CYP2D6 poor metabolisers were about twice as likely to switch off venlafaxine

Design

Retrospective observational study in two independent cohorts

Population

5,443 genotyped patients in Norway and 3,624 UK Biobank participants treated with venlafaxine

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

Two observational cohorts tested whether genetic metabolism of venlafaxine predicts treatment failure, defined as switching to another antidepressant within a year. One came from a Norwegian therapeutic drug monitoring service (5,443 genotyped patients) and the other from the UK Biobank (3,624 people with prescription data). People on strong CYP2D6 or CYP2C19 inhibitors or inducers were excluded.

In the Norwegian cohort, compared with normal metabolisers, odds of switching were 2.05 times higher in CYP2D6 poor metabolisers, 1.25 times in intermediate and 1.78 times in ultra-rapid metabolisers. The UK cohort confirmed the poor metaboliser signal (OR 1.58, 95% CI 1.14 to 2.19). People who were poor metabolisers for both CYP2D6 and CYP2C19 had about six times the odds of switching, from a small group with a wide interval.

Genotyping is not routinely available in most Indian clinics, and switching is a proxy for failure that also captures side effects and preference. But the result is a reminder to think about metabolism when a patient does badly on venlafaxine, particularly when interacting drugs are involved.

• Check for co-prescribed CYP2D6 inhibitors such as fluoxetine, paroxetine and bupropion before blaming venlafaxine itself.
• Consider a metabolic cause when a patient has marked side effects at a low dose, or no response at a usual dose.
• Use therapeutic drug monitoring, where available, to check venlafaxine and O-desmethylvenlafaxine levels in unexpected responses.
• Where CYP2D6 genotype is already known, factor it into the choice of antidepressant.

Why it matters

Part of what looks like an antidepressant not suiting someone may be a predictable metabolic mismatch.

Don't overread it

Switching is a proxy for failure and the study is observational; it does not show that pre-emptive genotyping improves outcomes.

The statistics, in plain English

An odds ratio of 2.05 means poor metabolisers had about twice the odds of switching compared with normal metabolisers. That a second, independent cohort found the same direction (1.58) makes chance less likely. The six-fold figure for dual poor metabolisers rests on few people and its interval runs from 1.8 to 18.8, so its true size is very uncertain.

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