Impact of genetic variation on response to therapy
Citalopram is extensively metabolised by CYP2C19 to both active and inactive metabolites. Altered CYP2C19 activity may result in greater or lower plasma concentrations of citalopram.
The SmPC for citalopram states that for known poor CYP2C19 metabolisers an initial dose of 10mg daily for the first two weeks of treatment is recommended. Depending on the outcome of the treatment the dose can thereafter be increased to 20mg. This corresponds to a 50% reduction in the standard recommended starting dose and maintenance dose.
The SmPC for citalopram provides a range of doses and recommends individual adjustment according to response and indication. Knowledge of a patient’s CYP2C19 metaboliser phenotype 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 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 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 citalopram compared to normal and rapid metabolisers.
- Increased probability of treatment failure.
- Consider an alternative antidepressant without major CYP2C19 metabolism.
- If treatment with citalopram is still warranted, monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for increasing the dose.
CYP2C19 Rapid metabolisers
Some examples of CYP2C19 genotypes include: *1/*17
- Increased metabolism of citalopram compared to normal metabolisers.
- Increased probability of treatment failure.
- 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.
- If there are concerns regarding inadequate response despite dose titration, consider an alternative antidepressant without major CYP2C19 metabolism.
CYP2C19 Normal metabolisers
Some examples of 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 citalopram compared to normal metabolisers.
- Increased plasma concentration compared to normal metabolisers
- Increased probability of adverse effects.
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for decreasing the dose.
CYP2C19 Poor metabolisers
Some examples of CYP2C19 genotypes include: *2/*2, *3/*3, *2/*3
- Significantly reduced metabolism of citalopram compared to normal metabolisers.
- Increased probability of adverse effects.
- Consider an alternative antidepressant without major CYP2C19 metabolism.
- If treatment with citalopram is still warranted, an initial dose of 10mg daily for the first two weeks of treatment is recommended.
- Monitor for efficacy and adverse effects and titrate according to response.
- Maximum licensed maintenance dose is 20mg daily.
Further information
Citalopram is primarily metabolised by CYP2C19 with some contribution from CYP3A4 and CYP2D6. The CYP2C19 genotype may influence the fractional contributions of the different metabolism pathways to overall elimination. There is a potential for drug interactions with inhibitors, inducers, and substrates of CYP2C19, CYP2D6 and CYP3A4 enzymes. 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 citalopram treatment without significant concerns regarding adverse effects may not benefit from retrospective dose modifications based on CYP2C19 pharmacogenomic results.
Antidepressants that are not metabolised by CYP2C19, or to a lesser extent, include mirtazepine, paroxetine, venlafaxine and fluvoxamine.
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 1 July 2025.)
Sandoz Limited (2024) Citalopram 40mg Tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/4965/smpc (Accessed online 1 July 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., Nijenhuis, M., Soree, B., de Boer-Veger, N. J., Buunk, A-M., Guchelaar, H. J., 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 1 July 2025.)
