CYP2D6, CYP2C19 and Tertiary Amine Tricyclic Antidepressants (TCAs): Amitriptyline, Clomipramine, Doxepin, Imipramine, Trimipramine

These recommendations only apply when using higher doses for treatment of conditions such as depression. For neuropathic pain where lower doses are used, no dose modifications are recommended, however intermediate and poor metabolizers may have increased risk of side effects and ultra rapid metabolizers have an increased risk of failing therapy. Evidence for these recommendations is primarily based on amitriptyline evidence, but because of comparable pharmacokinetics, it is reasonable to apply to other tertiary amines as well.

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the list below.

If either CYP2D6 or CYP2C19 genotypes are unavailable, scroll down to “Instructions for Unavailable Genotypes.”

Important Instructions: Please select the appropriate CYP2C19 phenotype from the list below and then use CYP2D6 Activity Score to select the appropriate recommendation.

Instructions for Unavailable Genotypes

If for CYP2C19 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2C19 was not genotyped, but CYP2D6 is available, utilize the CYP2C19 Normal Metabolizer page and select the appropriate CYP2D6 Activity Score for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2C19 genotype; consider testing or repeat testing of CYP2C19 as appropriate.

If for CYP2D6 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2D6 was not genotyped, but CYP2C19 is available, select the appropriate page above based on CYP2C19 phenotype and then utilize the recommendation for CYP2D6 Normal Metabolizer (Activity Score of 1.25-2.25)* phenotype. These recommendations may be affected by the patient’s unavailable CYP2D6 genotype; consider testing or repeat testing of CYP2D6 as appropriate.

Unable to Genotype or Assay Failure

  • The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

  • This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

*Previously some labs have designated an Activity Score of 1 as Normal Metabolizers

Reference

  • Hicks JK et al. Clin Pharmacol Ther. 2017 Jul;102(1):37-44. PMID: 27997040.

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