Approximately 105 major genetic allelic variants encode for CYP2D6-metabolizing enzymes, while 35 encode for CYP2C19.

“These genetic variations have been categorized into 4 main metabolizer phenotypes,” the authors reported: poor, intermediate, extensive (ie, normal), and ultrarapid. In addition, concurrent administration of specific medications can reduce CYP2D6 and CYP2C19 activity.

Fluoxetine, paroxetine, and venlafaxine are largely metabolized by CYP2D6, while citalopram and escitalopram are primarily metabolized by CYP2C19. “In addition to a primary metabolic route that is subject to genetic variation, fluoxetine and paroxetine are also potent inhibitors of CYP2D6,” they noted.


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Those who are poor metabolizers may have an increased drug plasma level, potentially increasing the rate of adverse effects, or an inability to activate prodrugs to active metabolite, affecting drug efficacy. Intermediate and extensive metabolizers are less likely to have clinical relevance with respect to adverse events, while those who are ultrarapid metabolizers have lower drug bioavailability and, perhaps, efficacy. Where phenotype prediction cannot be categorized, a range may be suggested, such as poor to intermediate or extensive to ultrarapid.

Calling the CPIC’s recommendations “a template for psychiatric precision medicine,” the investigators, working through a Pharmacogenetics Task Force, implemented decision support guidelines linked to web-based educational material (“Ask Mayo Expert”) to provide Mayo Clinic physicians with up-to-date information on a patient’s genotype. Included is information about specific genotypes and drugs as well as decision support tools.

Currently, these guidelines “apply only to patients for whom the genotype is already known, as reflected in the electronic medical record,” with clinicians alerted “only if a high-risk genotype for which action may be indicated on prescribing the involved drug is known.”

For example, for patients who are poor metabolizers, using an alternative medication rather than reducing the dose of fluoxetine and venlafaxine is recommended, per CPIC guidelines. However, “because of lack of evidence for a clear clinical association between ultrarapid metabolizers and low antidepressant plasma levels, we did not implement guidelines for ultrarapid metabolizer phenotypes,” Dr. Fyre reported.