Antidepressant side effects connected to your genes
The mystery of why only some people taking antidepressants get side effects may have a genetic solution, suggesting that gene testing may one day lead to better drug selection for patients undergoing prescription depression therapy.
The study, reported in the October issue of the American Journal of Psychiatry, was undertaken by Professor Alan Schatzberg and Associate Professor Dr Greer Murphy, from the School of Psychiatry and Behavioural Sciences at the Stanford University Medical Center.
"Antidepressants are among the most widely prescribed medications in the world," said Dr Murphy. "One of the mysteries at this point is why some people get debilitating side effects and others don't."
The researchers examined genetic differences among patients that could account for varied responses to drug treatment. They were specifically interested in variations of one type of serotonin receptor called 5HT2a, which is believed to be associated with many antidepressant side effects.
A group of 246 patients being treated for depression were randomly assigned one of two commonly prescribed antidepressants - paroxetine or mirtazapine - and monitored for eight weeks.
Paroxetine and mirtazapine work by affecting levels of the neurotransmitter serotonin. Serotonin has many effects, including mood control, but it also affects the gastrointestinal tract, the sleep-wake cycle and levels of alertness. It binds to specific receptors, like 5HT2a, found abundantly in the brain and peripheral nervous system.
Both paroxetine and mirtazapine allow levels of seratonin in the brain to build up, but the two drugs work in different ways.
Mirtazapine works by completely blocking the seratonin receptor, preventing it from latching on to the serotonin (thereby allowing serotonin to build up). Paroxetine, on the other hand, is a selective serotonin re-uptake inhibitor. It doesn't block the seratonin receptor, but works by preventing the re-uptake of serotonin, allowing more to remain in the brain
When the researchers correlated variations of the 5HT2a gene with variations of a patient's experience taking the drug paroxetine, the results were striking.
People with one version of the gene experienced severe side effects and were likely to discontinue taking the drug. Two other versions of the gene, however, displayed much fewer side effects.
In the mirtazapine patients, on the other hand, there was no effect due to variations in the serotonin receptor gene.
Such findings suggest that we can better prescribe some medications to treat depression if we can analyse the patient's genetic code. Some gene variations would rule out the use of some drugs.
The researchers then turned their attention to how different patients metabolised the drugs. They examined a particular liver enzyme called CYP2D6, which plays a key role in breaking down many medications, including paroxetine and mirtazapine.
Most people have a normal level of this enzyme, but 7 to 10 percent have a variation in the gene for the enzyme that makes it work very slowly, causing the drug to build up in the blood and potentially leading to significant side effects. Another 3 to 4 percent have genetic changes that cause excessive enzyme activity, resulting in the drug breaking down rapidly, perhaps before it has had a chance to work.
It's been assumed that genetic variation in this enzyme is responsible for differences in patient experience of a particular drug.
"I can't tell you how often this hypothesis is stated," said Murphy. "Whole marketing campaigns have been built on whether or not a drug interacted with this enzyme."
The enzyme has at least 40 genetic variations, but to their surprise, the researchers found that the variation did not alter treatment outcome or side effects. This indicates we still have a lot to learn about how these drugs interact with our bodies.
The researchers emphasise that this study, like all genetic association studies, will need to be replicated, and the results may not apply to other antidepressants. However, it does indicate there's value in learning more about how gene variations alter the way drugs work in our bodies.