Impact of genetic variation on response to therapy
Sertraline is extensively metabolised by multiple pathways including CYP2C19, CYP2B6 and CYP2D6. There is evidence that CYP2C19 or CYP2B6 genetic variation may result in greater or lower plasma concentrations of sertraline, but studies have found little to no effect of CYP2D6 genetic variation on sertraline exposure.
The SmPC for sertraline states that plasma levels were about 50% higher in poor metabolisers of CYP2C19 versus extensive (normal) metabolisers and recommends titration of dose based on clinical response.
The SmPC for sertraline provides a range of doses and recommends individual adjustment according to response and indication. Knowledge of a patient’s CYP2C19 and/or CYP2B6 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 or 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
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
- Predictive of a small increase in metabolism of sertraline compared to normal metabolisers.
- 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
- Predictive of a small increase in metabolism of sertraline compared to normal metabolisers.
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
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 sertraline compared to normal metabolisers.
- Increased probability of adverse effects.
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate slowly 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
- Greatly reduced metabolism of sertraline compared to normal metabolisers.
- Increased probability of adverse effects.
- Initiate with lowest recommended starting dose and consider a 50% reduction in maintenance dose.
- Monitor for efficacy and adverse effects and titrate slowly according to response.
- Have a low threshold for considering alternative therapy without major CYP2C19 metabolism, especially where there are concerns regarding adverse effects.
CYP2B6 metaboliser status unknown
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2B6 Ultra-rapid metabolisers
Some examples of CYP2B6 genotypes include: *4/*4
- Increased metabolism of sertraline compared to normal metabolisers.
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2B6 Rapid metabolisers
Some examples of CYP2B6 genotypes include: *1/*4, *2/*4, *4/*5
- Small increase in metabolism of sertraline compared to normal metabolisers.
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2B6 Normal metabolisers
Some examples of CYP2B6 genotypes include: *1/*1, *1/*2, *1/*5, *2/*2, *2/*5, *5/*5
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2B6 Intermediate metabolisers
Some examples of CYP2B6 genotypes include: *1/*6, *2/*6, *4/*6, *5/*6, *5/*9
- Reduced metabolism of sertraline compared to normal metabolisers.
- May increase the 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.
CYP2B6 Poor metabolisers
Some examples of CYP2B6 genotypes include: *6/*6, *6/*9, *9/*9
- Significantly reduced metabolism of sertraline compared to normal metabolisers.
- Increased probability of adverse effects.
- Initiate treatment with standard starting dose and consider a 25% reduction in maintenance dose.
- Monitor for efficacy and adverse effects and titrate according to response. Have a low threshold for reducing the dose.
- Have a low threshold for considering alternative therapy without major CYP2B6 metabolism, especially where there are concerns regarding adverse effects.
CYP2C19 and CYP2B6 combined therapeutic recommendations
- Limited information is available on how to adjust initial doses based on combined genotype or phenotype information.
- Combinations of CYP2C19 and CYP2B6 variants and phenotypes are likely to result in additive effects on the pharmacokinetics of sertraline.
- Although treatment modification may not be warranted based on results for a single gene, treatment modification may be warranted where there is a combination of non-normal phenotype in both CYP2C19 and CYP2B6.
- 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 CYP2B6, have a low threshold for considering alternative therapy especially where there are concerns regarding inadequate response and/or adverse effects.
Further information
Sertraline is metabolised by CYP enzymes including CYP2C19, CYP2B6, CYP2D6, and CYP3A4. Pharmacokinetic studies suggest that the major metabolic pathway is CYP2C19. Sertraline may also act as a mild-moderate inhibitor of CYP2D6. There is a potential for drug interactions with inhibitors, inducers, and substrates of multiple CYP enzymes. Drug-drug interactions and other patient characteristics (including age, and 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 sertraline treatment without significant concerns regarding adverse effects may not benefit from retrospective dose modifications based on CYP2C19 or CYP2B6 pharmacogenomic results.
Antidepressants that are not metabolised by CYP2C19, or to a lesser extent, include 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).
Upjohn UK Limited (2024) Lustral 100mg film coated Tablets SmPC. Available at:https://www.medicines.org.uk/emc/product/2835/smpc (Accessed online 2 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 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).
