Genetic differences in cytochrome P450 enzymes and antidepressant treatment response

Author:

Hodgson Karen1,Tansey Katherine1,Dernovšek Mojca Zvezdana2,Hauser Joanna3,Henigsberg Neven4,Maier Wolfgang5,Mors Ole6,Placentino Anna7,Rietschel Marcella8,Souery Daniel9,Smith Rebecca1,Craig Ian W1,Farmer Anne E1,Aitchison Katherine J110,Belsy Sarah11,Davis Oliver SP112,Uher Rudolf113,McGuffin Peter1

Affiliation:

1. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK

2. University Psychiatric Clinic, Ljubljana, Slovenia

3. Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland

4. Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia

5. Department of Psychiatry, University of Bonn, Bonn, Germany

6. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

7. Psychiatric Unit (UOP 23), Department of Mental Health, Spedali Civili Hospital of Brescia, Biological Psychiatry Unit, IRCCS-FBF, Brescia, Italy

8. Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany

9. Laboratoire de Psychologie Médicale, Université Libre de Bruxelles; Psy Pluriel – Centre Européen de Psychologie Médicale, Brussels, Belgium

10. Department of Psychiatry, University of Alberta, Edmonton, Canada

11. Toxicology Unit, Department of Clinical Biochemistry, King’s College Hospital, London, UK

12. The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

13. Department of Psychiatry, Dalhousie University, Halifax, Canada

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:nortrip-tyline 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.

Publisher

SAGE Publications

Subject

Pharmacology (medical),Psychiatry and Mental health,Pharmacology

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