Citalopram and escitalopram plasma drug and metabolite concentrations

Genome-wide associations

Yuan Ji, Daniel J. Schaid, Zeruesenay Desta, Michiaki Kubo, Anthony J. Batzler, Karen Snyder, Taisei Mushiroda, Naoyuki Kamatani, Evan Ogburn, Daniel Hall-Flavin, David Flockhart, Yusuke Nakamura, David A. Mrazek, Richard M. Weinshilboum

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Aims 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.

Original languageEnglish
Pages (from-to)373-383
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume78
Issue number2
DOIs
Publication statusPublished - 01-01-2014

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Citalopram
Genome
Pharmaceutical Preparations
Major Depressive Disorder
Genome-Wide Association Study
Cytochrome P-450 Enzyme System
Single Nucleotide Polymorphism
Serotonin Uptake Inhibitors
Biotransformation
Chromosomes, Human, Pair 22
Chromosomes, Human, Pair 10
Cytochrome P-450 CYP2D6
Isoenzymes
Linear Models

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

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. / Citalopram and escitalopram plasma drug and metabolite concentrations : Genome-wide associations. In: British Journal of Clinical Pharmacology. 2014 ; Vol. 78, No. 2. pp. 373-383.
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abstract = "Aims 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.",
author = "Yuan Ji and Schaid, {Daniel J.} and Zeruesenay Desta and Michiaki Kubo and Batzler, {Anthony J.} and Karen Snyder and Taisei Mushiroda and Naoyuki Kamatani and Evan Ogburn and Daniel Hall-Flavin and David Flockhart and Yusuke Nakamura and Mrazek, {David A.} and Weinshilboum, {Richard M.}",
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Ji, Y, Schaid, DJ, Desta, Z, Kubo, M, Batzler, AJ, Snyder, K, Mushiroda, T, Kamatani, N, Ogburn, E, Hall-Flavin, D, Flockhart, D, Nakamura, Y, Mrazek, DA & Weinshilboum, RM 2014, 'Citalopram and escitalopram plasma drug and metabolite concentrations: Genome-wide associations', British Journal of Clinical Pharmacology, vol. 78, no. 2, pp. 373-383. https://doi.org/10.1111/bcp.12348

Citalopram and escitalopram plasma drug and metabolite concentrations : Genome-wide associations. / 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.

In: British Journal of Clinical Pharmacology, Vol. 78, No. 2, 01.01.2014, p. 373-383.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Citalopram and escitalopram plasma drug and metabolite concentrations

T2 - Genome-wide associations

AU - Ji, Yuan

AU - Schaid, Daniel J.

AU - Desta, Zeruesenay

AU - Kubo, Michiaki

AU - Batzler, Anthony J.

AU - Snyder, Karen

AU - Mushiroda, Taisei

AU - Kamatani, Naoyuki

AU - Ogburn, Evan

AU - Hall-Flavin, Daniel

AU - Flockhart, David

AU - Nakamura, Yusuke

AU - Mrazek, David A.

AU - Weinshilboum, Richard M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Aims 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.

AB - Aims 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.

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U2 - 10.1111/bcp.12348

DO - 10.1111/bcp.12348

M3 - Article

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SN - 0306-5251

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