Association between CYP2D6 and CYP2C19 genotypes and venlafaxine treatment failure: a retrospective study on two cohorts from Norway and the UK.

CYP2D6

Venlafaxine metabolism is driven mainly by the enzyme encoded by CYP2D6, with a secondary role for CYP2C19; metaboliser status modulates exposure and treatment failure.

This retrospective observational study analysed two independent naturalistic cohorts of venlafaxine-treated patients: 5,443 genotyped patients from the Center for Psychopharmacology in Oslo (2005-2025) and 3,624 UK Biobank participants. Patients co-treated with strong inhibitors or inducers of the relevant cytochromes were excluded. The primary outcome was treatment failure, defined as switching to another antidepressant within one year of last exposure. In the Norwegian cohort, CYP2D6 poor metabolisers had 2.05 times higher odds of switching than normal metabolisers (95% CI 1.53-2.71), replicated in UK Biobank (OR 1.58; 95% CI 1.14-2.19); the risk reached 6.11 in patients who were poor metabolisers for both genes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Replication of a strong signal across two distinct health systems, with explicit exclusion of drug-induced phenoconversion, makes the argument hard to dismiss: CYP2D6 genotype affects treatment persistence, not only concentrations. For prescribers this does not replace therapeutic drug monitoring, but it supports having the genotype available before initiation in a patient who has already failed a first line. The limitation lies in the endpoint: antidepressant switching is an imperfect surrogate for clinical failure, sensitive to local prescribing habits, and the retrospective design cannot show that pre-emptive genotyping would improve remission.

Analysis by Dr Thibaut Benquey