Abstract
Abstract Rationale: Cytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive. Objectives: We explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline. Methods: Patients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation. Results: P450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, β = -0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, β = -0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea. Conclusions: In this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.
| Original language | English |
|---|---|
| Article number | 3898 |
| Pages (from-to) | 2609-2617 |
| Number of pages | 9 |
| Journal | Psychopharmacology |
| Volume | 232 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - Jul 26 2015 |
Bibliographical note
Funding Information:We acknowledge the contribution of the following collaborators: Helen Dean, Amanda Elkin, Joanna Gray, Cerisse Gunasinghe, Desmond Campbell, David Dempster, Richard J Williamson, Caterina Giovannini, Julien Mendlewicz, Thomas Schulze, Jana Strohmaier, Christine Schmäl, Susanne Höfels, Anna Schuhmacher, Ute Pfeiffer, Sandra Weber, Anne Schinkel Stamp, Piotr Czerski Alenka Tancic, Jerneja Sveticic, Zrnka Kovacic, Pawe Kapelski, Maria Skibińska, Aleksandra Rajewska, Aleksandra Szczepankiewicz and Elzbieta Cegielska. We specially acknowledge the contribution of Jorge Perez, who was the principal investigator at Brescia, Italy, and who passed away in October 2007, and the late Professor Andrej Marusic, who was the lead investigator at Ljubljana, and who passed away in June 2008. 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 UK 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. Dr. Uher is supported by the Canada Research Chairs program ( http://www.chairs-chaires.gc.ca/ ). The sponsors had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the paper.
Publisher Copyright:
© 2015 The Author(s).
ASJC Scopus Subject Areas
- Pharmacology
