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CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients

Molecular Psychiatry volume 18, pages 8–9 (2013)Cite this article

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A Corrigendum to this article was published on 04 December 2012

Early discontinuation of antidepressant drugs (ADPs) therapy is common, occurring in about 30% of patients by week 6.1, 2 Among the most relevant reasons for ADP discontinuation are adverse drug reactions and lack of improvement,3 which can be explained by interindividual variability in drug metabolism. Thus, discontinuation of amitriptyline or fluoxetine, two of the most commonly used ADPs worldwide, which are mainly metabolized by CYP2D6, could be related to CYP2D6 genetic polymorphism.

However, little is known about the relationship of CYP2D6 and ADPs discontinuation. Although an absent CYP2D6-mediated poor metabolism (PMs) or ultrarapid metabolism (UM) has been respectively related to higher or lower plasma concentrations of the drug4 and to toxicity/adverse drug reaction5, 6 or lack of clinical improvement,6, 7 only one study has analyzed whether PMs discontinued more from ADPs than the rest.2 Contrary to expectations, PMs (homozygous carriers of the null activity allele CYP2D6*4) did not discontinue more. This result could be due to two aspects: first, other clinically relevant CYP2D6 allelic variants such as those with null (for example, *3, *5, *6) or reduced activity (e.g., *10, *17) were not analyzed, and some PMs were missed; second, starting ADP doses were at the lower limit of the approved range, which is a common practice nowadays to keep the side effects to a minimum and that may make PMs to tolerate adverse drug reactions. Although this careful and safe way to prescribe ADPs (starting treatment with low doses and increase them gradually if needed) may have the advantage of preventing PMs from discontinuation,2 it may have the disadvantage of increasing discontinuation in UMs.

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Acknowledgements

This work was supported partly by grant no. 59366 from Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico and Union Europea Fondo Social Europeo (FEDER), Instituto de Salud Carlos III-FIS (PI10/02758 and CP06/0030) and Gobierno de Extremadura (Consejeria de Empleo, Empresa e Innovacion y Fondo Social Europeo (BS10023 and PD10199)).

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Authors and Affiliations

  1. CICAB Clinical Research Center. Extremadura University Hospital Medical School and CIBERSAM, Badajoz, Spain

    E M Peñas-LLedó, P Dorado, M E G Naranjo & A LLerena

  2. Neurogenetics Department, National Institute of Neurology and Neurosurgery ‘Manuel Velasco Suárez’, Mexico City, Mexico

    H D Trejo, A Ortega & E Alonso

  3. Neuropsychopharmacology Department, National Institute of Neurology and Neurosurgery ‘Manuel Velasco Suárez’, Mexico City, Mexico

    H Jung

  4. Department of Biological Systems, Universidad Autónoma Metropolitana-Xochimilco, Mexico City, Mexico

    M López-López

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  1. E M Peñas-LLedó
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Correspondence to M López-López or A LLerena.

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Peñas-LLedó, E., Trejo, H., Dorado, P. et al. CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients. Mol Psychiatry 18, 8–9 (2013). https://doi.org/10.1038/mp.2012.91

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