Impact of genetic variation on response to therapy
Venlafaxine is extensively metabolised by CYP2D6 into its major active metabolite O-desmethylvenlafaxine (ODV). Both venlafaxine and ODV are inhibitors of serotonin and noradrenaline re-uptake. The SmPC for venlafaxine states that plasma concentrations of venlafaxine are higher in CYP2D6 poor metabolisers than extensive (normal) metabolisers however, because the total exposure (AUC) of venlafaxine and ODV is similar in both groups, that there is no need for different dosing regimens.
The SmPC for venlafaxine 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 venlafaxine to ODV compared to normal metabolisers.
- Decreased ratio of venlafaxine to ODV compared to normal metabolisers with uncertain clinical significance
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
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
- Decreased metabolism of venlafaxine to ODV compared to normal metabolisers.
- Increased ratio of venlafaxine to ODV compared to normal metabolisers, with uncertain clinical significance.
- Initiate treatment 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
- Decreased metabolism of venlafaxine to ODV compared to normal metabolisers.
- Increased ratio of venlafaxine to ODV compared to normal metabolisers.
- Has been associated with increased incidence of adverse effects.
- Consider alternative antidepressant therapy without major CYP2D6 metabolism.
- If treatment is still warranted, initiate treatment with standard starting dose. Monitor for efficacy and adverse effects and titrate according to response.
Further information
There is a potential for drug interactions with inhibitors, inducers and substrates of CYP2D6 and CYP3A4. The SmPC for venlafaxine states that in vivo studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6, and that venlafaxine is metabolised into less active metabolites by CYP3A4. 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 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 venlafaxine 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.)
Bristol Laboratories Ltd. (2025) Majoven XL 150mg prolonged released capsules, hard SmPC. Available at: https://www.medicines.org.uk/emc/product/9985/smpc (Accessed online 24 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.)
