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Response to CYP2D6 substrate antidepressants is predicted by a CYP2D6 composite phenotype based on genotype and comedications with CYP2D6 inhibitors

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles (CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4 weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0 ± 17.9, 50.0 ± 26.0, and 61.6 ± 23.4, p = 0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants.

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Acknowledgments

The authors thank Brigitte Lasserre and Sylvie Jegouzo for their help.

Conflict of interest

The authors have no financial relationship with the organization that sponsored the research.

Regarding potential conflicts of interest, all of them were indirect: F Gressier has received consulting fees within the last 3 years from Lundbeck and Servier. C Verstuyft reported no biomedical financial interests or potential conflicts of interest. P Hardy reported no biomedical financial interests or potential conflicts of interest. L Becquemont reports consulting fees from Sanofi-Aventis, Pfizer, Servier and lecture fees from Genzyme, GlaxoSmithKline, Bristol-Myers Squibb, and Merck Sharp and Dohme. E Corruble has received consulting fees within the last 3 years from Lundbeck, Servier, Sanofi-Aventis, Bristol-Myers Squibb, Eisai, Otsuka Pharmaceuticals.

Ethical standards

This study has been approved by the National ethics Committee and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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All persons gave their informed consent prior to their inclusion in the study.

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Authors and Affiliations

  1. INSERM U669, Department of Psychiatry, Univ Paris Sud, APHP, Bicêtre University Hospital, 78 rue du Général Leclerc, 94275, Le Kremlin Bicêtre, France

    F. Gressier, P. Hardy & E. Corruble

  2. Departments of Molecular Genetics, Pharmacogenetics, and Hormonology, APHP, Bicêtre Hospital, EA 4123, Univ Paris-Sud, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France

    C. Verstuyft & L. Becquemont

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  1. F. Gressier
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Correspondence to F. Gressier.

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Gressier, F., Verstuyft, C., Hardy, P. et al. Response to CYP2D6 substrate antidepressants is predicted by a CYP2D6 composite phenotype based on genotype and comedications with CYP2D6 inhibitors. J Neural Transm 122, 35–42 (2015). https://doi.org/10.1007/s00702-014-1273-4

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