Impact of genetic variation on response to therapy
Paroxetine is extensively metabolised by CYP2D6 into less active metabolites. Altered CYP2D6 activity may result in lower or greater plasma concentrations of paroxetine. There is strong evidence that CYP2D6 ultra rapid metabolisers have significantly lower, or undetectable, paroxetine plasma concentrations at steady state compared to normal metabolisers. There is strong evidence that CYP2D6 poor metabolisers have significantly higher paroxetine plasma concentrations at steady state compared to normal metabolisers.
The SmPC for paroxetine provides a range of doses and recommends individual adjustment according to response and indication. Knowledge of a patient’s CYP2D6 metaboliser phenotypes may help guide this by identifying patients who are at an increased risk of experiencing adverse effects or treatment failure.
Testing recommendations
The Royal College of Psychiatrists has published recommendations regarding pharmacogenomic testing that are summarised as follows:
- There is currently insufficient evidence of clinical benefit to recommend pharmacogenomic testing for CYP2D6 in routine prescription of psychotropic medication.
- Testing should be considered if an individual has had inadequate responses to previous medications, or has experienced marked, dose-associated adverse reactions to similar medications.
Therapeutic recommendations
CYP2D6 metaboliser status unknown
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2D6 Ultra-rapid metabolisers: Activity score >2.25
Some examples of CYP2D6 genotypes include (see note): *1/*1xN, *1/*2xN
- Increased metabolism of paroxetine compared to normal metabolisers.
- Increased probability of treatment failure.
- Use alternative therapy without major CYP2D6 metabolism.
CYP2D6 Normal metabolisers: Activity score ≥1.25 – ≤2.25
Some examples of CYP2D6 genotypes include (see note): *1/*1, *1/*2, *2/*2
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2D6 Intermediate metabolisers: Activity score >0 – <1.25
Some examples of CYP2D6 genotypes include (see note): *1/*4, *1/*5, *1/*4xN
- Reduced metabolism of paroxetine compared to normal metabolisers.
- Increased probability of adverse effects.
- Consider initiating with lowest recommended starting dose.
- Monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for decreasing the dose.
CYP2D6 Poor metabolisers: Activity score 0
Some examples of CYP2D6 genotypes include (see note): *4/*4, *4/*4xN, *3/*4, *5/*5
- Significantly reduced metabolism of paroxetine compared to normal metabolisers.
- Increased probability of adverse effects.
- Consider a 50% reduction in starting dose, and a 50% lower maintenance dose compared to normal metabolisers.
- Monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for decreasing the dose.
Note: This is a limited list of examples of CYP2D6 genotypes. N represents the number of additional copies of the gene.
Further information
There is a potential for drug interactions with inhibitors or inducers of CYP2D6 and with other substrates for CYP2D6. Paroxetine is both a substrate of CYP2D6 and is also a potent inhibitor of CYP2D6. Dose-dependent paroxetine-induced phenoconversion due to CYP2D6 auto-inhibition may occur, especially with higher doses. See User guide for further information on phenoconversion and drug interactions. Drug-drug interactions and other patient characteristics including age, renal and hepatic function should be considered when initiating and titrating antidepressant therapy. Consult the SmPC for more detailed information on drug interactions.
The main benefit of pharmacogenetic testing for antidepressants is to aid in medication selection by identifying patients who are more or less likely to experience side effects or treatment failure to certain medications. Patients who are already on stable and effective paroxetine treatment without significant concerns regarding adverse effects may not benefit from retrospective dose modifications based on CYP2D6 pharmacogenomic results.
Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram, escitalopram and sertraline.
References
Clinical Pharmacogenetics Implementation Consortium CPIC® (2023) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Available at: https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/ (Accessed online 23 June 2025.)
GlaxoSmithKline UK (2025) Seroxat Tablets 10mg SmPC. Available at: https://www.medicines.org.uk/emc/product/1161/smpc (Accessed online 23 June 2025).
Royal College of Psychiatrists (2023). College report CR237: The role of genetic testing in mental health settings. Available at: https://www.rcpsych.ac.uk/improving-care/campaigning-for-better-mental-health-policy/college-reports/2023-college-reports/the-role-of-genetic-testing-in-mental-health-settings-(cr237) (Accessed online 29 May 2025.)
Beunk, L et al. (2022). Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. European Journal of Human Genetics, 30(10), 1114-1120. https://doi.org/10.1038/s41431-021-01004-7 (Accessed online 23 June 2025.)
