Annotation of CPIC Guideline for imipramine and CYP2C19, CYP2D6

This annotation is based on the CPIC® guideline for tricyclic antidepressants and CYP2D6 and CYP2C19.

October 2019 Update

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts 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 (access tables below):

• 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 consensus project translates to a normal metabolizer.

December 2016 Update

Advance online publication December 2016.

• The 2016 update of CPIC guidelines regarding the use of pharmacogenomic tests in dosing of tricyclic antidepressants (TCAs) have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Literature up to July 2016 was reviewed, recommendations and supplemental information were updated.
• Excerpt from the 2016 dosing guideline update:
  • "Both amitriptyline and nortriptyline are used as representative TCAs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. However, the results of these studies may apply to other TCAs because these drugs have comparable pharmacokinetic properties."
  • "There is substantial evidence linking CYP2D6 and CYP2C19 genotypes to phenotypic variability in tricyclic side-effect and pharmacokinetic profiles. Modifying pharmacotherapy for patients who have CYP2D6 or CYP2C19 genomic variants that affect drug efficacy and safety could potentially improve clinical outcomes and reduce the failure rate of initial treatment."
  • " There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."
• The guideline includes dosing recommendation for TCAs based on:
  • CYP2D6 phenotype (Table 1 below)
  • CYP2C19 phenotype (Table 2 below)
• Download and read:
  • Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 Update
  • 2016 supplement
  • CYP2D6 Gene-specific Information Tables
  • CYP2C19 Gene-specific Information Tables
  • Imipramine Pre and Post Test Alerts
  • Imipramine Flow Chart
  • Imipramine Drug Resource Mappings

Table 1: Dosing recommendations for TCAs based on CYP2D6 phenotype:

Adapted from Tables 1 and 2 of the 2016 guideline update.

^a For tertiary amines (e.g., amitriptyline), if CYP2C19 genotype results are also available, see Table 2 for CYP2C19-based dosing recommendations and Table 3 below for CYP2D6/CYP2C19-based dosing recommendations.

^b Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations in the guideline for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

^c The rating scheme for the recommendation of classification is described in the Supplement. It may be reasonable to apply amitriptyline recommendation to other TCAs also metabolized by CYP2D6 including clomipramine, desipramine, doxepin, imipramine, and trimipramine. There are fewer clinical and pharmacokinetic data supporting genotype-guided dose adjustments for these drugs when compared to amitriptyline or nortriptyline (Supplemental Tables S8-S16).

^d CYP2D6 and CYP2C19 metabolizer status frequencies are based on average multi-ethnic frequencies. See the CYP2C19 and CYP2D6 Frequency Tables for population-specific allele and phenotype frequencies.

^e Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

^f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

^g Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

Table 2: Dosing recommendations for TCAs based on CYP2C19 phenotype:

Adapted from Tables 1 and 3 of the 2016 guideline update.

^a For tertiary amines (e.g., amitriptyline), if CYP2D6 genotype results are also available, see Table 1 for CYP2D6-based dosing recommendations above and Table 3 below for CYP2D6/CYP2C19-based dosing recommendations.

^b Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations in the guideline for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

^c The rating scheme for the recommendation of classification is described in the Supplement. It may be reasonable to apply amitriptyline recommendation to other TCAs also metabolized by CYP2C19 including clomipramine, doxepin, imipramine, and trimipramine. There are fewer clinical and pharmacokinetic data supporting dose adjustments for these drugs when compared to amitriptyline or nortriptyline (Supplemental Tables S8-S16).

^d CYP2D6 and CYP2C19 metabolizer status frequencies are based on average multi-ethnic frequencies. See the CYP2C19 and CYP2D6 Frequency Tables for population-specific allele and phenotype frequencies.

^e Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

^f Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

^g The predicted metabolizer phenotype for the*2/*17 genotype is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the CYP2C19*2 no function allele.

May 2013

Guidelines regarding the use of pharmacogenomic tests in dosing for tricyclic antidepressants have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Download: article and supplement

Excerpt from the dosing guidelines:

Amitriptyline and nortriptyline are used as model drugs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. Because the tricyclics have comparable pharmacokinetic properties, it may be reasonable to apply this guideline to other tricyclics including clomipramine (Supplementary Table S17), with the acknowledgement that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline.

See amitriptyline for excerpts and tables that summarize CYP2D6-based and CYP2C19-based dosing recommendations for amitriptyline when higher initial starting doses are warranted (article).