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CPIC® Guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19

Most recent guideline publication:

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors (August 2015)

Updates since publication:

October 2019: CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus among a panel of international CYP2D6 experts for a uniform system for translating CYP2D6 genotype to phenotype(more information). Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer  (table of all previous and new phenotype groupings).

As a result, the following changes have been made in the CYP2D6 allele functionality table and  CYP2D6 diplotype-phenotype table :

  • Diplotypes giving rise to activity scores of 1 changed from CYP2D6 normal metabolizer to CYP2D6 intermediate metabolizer assignments.
    • Impact on the recommendations in this guideline: Because the recommendations in this guideline do not differ between a CYP2D6 normal and intermediate metabolizer, the current published recommendations for normal and intermediate metabolizers will remain unchanged.
  • All activity scores for diplotypes containing a CYP2D6*10 allele have been updated accordingly (activity scores changed to reflect the lower value of 0.25 for *10). Prior to the consensus projects, the combination of a duplicated normal function allele with a *10 allele resulted in an activity score of 2.5 which translates to an ultrarapid metabolizer. The lower value of 0.25 for CYP2D6*10 results in an activity score of 2.25 for these allele combinations, which based on the new consensus project, now translates to a normal metabolizer. See table of all previous and new phenotype groupings.
    • Impact on the recommendations in this guideline: The authors of this guideline are currently reviewing evidence for the affected activity score (AS of 2.25) and will update this webpage and relevant tables accordingly.

Tables provided in the main manuscript of the guideline:

Table 1. Assignment of likely phenotypes based on diplotypes
Table 2. Dosing recommendations for CYP2D6 and paroxetine and fluvoxamine
Table 3. Dosing recommendations for CYP2C19 and citalopram, escitalopram, and sertraline

 

Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors (August 2015)

Tables and figures included in the supplementa or referenced in the guideline:

Supplemental Table S1. Genotypes that constitute the * alleles for CYP2D6 and their effect on CYP2D6 protein For an updated version of this table see the CYP2D6 allele definition table .
Supplemental Table S2. Association between allelic variants and CYP2D6 enzyme function For an updated version of this table see the CYP2D6 allele functionality table .
Supplemental Table S3. Frequencies of CYP2D6 in major race/ethnic groups For an updated version of this table see the CYP2D6 frequency table .
2015 CYP2D6 SSRI translation table For an updated version of this tables see the CYP2D6 diplotype-phenotype table .
Supplemental Table S4. Genotypes that constitute the * alleles for CYP2C19 and their effect on CYP2C19 protein For an updated version of this table see the CYP2C19 allele definition table .
Supplemental Table S5. Association between allelic variants and CYP2C19 enzyme function For an updated version of this table see the CYP2C19 allele functionality table .
Supplemental Table S6. Frequencies of CYP2C19 in major race/ethnic groups For an updated version of this table see the CYP2C19 frequency table .
2015 CYP2C19 SSRI translation table For an updated version of this tables see the CYP2C19 diplotype-phenotype table .
Supplemental Table S7. Evidence linking CYP2D6 genotype to fluvoxamine phenotype
Supplemental Table S8. Evidence linking CYP2D6 genotype to paroxetine phenotype
Supplemental Table S9. Evidence linking CYP2C19 and CYP2D6 genotype to citalopram/escitalopram phenotype
Supplemental Table S10. Evidence linking CYP2D6 genotype to fluoxetine phenotype
Supplemental Table S11. Evidence linking CYP2C19 genotype to sertraline phenotype

Supplemental Table S12. Drugs associated with gene-based dosing recommendations in this guideline

Citalopram

Escitalopram

Fluvoxamine

Paroxetine

Sertraline

Supplemental Table S13. Genes that pertain to this guideline

CYP2D6 gene resource mappings

CYP2C19 gene resource mappings

Supplemental Figure S2. CYP2D6/CYP2C19 pharmacogenetic test result: clinical implementation workflow for EHR

Supplemental Table S14. Example implementation of this guideline for CYP2D6: pharmacogenetic diplotype/phenotype summary entries. For an updated version of this table see the CYP2D6 diplotype-phenotype table .

Supplemental Table S15. Example Implementation of this Guideline for CYP2C19: Pharmacogenetic Diplotype/Phenotype Summary Entries. For an updated version of this table see the CYP2C19 diplotype-phenotype table .

Supplemental Figure S3. CYP2D6/CYP2C19 genotype and SSRI: point of care clinical decision support

Supplemental Table S16. Example implementation of this guideline: point of care clinical decision supportb

Clinical decision supportb:

Citalopram pre- and post-test alerts and flow chart

Escitalopram pre- and post-test alerts and flow chart

Fluvoxamine pre- and post-test alerts and flow chart

Paroxetine pre- and post-test alerts and flow chart

Sertraline pre- and post-test alerts and flow chart

aSome of the tables included in the guideline may have been updated on-line, particularly to reflect newly described or newly characterized alleles. These include the gene-specific information tables (https://www.pharmgkb.org/page/pgxGeneRef) that support CPIC guidelines by providing information regarding star (*) allele definitions, allele function, allele frequency by major ethnic groups, translations of diplotype to phenotype, and gene resource mappings.

bThese resources support the adoption of CPIC guidelines into the electronic health record with clinical decision support and provide information that clinical implementers find helpful.

This guideline has been endorsed by the American Society of Health-System Pharmacists (ASHP).