Researchers at the medical center have identified a genetic marker that can explain why some people experience side effects to common antidepressants while others do not. They also found that a key liver enzyme involved in breaking down these antidepressants surprisingly had no effect. The findings may lead to selecting an antidepressant based on a patient’s genetic profile.

"Antidepressants are among the most widely prescribed medications in the world," said lead author Greer Murphy Jr., MD, PhD, associate professor of psychiatry and behavioral sciences. "One of the mysteries at this point is why some people get debilitating side effects and others don’t."

Alan Schatzberg (seated) and Greer Murphy examine new data that shows how differences in genes can affect a patient’s response to antidepressants. Their findings uncovered specific genes that control side effects and showed how well different antidepressants work in individual patients. Photo: Mitzi Baker

To start solving the mystery, Murphy and Alan Schatzberg, MD, the Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences, wanted to find differences among patients in the function of proteins — and the genes that encode those proteins — that could account for the varied response to drug treatment. Their findings appear in the October issue of the American Journal of Psychiatry.

Good candidate proteins for studying an antidepressant response include the receptors that the drug interacts with in the brain and the enzymes in the liver that metabolize the drugs. Murphy and Schatzberg chose one of each for their research. In what Murphy said is the only double-blind randomized prospective genetic study in psychiatry, the researchers analyzed DNA samples from 246 depressed patients who were randomly assigned either paroxetine (marketed as Paxil) or mirtazapine (marketed as Remeron) for eight weeks.

All of the patients studied in 18 U.S. outpatient clinics were 65 years of age or older. Side effects are particularly relevant in this age group, Murphy said. Older people, for example, are more susceptible to injury from a fall caused by dizziness, which can be a side effect of some antidepressant drugs. "Being able to pick the best drug would be a huge advantage when you are dealing with older people," said Greer, who is also director of the Genetics Core of the Veterans Administration Sierra Pacific Mental Illness Research, Education and Clinical Center.

The two antidepressants work in completely different ways, though both affect serotonin, a neurotransmitter that binds to specific receptors found abundantly in the brain and peripheral nervous system. Serotonin has many effects, including mood control, but it also affects the gastrointestinal tract, the sleep-wake cycle and levels of alertness.

The researchers looked at one type of serotonin receptor called 5HT2a, thought to be involved in causing antidepressant side effects such as stomach upset, dizziness, insomnia, agitation and sexual dysfunction. Mirtazapine completely blocks this receptor, while paroxetine does not directly interact with serotonin receptors.

The researchers found that people with one version of the 5HT2a gene were much more likely to discontinue therapy due to intolerable side effects when compared to the other two versions (46 percent vs. 16 percent). "What we have potentially is the gene for people not being able to tolerate drugs like Paxil," said Schatzberg.

In the mirtazapine patients, there was no effect due to the serotonin receptor gene variation, as expected. The ability of both drugs to work as an antidepressant was unrelated to what version of this gene a patient had.

To explore whether drug response is directly affected by how efficiently the liver metabolizes the drug, they chose a particular liver enzyme called CYP2D6, a key player in the metabolism of 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, 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.

Many in the medical field have assumed that genetic variation in this enzyme is responsible for the side effects a patient experiences. "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, so the researchers used a microarray application that allowed them to detect all of the variants in a single experiment. To their surprise, the researchers found that the variation did not alter treatment outcome or side effects. Murphy emphasized that this study, like all genetic association studies, will need to be replicated, and the results may not apply to other antidepressants.

Funding for this study was provided by Organon Pharmaceuticals, Inc., the manufacturer of Remeron; the National Association for Research on Schizophrenia and Depression; The Nancy Pritzker Network and the Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education and Clinical Center.