CYP2D6: how one enzyme shapes codeine, tamoxifen and antidepressants

CYP2D6 belongs to the cytochrome P450 family, a group of enzymes in the liver that chemically modify medicines so they can be used or cleared. The enzyme is not one single fixed thing in the population. Different versions of the CYP2D6 gene produce enzyme that works strongly, weakly or not at all, and some people carry extra working copies.

Laboratories sort these combinations into labels: poor, intermediate, normal and ultra-rapid. The labels describe how fast the enzyme works, not how healthy a person is. The enzyme-level picture is the same whether the result comes from a private test or an NHS service, and a separate guide on this site explains the terms.

Codeine is converted to morphine by CYP2D6. The US Food and Drug Administration's table of pharmacogenetic associations describes the risk of life-threatening respiratory depression in ultra-rapid metabolisers and notes that poor metabolisers may get reduced effect. UK regulators have acted on the first problem by restricting codeine in children and breastfeeding mothers.

The practical result for an individual is that two people can take the same product with very different experiences, one feeling nothing and the other feeling excessively drowsy. A full guide to the children and breastfeeding advice is separate from this page.

Tamoxifen is used after breast cancer to lower the chance of recurrence. It is itself a prodrug, and the MHRA explains that CYP2D6 is needed to form endoxifen, the more active product. That raises an obvious question for people who also need an antidepressant, because several antidepressants block CYP2D6.

The MHRA described a cohort study in which paroxetine, a potent CYP2D6 inhibitor, was associated with higher breast cancer mortality in proportion to how long it overlapped with tamoxifen, with other SSRIs not showing the same effect. The agency advised avoiding strong CYP2D6 inhibitors where possible. That is advice for prescribers, not an instruction to stop a medicine yourself.

• Do not stop or switch an antidepressant on your own; sudden changes can cause withdrawal effects and relapse of low mood.

• Tell your oncology team and GP about every antidepressant, including a recent change of dose.

• Ask a pharmacist to check any new prescription or over-the-counter product against tamoxifen.

Antidepressants relate to CYP2D6 in two ways. Some are broken down by it, so a person with poor enzyme activity may have higher blood levels of that antidepressant. Others block it, which affects other medicines taken alongside. Which is which varies drug by drug, and the prescriber chooses with that in mind.

In UK practice a standard choice of antidepressant does not require a gene test. Genetic results may be considered when someone has repeated unexplained side effects or lack of response, but they are an addition to clinical judgement. If you are new to antidepressants, the general depression guide and the page on sertraline give wider context.

For tamoxifen the MHRA stated that current data on genetic polymorphisms were insufficient to support recommending genotyping before treatment. That statement dates from the original drug safety update, republished in 2014, and treatment guidance can change, so ask your specialist team what applies now.

For codeine, the practical safeguards are age limits, avoidance in known ultra-rapid metabolisers, and symptom awareness. In all cases a result is interpreted by a clinician with your full list of medicines in front of them.

Seek urgent help (999 or A&E) for slow, shallow or stopped breathing, extreme drowsiness or inability to wake someone after codeine. For other concerns about new side effects with tamoxifen or an antidepressant, contact the prescriber or NHS 111.

You can also report suspected side effects of any medicine through the MHRA Yellow Card scheme.