Impact of genetic variation on response to therapy
The metabolism of amitriptyline is influenced by genetic variations, primarily in CYP2D6 and CYP2C19 genes.
Amitriptyline is a tertiary amine tricyclic antidepressant (TCA). TCAs have similar but distinct chemical structures known as tertiary and secondary amines with different pharmacological properties. Tertiary amines are mainly metabolised by CYP2C19 to secondary amines which are also pharmacologically active. Tertiary amines have a greater serotonergic effect, and secondary amines have a greater noradrenergic effect. Both the tertiary and 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 variations in CYP2C19 altering the ratio of tertiary amine parent drug (e.g. amitriptyline) to secondary amine metabolites (e.g. nortriptyline), or due to genetic variation in CYP2D6 altering drug clearance.
The SmPC for amitriptyline states that known poor metabolisers of CYP2D6 or CYP2C19 may have higher plasma concentrations of amitriptyline and its active metabolite nortriptyline, and to consider a 50% reduction of the recommended starting dose.
For most therapeutic indications the SmPC for amitriptyline provides a range of doses and recommends individual adjustment according to response and indication. Knowledge of a patient’s CYP2C19 and/or CYP2D6 metaboliser phenotypes 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 and CYP2C19 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
CYP2C19
CYP2C19 metaboliser status unknown
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2C19 Ultra-rapid metabolisers
Some examples of CYP2C19 genotypes include: *17/*17
- Increased metabolism of amitriptyline to secondary amine metabolites (e.g. nortriptyline) compared to normal metabolisers.
- May affect response with potential for sub-optimal response
- Consider alternative therapy without major CYP2C19 metabolism.
- If treatment is still indicated, initiate treatment with standard starting dose. Monitor for efficacy and adverse effects and titrate according to response.
CYP2C19 Rapid metabolisers
Some examples of CYP2C19 genotypes include: *1/*17
- Increased metabolism of amitriptyline to secondary amine metabolites (e.g. nortriptyline) compared to normal metabolisers.
- May affect response with potential for sub-optimal response
- Consider alternative therapy without major CYP2C19 metabolism.
- If treatment is still indicated, initiate treatment with standard starting dose. Monitor for efficacy and adverse effects and titrate according to response.
CYP2C19 Normal metabolisers
Some examples CYP2C19 genotypes include: *1/*1
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2C19 Intermediate metabolisers
Some examples of CYP2C19 genotypes include: *1/*2, *1/*3, *2/*17, *3/*17
- Reduced metabolism of amitriptyline to secondary amine metabolites (e.g. nortriptyline) compared to normal metabolisers.
- May affect response and/or increase the chance of adverse effects.
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2C19 Poor metabolisers
Some examples of CYP2C19 genotypes include: *2/*2, *3/*3, *2/*3
- Greatly reduced metabolism of amitriptyline to secondary amine metabolites (e.g. nortriptyline) compared to normal metabolisers.
- May affect response and/or increase the chance of adverse effects.
- Consider alternative therapy without major CYP2C19 metabolism.
- If treatment is still indicated, consider a 50% reduction in starting dose. Monitor for efficacy and adverse effects and titrate according to response.
CYP2D6
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 amitriptyline and active metabolites to less active compounds compared to normal metabolisers.
- Increased potential for lack of response.
- Consider alternative therapy without major CYP2D6 metabolism.
- If treatment is still indicated, initiate treatment 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 amitriptyline and active metabolites to less active compounds compared to normal metabolisers.
- Increased probability of adverse effects.
- Consider 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 amitriptyline and active metabolites to less active compounds compared to normal metabolisers.
- Increased probability of adverse effects.
- Use alternative therapy without major CYP2D6 metabolism.
- If no suitable alternative available, consider 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.
CYP2C19 and CYP2D6 combined therapeutic recommendations
- Limited information is available on how to adjust initial doses based on combined genotype or phenotype information.
- Combinations of CYP2D6 and CYP2C19 variants and phenotypes are likely to have additive effects on the pharmacokinetics of TCAs.
- Where pharmacogenomic results for both genes are available, it is suggested to combine the therapeutic recommendations for the two genes in an additive way.
- Where there is conflicting advice, or where a patient is either a poor or ultrarapid metaboliser of both CYP2C19 and CYP2D6, have a low threshold for considering alternative therapy especially where there are concerns regarding inadequate response and/or adverse effects.
Further information
Drug metabolism and drug interactions
The SmPC for amitriptyline states that in vitro the metabolism of amitriptyline is mainly by demethylation by CYP2C19 and CYP3A4 enzymes, and hydroxylation by CYP2D6 enzymes followed by conjugation with glucuronic acid. Other CYP P450 isozymes including CYP1A2 and CYP2C9 are also involved.
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 amitriptyline plasma concentrations. Consult the SmPC for detailed information on drug interactions.
Alternative therapies without major CYP2C19 or CYP2D6 metabolism
Antidepressants without major CYP2C19 metabolism include nortriptyline, fluvoxamine and mirtazepine.
Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram, escitalopram and sertraline.
Indications other than depression
The evidence for dosing recommendations is strongest for depression. Compared to treatment for depression, amitriptyline is often used at lower doses for treatment of neuropathic pain, chronic tension type headache, and migraine. When a lower dosage is used, it is less likely that CYP2D6 or CYP2C19 poor or intermediate metabolisers will experience adverse effects due to high plasma concentrations of amitriptyline. For these indications it is recommended to titrate the dose to clinical response aiming for symptom improvement and minimal side effects.
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). Amitriptyline 25 mg Film-Coated Tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/10850/smpc Accessed online 29th May 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 29th May 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.
