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CPIC® Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19

Most recent guideline publication:

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update (December 2016)

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 the CYP2D6 genotype to 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: The recommendation for CYP2D6 IM (reduce starting dose by 25%) should be considered for CYP2D6 AS of 1 (strength of recommendation: optional). The authors of this guideline are in the process of updating this guideline to reflect this change and evaluate new evidence since the publication of this guideline.
  • All activity scores for diplotypes containing a CYP2D6*10 allele have been updated accordingly (activity scores changed to reflect the lower activity value of 0.25 for CYP2D6*10). See table of all previous and new phenotype groupings.
    • Impact on the recommendations in this guideline: Prior to the consensus projects, the combination of a duplicated normal function allele with a CYP2D6*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.

Tables and figure provided in the main manuscript of the guideline:

Table 1. Assignment of likely phenotypes based on diplotypes
Table 2. Dosing recommendations for tricyclic antidepressants based on CYP2D6 phenotype
Table 3. Dosing recommendations for the tertiary amines amitriptyline, clomipramine, doxepin, imipramine, and trimipramine based on CYP2C19 phenotype
Table 4. Dosing recommendations for amitriptyline based on both CYP2D6 and CYP2C19 phenotypes
Figure 1. Major metabolic pathway of the tertiary amine amitriptyline and the secondary amine nortriptyline

Supplement to: Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update (December 2016)

Tables and figures provided in the guideline publication supplement or referenced in the guidelinea:

Supplemental Table S1. Association between allelic variants and CYP2D6 enzyme activity
Supplemental Table S2. Examples of CYP2D6 genotypes with resulting activity scores and phenotype classification
Supplemental Table S3. Tricyclic antidepressant metabolism by CYP2D6 and CYP2C19
Supplemental Table S4. Tricyclic antidepressant side effects
Supplemental Table S5. Evidence linking CYP2D6 genotype to amitriptyline phenotype
Supplemental Table S6. Evidence linking CYP2C19 genotype to amitriptyline phenotype
Supplemental Table S7. Evidence linking CYP2D6 genotype to nortriptyline phenotype
Supplemental Table S8. Evidence linking CYP2D6 genotype to imipramine phenotype
Supplemental Table S9. Evidence linking CYP2C19 genotype to imipramine phenotype
Supplemental Table S10. Evidence linking CYP2D6 genotype to desipramine phenotype
Supplemental Table S11. Evidence linking CYP2D6 genotype to clomipramine phenotype
Supplemental Table S12. Evidence linking CYP2C19 genotype to clomipramine phenotype
Supplemental Table S13. Evidence linking CYP2D6 genotype to trimipramine phenotype
Supplemental Table S14. Evidence linking CYP2C19 genotype to trimipramine phenotype
Supplemental Table S15. Evidence linking CYP2D6 genotype to doxepin phenotype
Supplemental Table S16. Evidence linking CYP2C19 genotype to doxepin phenotype
CYP2D6 allele definition table
CYP2D6 allele functionality table
CYP2D6 frequency table
CYP2D6 diplotype-phenotype table
CYP2C19 allele definition table
CYP2C19 allele functionality table
CYP2C19 frequency table
CYP2C19 diplotype-phenotype table

Gene resource mapping:

CYP2D6 gene resource mappings

CYP2C19 gene resource mappings

Drug resource mapping

Amitriptyline

Clomipramine

Desipramine

Doxepin

Imipramine

Nortriptyline

Trimipramine

Clinical decision support:b

Amitriptyline pre- and post-test alerts and flow chart

Nortriptyline 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.

Original guideline publication (May 2013):

 

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