Genetic differences in cytochrome P450 enzymes and antidepressant treatment response

Karen Hodgson; Katherine Tansey; Mojca Zvezdana Dernovšek; Joanna Hauser; Neven Henigsberg; Wolfgang Maier; Ole Mors; Anna Placentino; Marcella Rietschel; Daniel Souery; Rebecca Smith; Ian W. Craig; Anne E. Farmer; Katherine J. Aitchison; Sarah Belsy; Oliver Sp Davis; Rudolf Uher; Peter McGuffin

doi:10.1177/0269881113512041

Genetic differences in cytochrome P450 enzymes and antidepressant treatment response

Karen Hodgson, Katherine Tansey, Mojca Zvezdana Dernovšek, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Rebecca Smith, Ian W. Craig, Anne E. Farmer, Katherine J. Aitchison, Sarah Belsy, Oliver Sp Davis, Rudolf Uher, Peter McGuffin

Medicine

Research output: Contribution to journal › Article › peer-review

80 Citations (Scopus)

Abstract

Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline: nortriptyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.

Original language	English
Pages (from-to)	133-141
Number of pages	9
Journal	Journal of Psychopharmacology
Volume	28
Issue number	2
DOIs	https://doi.org/10.1177/0269881113512041
Publication status	Published - Feb 2014

Bibliographical note

Funding Information:
The GENDEP project was funded by the European Commission Framework 6 Grant, EC Contract Ref.: LSHB-CT-2003–503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline, the Medical Research Council, the Biomedical Research Centre for Mental Health at the Institute of Psychiatry and South London and Maudsley NHS Foundation Trust (funded by the United Kingdom National Institute for Health Research of the Department of Health) contributed to the funding of the sample collection at the Institute of Psychiatry, London, through add-on projects or latterly staff funding. The sponsors had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the paper.

ASJC Scopus Subject Areas

Pharmacology
Psychiatry and Mental health
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1177/0269881113512041

Cite this

Hodgson, K., Tansey, K., Dernovšek, M. Z., Hauser, J., Henigsberg, N., Maier, W., Mors, O., Placentino, A., Rietschel, M., Souery, D., Smith, R., Craig, I. W., Farmer, A. E., Aitchison, K. J., Belsy, S., Davis, O. S., Uher, R., & McGuffin, P. (2014). Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. Journal of Psychopharmacology, 28(2), 133-141. https://doi.org/10.1177/0269881113512041

Hodgson, K, Tansey, K, Dernovšek, MZ, Hauser, J, Henigsberg, N, Maier, W, Mors, O, Placentino, A, Rietschel, M, Souery, D, Smith, R, Craig, IW, Farmer, AE, Aitchison, KJ, Belsy, S, Davis, OS, Uher, R & McGuffin, P 2014, 'Genetic differences in cytochrome P450 enzymes and antidepressant treatment response', Journal of Psychopharmacology, vol. 28, no. 2, pp. 133-141. https://doi.org/10.1177/0269881113512041

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title = "Genetic differences in cytochrome P450 enzymes and antidepressant treatment response",

abstract = "Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline: nortriptyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.",

author = "Karen Hodgson and Katherine Tansey and Dernov{\v s}ek, {Mojca Zvezdana} and Joanna Hauser and Neven Henigsberg and Wolfgang Maier and Ole Mors and Anna Placentino and Marcella Rietschel and Daniel Souery and Rebecca Smith and Craig, {Ian W.} and Farmer, {Anne E.} and Aitchison, {Katherine J.} and Sarah Belsy and Davis, {Oliver Sp} and Rudolf Uher and Peter McGuffin",

note = "Funding Information: The GENDEP project was funded by the European Commission Framework 6 Grant, EC Contract Ref.: LSHB-CT-2003–503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline, the Medical Research Council, the Biomedical Research Centre for Mental Health at the Institute of Psychiatry and South London and Maudsley NHS Foundation Trust (funded by the United Kingdom National Institute for Health Research of the Department of Health) contributed to the funding of the sample collection at the Institute of Psychiatry, London, through add-on projects or latterly staff funding. The sponsors had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the paper.",

year = "2014",

month = feb,

doi = "10.1177/0269881113512041",

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pages = "133--141",

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T1 - Genetic differences in cytochrome P450 enzymes and antidepressant treatment response

AU - Hodgson, Karen

AU - Tansey, Katherine

AU - Dernovšek, Mojca Zvezdana

AU - Hauser, Joanna

AU - Henigsberg, Neven

AU - Maier, Wolfgang

AU - Mors, Ole

AU - Placentino, Anna

AU - Rietschel, Marcella

AU - Souery, Daniel

AU - Smith, Rebecca

AU - Craig, Ian W.

AU - Farmer, Anne E.

AU - Aitchison, Katherine J.

AU - Belsy, Sarah

AU - Davis, Oliver Sp

AU - Uher, Rudolf

AU - McGuffin, Peter

N1 - Funding Information: The GENDEP project was funded by the European Commission Framework 6 Grant, EC Contract Ref.: LSHB-CT-2003–503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline, the Medical Research Council, the Biomedical Research Centre for Mental Health at the Institute of Psychiatry and South London and Maudsley NHS Foundation Trust (funded by the United Kingdom National Institute for Health Research of the Department of Health) contributed to the funding of the sample collection at the Institute of Psychiatry, London, through add-on projects or latterly staff funding. The sponsors had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the paper.

PY - 2014/2

Y1 - 2014/2

N2 - Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline: nortriptyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.

AB - Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline: nortriptyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.

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Genetic differences in cytochrome P450 enzymes and antidepressant treatment response

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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