Personalized Medication

More medications than ever before are available for people who suffer from major depression. Yet only about a third of these patients find an antidepressant that completely relieves their symptoms. Another third experience no improvement at all. Side-effects also vary: some people throw up, others can’t sleep or sleep too much, and still others experience sexual dysfunction.

The reason for those varied responses probably comes down to genetics. Our genes can affect everything from how our bodies break down a drug to what that drug’s concentration might be in the nervous system to what’s causing the depression in the first place. If we could make accurate predictions about how people will respond to particular drugs, many more people would be helped – and with fewer adverse events.

Daniel Mueller and his colleagues in U of T’s psychiatry department have reviewed more than 200 published papers looking at how genes affect an individual’s response to antidepressant medications. The findings so far don’t warrant testing all drugs prior to prescribing them, but it does make sense in a few cases. Genetic tests are already being used in Toronto’s Centre for Addiction and Mental Health.

Researchers have identified a family of enzymes that are important to metabolizing antidepressants. These enzymes vary a lot from person to person, and among ethnicities. Depending on your genetics, you might be classified as a “poor metabolizer,” an “intermediate metabolizer,” an “extensive metabolizer” or an “ultra-rapid metabolizer.”

The exact relationship between metabolizer status and response to medication is still unclear. But poor metabolizers often see little benefit from antidepressants. Studies have also found that poor metabolizers were more likely to be hospitalized longer following treatment, and, when female, more likely to suffer sexual dysfunction. Asians tend to be poorer metabolizers than other ethnic groups.

Ultra-rapid metabolizers also experience difficulties with medications. Because the drug is broken down so quickly, they need higher doses to get the same effect. But they also have more side effects. About 40 per cent of African-Americans — compared to just two per cent of Europeans — are ultra-rapid metabolizers.

Researchers are also zeroing in on a piece of a gene that affects the availability of the brain chemical serotonin. There’s a short, or “s” version, of this gene and a long or “l” version; people can have two of a kind or one of each. A few published studies suggest that people with two “s” versions take longer and are less likely overall to get completely better when using drugs such as Prozac. They might also be prone to worse side effects, including insomnia and mania. The authors list and comment on dozens more potential genetic connections.

“There are more factors involved in medication response than just these few genes,” says Mueller, “however it’s a good starting point. We already have the first tools in our hands.”