Impact of genetic variation on response to therapy
The metabolism of nortriptyline is influenced by genetic variations in the CYP2D6 gene.
Nortriptyline is a secondary amine tricyclic antidepressant (TCA). Secondary amines are metabolised by CYP2D6 to less active metabolites. Patients may be at a higher risk of lack of response or adverse drug reactions due to genetic variation in CYP2D6 altering drug clearance.
The SmPC for nortriptyline states that known poor metabolisers of CYP2D6 may have higher plasma concentrations of nortriptyline at usual doses.
The SmPC for nortriptyline provides a range of doses and recommends individual adjustment according to response and indication. Knowledge of a patient’s CYP2D6 metaboliser phenotype may help guide this by identifying patients who are at an increased risk of experiencing adverse drug reactions or lack of symptom response.
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 nortriptyline compared to normal metabolisers.
- Increased potential for lack of response.
- Use alternative therapy without major CYP2D6 metabolism.
- If no alternative available and treatment is still indicated, initiate with standard starting dose. Monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for increasing the dose but be alert to potential increased plasma concentrations of cardiotoxic metabolites (see Further Information regarding therapeutic drug monitoring).
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 nortriptyline compared to normal metabolisers.
- Increased probability of adverse effects.
- Initiate with a 25% reduction in starting dose.
- Monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for reducing the dose.
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 nortriptyline compared to normal metabolisers.
- Increased probability of adverse effects.
- Use alternative therapy without major CYP2D6 metabolism.
- If no alternative available and treatment still indicated, initiate with a 50% reduction in starting dose. Monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for further reducing 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
Drug interactions
Drug-drug interactions should be considered in addition to the therapeutic recommendations in this monograph. It has been suggested that patients taking strong CYP2D6 inhibitors should be treated similarly to CYP2D6 poor metabolisers and may have significant increases in nortriptyline plasma concentrations. Consult the SmPC for detailed information on drug interactions.
Alternative therapies without major CYP2D6 metabolism
Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram, escitalopram and sertraline.
Therapeutic drug monitoring
International pharmacogenetics guidelines recommend the use of therapeutic drug monitoring (TDM) to guide dose adjustments for TCAs in some cases. In the UK, it is not usual practice to monitor plasma drug concentrations for antidepressants to adjust doses. The Maudsley Prescribing Guidelines in Psychiatry do not recommend TDM for TCAs and recommend ECG monitoring to assess cardiotoxicity. In the context of pharmacogenetics-informed prescribing, rather than TDM, we recommend clinical monitoring of symptoms, treatment adherence, and adverse drug reactions, and titrating the dose according to response.
References
Brown & Burk UK Ltd (2025). Nortriptyline 25 mg Film-Coated Tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/13723/smpc Accessed online 11th 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 29th May 2025.
Clinical Pharmacogenetics Implementation Consortium CPIC® (2019) Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19. Available at: https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/ (Accessed online 11th June 2025).
Kleine Schaars, K., Nijenhuis, M., Soree, B. et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction between CYP2D6 and CYP2C19 and tricyclic antidepressants. Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-025-02008-3
Taylor, D. M., Barnes, T. R. E., & Young, A. H. (2025). The Maudsley prescribing guidelines in psychiatry (15th ed.). Wiley-Blackwell.
