Clinical Pharmacology & Therapeutics - Abstract of article: Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants

Clinical Pharmacology & Therapeutics - Abstract of article: Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants

CPIC Guidelines

Clinical Pharmacology & Therapeutics (2013); 93 5, 402–408. doi:10.1038/clpt.2013.2

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants

J K Hicks¹, J J Swen², C F Thorn³, K Sangkuhl³, E D Kharasch⁴, V L Ellingrod^5,6, T C Skaar⁷, D J Müller⁸, A Gaedigk⁹ and J C Stingl¹⁰

1. ¹Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA


2. ²Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands


3. ³Department of Genetics, Stanford University, Stanford, California, USA


4. ⁴Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA


5. ⁵Department of Clinical, Social and Administrative Sciences, College of Pharmacy, Ann Arbor, Michigan, USA


6. ⁶Department of Psychiatry, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA


7. ⁷Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA


8. ⁸Neurogenetics Section, Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada


9. ⁹Division of Pediatric Pharmacology and Medical Toxicology, Children’s Mercy Hospital & Clinics, Kansas City, Missouri, USA


10. ¹⁰Division of Research, Federal Institute for Drugs and Medical Devices, Bonn, Germany

Correspondence: J C Stingl, (cpic@pharmgkb.org)

Received 1 October 2012; Accepted 27 December 2012
Accepted article preview online 16 January 2013; Advance online publication 13 March 2013

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Abstract

Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants.