- Design
- Retrospective observational study of two independent cohorts
- Population
- 5,443 genotyped Norwegian patients and 3,624 UK Biobank participants on venlafaxine
- Primary outcome
- Switching to another antidepressant within 1 year
- Effect
- CYP2D6 poor vs normal metaboliser OR 2.05 (1.53–2.71) Norway; OR 1.58 (1.14–2.19) UK
Two observational cohorts — 5,443 genotyped patients from a Norwegian drug-monitoring service and 3,624 from UK Biobank — were used to ask whether CYP2D6 and CYP2C19 genotype predicted switching away from venlafaxine within a year. People on strong inhibitors or inducers were excluded.
In Norway, CYP2D6 poor metabolisers had about twice the odds of switching compared with normal metabolisers (OR 2.05, 95% CI 1.53 to 2.71), with smaller raised odds in intermediate (OR 1.25) and ultra-rapid metabolisers (OR 1.78). UK Biobank showed the same direction in poor metabolisers (OR 1.58, 1.14 to 2.19). People who were poor metabolisers for both enzymes had markedly higher odds, but on small numbers (OR 6.11, 1.81 to 18.77).
Switching is a proxy for failure that also captures side-effects and patient choice. This supports genotype as one explanation when venlafaxine is poorly tolerated or ineffective, and it supports checking for interacting drugs that make a normal metaboliser behave like a poor one. It is not yet a case for routine pre-emptive testing.
- When venlafaxine is poorly tolerated at low doses, consider that the patient may be a CYP2D6 poor metaboliser.
- Check for fluoxetine, paroxetine or bupropion, which inhibit CYP2D6 and mimic poor-metaboliser status.
- Where genotype results already exist, review them before choosing venlafaxine.
- Therapeutic drug monitoring of venlafaxine and O-desmethylvenlafaxine can help where it is available.
- Routine genotyping before every prescription is not yet supported by trial evidence.
Why it matters
Some apparent drug failures may be metabolism problems, which changes what you try next.
Don't overread it
This is an association with switching, not a trial showing that genotype-guided prescribing improves outcomes.
The statistics, in plain English
An odds ratio of 2.05 means poor metabolisers had about twice the odds of switching. The dual poor-metaboliser estimate of 6.11 has a very wide interval (1.81 to 18.77), which tells you it rests on few people. Because this is observational, other differences between groups could explain part of the effect.
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