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. Farmer; Magnus Ingelman-Sundberg; Ian W. Craig; Katherine J. Aitchison

doi:10.1177/0269881111414451

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

Résultat de recherche: Article › examen par les pairs

67 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Pages (de-à)	398-407
Nombre de pages	10
Journal	Journal of Psychopharmacology
Volume	26
Numéro de publication	3
DOI	https://doi.org/10.1177/0269881111414451
Statut de publication	Published - mars 2012
Publié à l'externe	Oui

Note bibliographique

Funding Information:
The GENDEP clinical pharmacogenomics study was part of an integrated project funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Nader Perroud was funded by the Swiss National Science foundation: PASMA-118605. Lundbeck provided both nortriptyline and escitalopram free of charge for GENDEP. Roche Molecular Systems (USA) supplied the AmpliChip CYP450 Test® microarrays and some associated support. GlaxoSmithKline and the Medical Research Council (UK) contributed by funding add-on projects in the London centre. In its latter stages, GENDEP received additional funding at the Institute of Psychiatry site from the Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King’s College London (National Institute for Health Research, Department of Health, UK). However, the authors’ work was independent of the funders, with the legal sponsor of the study being the Institute of Psychiatry at King’s College London. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing of this report.

ASJC Scopus Subject Areas

Pharmacology
Psychiatry and Mental health
Pharmacology (medical)

PubMed: MeSH publication types

Controlled Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

ODD de l’ONU

Cette action contribue à la réalisation des objectifs de développement durable suivants

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10.1177/0269881111414451

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Huezo-Diaz, P., Perroud, N., Spencer, E. P., Smith, R., Sim, S., Virding, S., Uher, R., Gunasinghe, C., Gray, J., Campbell, D., Hauser, J., Maier, W., Marusic, A., Rietschel, M., Perez, J., Giovannini, C., Mors, O., Mendlewicz, J., McGuffin, P., ... Aitchison, K. J. (2012). CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. Journal of Psychopharmacology, 26(3), 398-407. https://doi.org/10.1177/0269881111414451

Huezo-Diaz, P, Perroud, N, Spencer, EP, Smith, R, Sim, S, Virding, S, Uher, R, Gunasinghe, C, Gray, J, Campbell, D, Hauser, J, Maier, W, Marusic, A, Rietschel, M, Perez, J, Giovannini, C, Mors, O, Mendlewicz, J, McGuffin, P, Farmer, AE, Ingelman-Sundberg, M, Craig, IW & Aitchison, KJ 2012, 'CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP', Journal of Psychopharmacology, vol. 26, n° 3, pp. 398-407. https://doi.org/10.1177/0269881111414451

@article{7791e9904a2e40dc8fa7c8b7ba81c36b,

title = "CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP",

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.",

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

note = "Funding Information: The GENDEP clinical pharmacogenomics study was part of an integrated project funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Nader Perroud was funded by the Swiss National Science foundation: PASMA-118605. Lundbeck provided both nortriptyline and escitalopram free of charge for GENDEP. Roche Molecular Systems (USA) supplied the AmpliChip CYP450 Test{\textregistered} microarrays and some associated support. GlaxoSmithKline and the Medical Research Council (UK) contributed by funding add-on projects in the London centre. In its latter stages, GENDEP received additional funding at the Institute of Psychiatry site from the Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King{\textquoteright}s College London (National Institute for Health Research, Department of Health, UK). However, the authors{\textquoteright} work was independent of the funders, with the legal sponsor of the study being the Institute of Psychiatry at King{\textquoteright}s College London. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing of this report. ",

year = "2012",

month = mar,

doi = "10.1177/0269881111414451",

language = "English",

volume = "26",

pages = "398--407",

journal = "Journal of Psychopharmacology",

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T1 - CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP

AU - Huezo-Diaz, Patricia

AU - Perroud, Nader

AU - Spencer, Edgar P.

AU - Smith, Rebecca

AU - Sim, Sarah

AU - Virding, Susanne

AU - Uher, Rudolf

AU - Gunasinghe, Cerisse

AU - Gray, Jo

AU - Campbell, Desmond

AU - Hauser, Joanna

AU - Maier, Wolfgang

AU - Marusic, Andrej

AU - Rietschel, Marcella

AU - Perez, Jorge

AU - Giovannini, Caterina

AU - Mors, Ole

AU - Mendlewicz, Julien

AU - McGuffin, Peter

AU - Farmer, Anne E.

AU - Ingelman-Sundberg, Magnus

AU - Craig, Ian W.

AU - Aitchison, Katherine J.

N1 - Funding Information: The GENDEP clinical pharmacogenomics study was part of an integrated project funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Nader Perroud was funded by the Swiss National Science foundation: PASMA-118605. Lundbeck provided both nortriptyline and escitalopram free of charge for GENDEP. Roche Molecular Systems (USA) supplied the AmpliChip CYP450 Test® microarrays and some associated support. GlaxoSmithKline and the Medical Research Council (UK) contributed by funding add-on projects in the London centre. In its latter stages, GENDEP received additional funding at the Institute of Psychiatry site from the Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King’s College London (National Institute for Health Research, Department of Health, UK). However, the authors’ work was independent of the funders, with the legal sponsor of the study being the Institute of Psychiatry at King’s College London. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing of this report.

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

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SN - 0269-8811

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SP - 398

EP - 407

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

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ER -

CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP

Résumé

Note bibliographique

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODD de l’ONU

Accès au document

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