CYP2D6 poor metabolisers were more likely to switch away from venlafaxine

Design

Retrospective observational study in two independent cohorts

Population

5,443 venlafaxine-treated patients in Norway and 3,624 in the UK Biobank

Primary outcome

Switch to another antidepressant within 1 year

Effect

CYP2D6 poor vs normal metabolisers OR 2.05 (95% CI 1.53 to 2.71) Norway; OR 1.58 (1.14 to 2.19) UK

A retrospective study in The Lancet Psychiatry (1 October 2026) linked CYP2D6 and CYP2C19 genotype to venlafaxine outcomes in two cohorts: 5,443 patients from a therapeutic drug monitoring service in Oslo and 3,624 from the UK Biobank. Treatment failure was defined as switching to another antidepressant within a year. Patients on strong CYP inhibitors or inducers were excluded.

In the Norwegian cohort, odds of switching were about twice as high in CYP2D6 poor metabolisers as in normal metabolisers (odds ratio 2.05), and raised too in intermediate (1.25) and ultra-rapid metabolisers (1.78). The poor-metaboliser finding held in the UK Biobank (OR 1.58). The small group who were poor metabolisers for both CYP2D6 and CYP2C19 had six times the odds of switching, with a very wide interval.

Switching is a proxy for failure, not a measure of response, and genotype was not used to guide treatment here. So this does not establish that testing before venlafaxine improves outcomes. It does make genotype a reasonable explanation to consider when venlafaxine fails or is poorly tolerated at ordinary doses, and it is a reminder that paroxetine, fluoxetine and bupropion can produce the same effect by inhibiting CYP2D6.

• When venlafaxine fails or causes unexpected side-effects at usual doses, consider CYP2D6 status as one explanation.
• Check for CYP2D6 inhibitors such as fluoxetine, paroxetine and bupropion before blaming the drug.
• Use a venlafaxine level, where available, to see whether exposure is unusually high or low.
• If a genotype result is already on file, read it before choosing venlafaxine.

Why it matters

It gives a measurable reason why a drug that works for many fails for some, and replicates it in a second population.

Don't overread it

Switching was a proxy for failure, and the study did not test whether genotyping before prescribing improves outcomes.

The statistics, in plain English

An odds ratio of 2.05 means the odds of switching were about twice as high in poor metabolisers. Replication in an independent cohort (1.58) makes chance less likely. The dual poor-metaboliser figure of 6.11 rests on very few people, which is why its interval runs from 1.8 to almost 19.

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