Impact of genetic variation on response to therapy
Vortioxetine is extensively metabolised by CYP2D6 into less active metabolites. Altered CYP2D6 activity may result in lower or greater plasma concentrations of vortioxetine.
The SmPC for vortioxetine states that the plasma concentration was approximately two times higher in CYP2D6 poor metabolisers than in extensive (normal) metabolisers. In ultrarapid metabolisers the plasma concentration was lower than in extensive (normal) metabolisers. The plasma concentrations obtained with vortioxetine 10 mg/day in ultrarapid metabolisers were between those obtained in normal metabolisers at doses of 5 mg/day and 10 mg/day.
The SmPC for vortioxetine recommends that dose adjustment may be considered in CYP2D6 poor and ultrarapid metabolisers according to individual response. 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 vortioxetine compared to normal metabolisers.
- Increased probability of treatment failure.
- Consider alternative therapy without major CYP2D6 metabolism, especially where there are concerns regarding efficacy.
- If treatment is still warranted, initiate at standard starting dose and titrate according to response. Have a low threshold for increasing the dose.
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 vortioxetine compared to normal metabolisers.
- Increased probability of adverse effects.
- Initiate with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2D6 Poor metabolisers: Activity score 0
Some examples of CYP2D6 genotypes include (see note): *4/*4, *4/*4xN, *3/*4, *5/*5
- Greatly reduced metabolism of vortioxetine compared to normal metabolisers.
- Increased probability of adverse effects.
- Consider alternative therapy without major CYP2D6 metabolism.
- If treatment is still warranted, consider a 50% reduction in starting dose.
- Monitor for efficacy and adverse effects and titrate according to response to a maximum maintenance dose of 10mg daily.
Note: This is a limited list of examples of CYP2D6 genotypes. N represents the number of additional copies of the gene.
Further information
Vortioxetine is extensively metabolised, primarily by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9. It is likely that the CYP2D6 genotype influences the fractional contributions of the different metabolism pathways to overall elimination. There is a potential for drug interactions with inhibitors, inducers and substrates of CYP2D6, CYP3A4/5 and CYP2C9, and the extent of drug-drug interactions is predicted to be dependent on the CYP2D6 genotype. Co-administration of strong CYP3A4/CYP2C9 inhibitors to CYP2D6 poor metabolisers could also potentially result in higher exposure. Consult the SmPC for detailed information on drug interactions.
Other patient characteristics including age, renal and hepatic function should be considered when initiating and titrating antidepressant therapy.
The main benefit of pharmacogenomic 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 vortioxetine 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.)
Lundbeck Limited (2025) Brintellix film coated Tablets 30mg SmPC. Available at: https://www.medicines.org.uk/emc/product/7121/smpc (Accessed online 25 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.)
