Selective Serotonin Reuptake Inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).

Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.

Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified‐Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype.

CYP2D6 and CYP2C19 polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for CYP2D6 and CYP2C19 genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants.

Purpose:Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes. CYP2D6 alleles confer no, decreased, normal, or increased activity and cause a wide range of activity among individuals and between populations. However, there is no standard approach to translate diplotypes into predicted phenotype.Methods:We exploited CYP2D6 allele-frequency data that have been compiled for Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (>60,000 subjects, 173 reports) in order to estimate genotype-predicted phenotype status across major world populations based on activity score (AS) assignments.Results:Allele frequencies vary considerably across the major ethnic groups predicting poor metabolizer status (AS = 0) between 0.4 and 5.4% across world populations. The prevalence of genotypic intermediate (AS = 0.5) and normal (AS = 1, 1.5, or 2) metabolizers ranges between 0.4 and 11% and between 67 and 90%, respectively. Finally, 1 to 21% of subjects (AS >2) are predicted to have ultrarapid metabolizer status.Conclusions:This comprehensive study summarizes allele frequencies, diplotypes, and predicted phenotype across major populations, providing a rich data resource for clinicians and researchers. Challenges of phenotype prediction from genotype data are highlighted and discussed.Genet Med 19 1, 69–76.

nature publishing groupPolymorphisms 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.The use of tricyclics to treat psychological disorders has declined in part because of the occurrence of undesirable side effects. Although tricyclics are still used to treat depression, 1 their main therapeutic use is often for pain management. 2,3 Interindividual differences in side effects and treatment response have been associated with variability of tricyclic plasma concentrations. 4,5 Because both enzymes influence plasma concentrations, the effectiveness and tolerability of tricyclics are affected by CYP2D6 metabolism and partially by CYP2C19 metabolism. 4 The purpose of this guideline is to provide information regarding how to use existing CYP2D6 and/or CYP2C19 genotyping test results to guide dosing of tricyclics for psychological disorders and pain management, focusing particularly on amitriptyline and nortriptyline.Optimal therapeutic plasma concentrations for the tricyclics have been defined. 6 Poor or ultrarapid metabolizers of CYP2D6 and CYP2C19 may have tricyclic plasma concentrations outside the recommended therapeutic range, thereby increasing the risk of treatment failure or side effects. 7-10 Therefore, this guideline takes into consideration both clinical outcomes and observed tricyclic plasma concentrations based on genotype/phenotype characteristics. Detailed guidelines for use of other laboratory tests including therapeutic drug monitoring of tricyclics are beyond the scope of this article. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health's Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically at http://www.pharmgkb.org based on new developments in the field. FOCUSED LITERATURE REVIEWA systematic literature review focused on CYP2D6 and CYP2C19 genotyping and its relevance to gene-based dosing of tricyclics was conducted (see Supplementary Data online). This guideline was developed based on interpretation of the literature by the authors and experts in the field. GENES: CYP2D6 AND CYP2C19 CYP2D6 backgroundThe CYP2D6 gene is highly polymorphic. 11 More than 100 known allelic variants and subvariants have been identified, and there are substantial ethnic differences in observed allele frequencies (Supplementary Data online). The most commonly reported CYP2C19 backgroundSimilar to CYP2D6, the CYP2C19 gene is highly polymorphic; more than 30 known allelic variants and subvariants have been identif...

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