Citalopram and escitalopram plasma drug and metabolite concentrations: genome‐wide associations

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...

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Veröffentlicht in:British journal of clinical pharmacology 2014-08, Vol.78 (2), p.373-383
Hauptverfasser: 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.
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container_issue 2
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container_title British journal of clinical pharmacology
container_volume 78
creator 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.
description 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.
doi_str_mv 10.1111/bcp.12348
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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.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.12348</identifier><identifier>PMID: 24528284</identifier><language>eng</language><publisher>England: Blackwell Science Inc</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Biotransformation ; citalopram ; Citalopram - blood ; Citalopram - metabolism ; Citalopram - therapeutic use ; Cytochrome P-450 CYP2C19 - genetics ; Cytochrome P-450 CYP2D6 - genetics ; Depressive Disorder, Major - drug therapy ; Depressive Disorder, Major - metabolism ; escitalopram ; Female ; Genome-Wide Association Study ; Humans ; major depressive disorder ; Male ; Middle Aged ; Molecular Sequence Data ; Pharmacogenetics ; plasma drug concentration ; Polymorphism, Single Nucleotide ; selective serotonin reuptake inhibitor ; Serotonin Uptake Inhibitors - blood ; Serotonin Uptake Inhibitors - metabolism ; Serotonin Uptake Inhibitors - therapeutic use ; Young Adult</subject><ispartof>British journal of clinical pharmacology, 2014-08, Vol.78 (2), p.373-383</ispartof><rights>2014 The British Pharmacological Society</rights><rights>2014 The British Pharmacological Society.</rights><rights>2014 The British Pharmacological Society 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5148-97cd771bc3e0c9d7ea7f3e90c8cbd0b5b4107d3f46ecf28374af6450746149673</citedby><cites>FETCH-LOGICAL-c5148-97cd771bc3e0c9d7ea7f3e90c8cbd0b5b4107d3f46ecf28374af6450746149673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbcp.12348$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbcp.12348$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,782,786,887,1419,1435,27931,27932,45581,45582,46416,46840</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24528284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ji, Yuan</creatorcontrib><creatorcontrib>Schaid, Daniel J.</creatorcontrib><creatorcontrib>Desta, Zeruesenay</creatorcontrib><creatorcontrib>Kubo, Michiaki</creatorcontrib><creatorcontrib>Batzler, Anthony J.</creatorcontrib><creatorcontrib>Snyder, Karen</creatorcontrib><creatorcontrib>Mushiroda, Taisei</creatorcontrib><creatorcontrib>Kamatani, Naoyuki</creatorcontrib><creatorcontrib>Ogburn, Evan</creatorcontrib><creatorcontrib>Hall‐Flavin, Daniel</creatorcontrib><creatorcontrib>Flockhart, David</creatorcontrib><creatorcontrib>Nakamura, Yusuke</creatorcontrib><creatorcontrib>Mrazek, David A.</creatorcontrib><creatorcontrib>Weinshilboum, Richard M.</creatorcontrib><title>Citalopram and escitalopram plasma drug and metabolite concentrations: genome‐wide associations</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>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.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biotransformation</subject><subject>citalopram</subject><subject>Citalopram - blood</subject><subject>Citalopram - metabolism</subject><subject>Citalopram - therapeutic use</subject><subject>Cytochrome P-450 CYP2C19 - genetics</subject><subject>Cytochrome P-450 CYP2D6 - genetics</subject><subject>Depressive Disorder, Major - drug therapy</subject><subject>Depressive Disorder, Major - metabolism</subject><subject>escitalopram</subject><subject>Female</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>major depressive disorder</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Pharmacogenetics</subject><subject>plasma drug concentration</subject><subject>Polymorphism, Single Nucleotide</subject><subject>selective serotonin reuptake inhibitor</subject><subject>Serotonin Uptake Inhibitors - blood</subject><subject>Serotonin Uptake Inhibitors - metabolism</subject><subject>Serotonin Uptake Inhibitors - therapeutic use</subject><subject>Young Adult</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kctKxDAUhoMoznhZ-ALSpS465tq0LgQt3mBAF7oOaXo6RtqmNh2H2fkIPqNPYrU66sJsDuT_-M6BH6E9giekf0eZaSaEMh6voTFhkQgpoWIdjTHDUSioICO05f0jxoSRSGyiEeWCxjTmY6RT2-nSNa2uAl3nAXjz89GU2lc6yNv57DOsoNOZK20HgXG1gbprdWdd7Y-DGdSugreX14XNIdDeO2OHbAdtFLr0sPs1t9H9xfldehVOby6v09NpaAThcZhIk0tJMsMAmySXoGXBIMEmNlmOM5FxgmXOCh6BKWjMJNdFxAWWPCI8iSTbRieDt5lnFeTDdaVqWlvpdqmctupvUtsHNXPPihMmY5r0goMvQeue5uA7VVlvoCx1DW7uFemX0oTLKO7RwwE1rfO-hWK1hmD1UYnqK1GflfTs_u-7VuR3Bz1wNAALW8Lyf5M6S28H5TvYK5lh</recordid><startdate>201408</startdate><enddate>201408</enddate><creator>Ji, Yuan</creator><creator>Schaid, Daniel J.</creator><creator>Desta, Zeruesenay</creator><creator>Kubo, Michiaki</creator><creator>Batzler, Anthony J.</creator><creator>Snyder, Karen</creator><creator>Mushiroda, Taisei</creator><creator>Kamatani, Naoyuki</creator><creator>Ogburn, Evan</creator><creator>Hall‐Flavin, Daniel</creator><creator>Flockhart, David</creator><creator>Nakamura, Yusuke</creator><creator>Mrazek, David A.</creator><creator>Weinshilboum, Richard M.</creator><general>Blackwell Science Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>201408</creationdate><title>Citalopram and escitalopram plasma drug and metabolite concentrations: genome‐wide associations</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5148-97cd771bc3e0c9d7ea7f3e90c8cbd0b5b4107d3f46ecf28374af6450746149673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biotransformation</topic><topic>citalopram</topic><topic>Citalopram - blood</topic><topic>Citalopram - metabolism</topic><topic>Citalopram - therapeutic use</topic><topic>Cytochrome P-450 CYP2C19 - genetics</topic><topic>Cytochrome P-450 CYP2D6 - genetics</topic><topic>Depressive Disorder, Major - drug therapy</topic><topic>Depressive Disorder, Major - metabolism</topic><topic>escitalopram</topic><topic>Female</topic><topic>Genome-Wide Association Study</topic><topic>Humans</topic><topic>major depressive disorder</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>Pharmacogenetics</topic><topic>plasma drug concentration</topic><topic>Polymorphism, Single Nucleotide</topic><topic>selective serotonin reuptake inhibitor</topic><topic>Serotonin Uptake Inhibitors - blood</topic><topic>Serotonin Uptake Inhibitors - metabolism</topic><topic>Serotonin Uptake Inhibitors - therapeutic use</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ji, Yuan</creatorcontrib><creatorcontrib>Schaid, Daniel J.</creatorcontrib><creatorcontrib>Desta, Zeruesenay</creatorcontrib><creatorcontrib>Kubo, Michiaki</creatorcontrib><creatorcontrib>Batzler, Anthony J.</creatorcontrib><creatorcontrib>Snyder, Karen</creatorcontrib><creatorcontrib>Mushiroda, Taisei</creatorcontrib><creatorcontrib>Kamatani, Naoyuki</creatorcontrib><creatorcontrib>Ogburn, Evan</creatorcontrib><creatorcontrib>Hall‐Flavin, Daniel</creatorcontrib><creatorcontrib>Flockhart, David</creatorcontrib><creatorcontrib>Nakamura, Yusuke</creatorcontrib><creatorcontrib>Mrazek, David A.</creatorcontrib><creatorcontrib>Weinshilboum, Richard M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ji, Yuan</au><au>Schaid, Daniel J.</au><au>Desta, Zeruesenay</au><au>Kubo, Michiaki</au><au>Batzler, Anthony J.</au><au>Snyder, Karen</au><au>Mushiroda, Taisei</au><au>Kamatani, Naoyuki</au><au>Ogburn, Evan</au><au>Hall‐Flavin, Daniel</au><au>Flockhart, David</au><au>Nakamura, Yusuke</au><au>Mrazek, David A.</au><au>Weinshilboum, Richard M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Citalopram and escitalopram plasma drug and metabolite concentrations: genome‐wide associations</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2014-08</date><risdate>2014</risdate><volume>78</volume><issue>2</issue><spage>373</spage><epage>383</epage><pages>373-383</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><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.</abstract><cop>England</cop><pub>Blackwell Science Inc</pub><pmid>24528284</pmid><doi>10.1111/bcp.12348</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via Wiley Online Library; Wiley Online Library (Open Access Collection); Alma/SFX Local Collection
subjects Adult
Aged
Aged, 80 and over
Biotransformation
citalopram
Citalopram - blood
Citalopram - metabolism
Citalopram - therapeutic use
Cytochrome P-450 CYP2C19 - genetics
Cytochrome P-450 CYP2D6 - genetics
Depressive Disorder, Major - drug therapy
Depressive Disorder, Major - metabolism
escitalopram
Female
Genome-Wide Association Study
Humans
major depressive disorder
Male
Middle Aged
Molecular Sequence Data
Pharmacogenetics
plasma drug concentration
Polymorphism, Single Nucleotide
selective serotonin reuptake inhibitor
Serotonin Uptake Inhibitors - blood
Serotonin Uptake Inhibitors - metabolism
Serotonin Uptake Inhibitors - therapeutic use
Young Adult
title Citalopram and escitalopram plasma drug and metabolite concentrations: genome‐wide associations
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