Paroxetine (Paxil)- CYP2D6
Rationale
This drug gene interaction (DGI) pertains to the interaction between the CYP2D6 gene and paroxetine. Paroxetine (Paxil®) belongs to a class of drugs known as selective serotonin re-uptake inhibitors (SSRIs). SSRIs work by blocking the re-uptake of serotonin. The increase in serotonin levels has been linked to the management of depression, social anxiety disorder, obsessive-compulsive disorder, panic disorder, premenstrual dysphoric disorder, and post-traumatic stress disorder among other conditions. Extensive literature indicates that patients with specific genetic differences in the CYP2D6 gene may require dose adjustments of paroxetine or an alternative medication in order to achieve therapeutic benefits or to avoid side effects.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
Genetic Variant Information
The CYP2D6 (sounds like “sip-2-dee-6”) gene encodes an enzyme that is involved in the metabolism of paroxetine. There are different CYP2D6 gene versions, or variants, and each has a different effect on how well paroxetine is metabolized in the body. Some variants result in a non-functioning or low-functioning CYP2D6 enzyme while other variants result in a normal-functioning CYP2D6 enzyme. A duplication of variants can lead to a hyper-active CYP2D6 enzyme. Different ‘metabolizer statuses’ are assigned to patients depending on their genetic information (genotype).
See chart below for a description of each metabolizer status and any implications for treatment.
Ultrarapid metabolizer MORE THAN TWO copies of function alleles.
Increased metabolism to less active compounds when compared to normal metabolizers. Lower/undetectable plasma concentrations may increase probability of pharmacotherapy failure.
CYP2D6 metabolizer status |
Variants (genotype) |
Implication for paroxetine |
|---|---|---|
| Poor metabolizer | ONLY no-function alleles | Greatly reduced metabolism of paroxetine when compared to normal metabolizers. Higher plasma concentrations may increase the probability of side effects. |
| Intermediate metabolizer | ONE decreased function allele AND ONE no-function allele
OR TWO decreased function alleles OR ONE normal function AND ONE no-function allele |
Reduced metabolism of paroxetine when compared to normal metabolizers. Higher plasma concentrations may increase the probability of side effects. |
| Normal metabolizer | TWO normal function alleles
OR TWO decreased function alleles OR ONE normal function AND ONE no-function allele OR ONE normal function AND ONE decreased function allele |
Normal metabolism of paroxetine. |
| Ultrarapid metabolizer | MORE THAN TWO copies of functional alleles | Increased metabolism to less active compounds when compared to normal metabolizers. Lower/undetectable plasma concentrations may increase probability of pharmacotherapy failure. |
The patient’s reported genotype corresponds to a phenotype (i.e., metabolizer status). To see an interpretation table assigning metabolizer status by genetic variant, click here to visit CPIC and scroll down to click and download “CYP2D6_Diplotype_Phenotype_Table”.
Results Interpretation
Paroxetine is a medicine used to manage several different conditions and your genes can affect how well the drug works. CPIC updates guidelines on how to best use these genetic results to support patient care. To view dosing recommendations for SSRIs based on CYP2C19 phenotypes, click on the most recent guideline publication on CPIC’s website and scroll down to Table 2.
Please review the FDA packet insert for additional clinical considerations such as contradictions as well as dose adjustments based on age, organ function, and drug-drug interactions.
Quality of Results
Genotyping for CYP2D6 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be > 99%.
Supporting Evidence
This link will take you to the main page on the CPIC website relating to CYP2D6, CYP2C19 and SSRIs. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different races/ethnic groups, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status). Additionally, examples of point of care clinical decision support can be found at the bottom of the page.
Please note that additional drugs may have CYP2D6 interactions. For more information on drug-gene interactions, please use the search feature on the CPIC website.