcp12348-sec-0004" sec-type="section"> <title>Conclusions</title> <p> <italic>In vitro</italic> and <italic>in vivo</italic> 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.</p> </sec> </abstract>