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Guidelines for tricyclic dosing based on pharmacogenomic testing

An international consortium of authors provides guidelines for the use of pharmacogenomic testing for CYP2D6 and CYP2C19 in patients receiving treatment with tricyclic antidepressants, based on a systematic literature review. “The use of tricyclics to treat psychological disorders has declined in part because of the occurrence of undesirable side effects,” they note, which differentially affect patients in part based on differences in CYP metabolism. “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.”

The authors present recommendations for drug choice and dosing based on genotype, making the following points regarding amitriptyline and nortriptyline:

  • CYP2D6 ultra metabolizers will likely have low plasma concentrations of drug, increasing the probability of treatment failure. “Avoid tricyclic use due to potential lack of efficacy…if a tricyclic is warranted, consider increasing the starting dose. Use therapeutic drug monitoring to guide dose adjustments.”
  • CYP2D6 poor metabolizers will have higher plasma concentrations, increasing the likelihood of side effects. “Avoid tricyclic use due to potential for side effects…if a tricyclic is warranted, consider a 50% reduction of recommended starting dose. Use therapeutic drug monitoring to guide dose adjustments.”

Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013:93(5):402-408. doi:10.1038/clpt.2013.2