Antidepressant Effectiveness May Depend on Genes

THURSDAY Aug 2, 2007 -- Researchers say they've found a key gene variation influencing whether or not people respond to the antidepressant Celexa.

Having both this variant and a previously discovered gene means a person is 23 percent more likely to respond to the drug than people without either variation. Celexa (citalopram) is one of a widely used class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs), which also include Paxil, Prozac and Zoloft.

While these medications do appear to reduce depression for many who use them, their benefits vary widely among patients. The reasons behind that variance have remained unclear, experts say.

But the new finding "suggests that we're going down the right path, although we're not there yet," said Dr. Gonzalo Laje, co-author of the study, which is published in the August issue of the American Journal of Psychiatry. "We are better able to see how genetic variations help determine how a person may or may not respond to a certain medication. This is an advancement toward personalized medicine."

Laje is associate clinical investigator at the U.S. National Institute of Mental Health, which conducted the study.

However, the increased likelihood of response for people carrying the gene was relatively modest, indicating that only the sum of many genes -- most yet to be discovered -- will give scientists the whole story, experts said.

"There's no one marker that's going to tell you whether you respond or not. It's a lot of markers, each one having a small effect," said Dr. Julio Licinio, chairman of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine. "This is another building block, but it's not the whole story. In the future, as we put all these markers together, we may be able to develop a genetic panel to tell us whether a person is likely to respond to an SSRI or not."

Different people respond differently to different medications, and that's true for a wide variety of drugs, not just antidepressants. But with depression, especially, some patients respond happily to the first medication they try, while others have to go through a frustrating trial-and-error process before finding the right solution for their illness, if they find a solution at all.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the largest effectiveness study ever done on depression, examined the benefits of antidepressants in "real world" settings.

SSRIs are considered among the most effective treatments available for depression. However, doctors haven't had good evidence on the best course of action to take if or when a patient fails to respond to a particular SSRI.

The STAR*D trial was designed to answer that question.

An earlier analysis of STAR*D data had found that people with a variation in the HTR2A gene were more likely to respond to Celexa.

For this analysis, the researchers looked at DNA from more than 1,800 patients who had also participated in the STAR*D trial, comparing genes in people who had responded to Celexa and those who hadn't.

This time, it appeared that people with a variation in the GRIK4 gene had a higher likelihood of responding to the drug. The researchers also confirmed that the HTR2A variation also made people more likely to respond.

HTR2A produces a protein that acts as a receptor for serotonin, a neurotransmitter long implicated in depression.

GRIK4 makes a protein that acts as a receptor for the glutamate neurotransmitter system, which is beginning to be implicated in depression.

"This gives us very relevant information to where we should be looking. We are understanding that glutamate receptors are important for antidepressant outcomes," Laje said.

Another paper in the same issue of the journal found that about 25 percent of people who enrolled in STAR*D actually dropped out during the first three months, with one third of those not coming back after their first visit. Those most likely to discontinue treatment included younger individuals, those with less education, blacks, Hispanics and people with drug or alcohol abuse problems or anxiety.

More information

For more on depression, head to the U.S. National Institute of Mental Health.

Posted: August 2007


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