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April 7, 2013

Antidepressant Suicide Genes

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New research announced today and being published Monday is a first step toward using genetic differences to reveal whether a depressed patient is at risk of having suicidal thoughts in response to antidepressants. This ScienCentral News video explains.

Treating Depression

Researchers at the National Institute of Mental Health have discovered two gene differences-- or "markers"-- that seem to increase the risk of suicidal thoughts after starting an antidepressant. If confirmed, the finding could lead to a test to identify patients at risk for the rare but serious adverse reaction. They say that's crucial because untreated depression is the most important cause of actual suicides.

"Antidepressants are the treatment for depression and the treatment for depression is the best way to prevent suicide," says Gonzalo Laje, who led the NIMH work. "Our long term goal is to make sure that people with depression feel that they can safely take an antidepressant."

The Food and Drug Administration's (FDA) issued a "Black Box" warning -- its highest-level warning-- against this side effect in children and adolescents. But, following that warning, in 2004 actual suicides spiked in those age groups. (Read this reporter's commentary on that agency's expansion of the warning to young adults here). NIMH researchers attribute that to a decrease in antidepressant prescriptions. (Statistics for 2005 and on are not yet available.)

"This would be one way of addressing that problem," says Laje. "If we have genetic markers or blood tests that would tell us who is at a higher risk of developing suicidal thougts when they take an antidepressant, we can provide them a different type of treatment, give them a different follow-up, or in the case of primary care physicians or pediatricians in the community treating patients, they can refer them to a pyschiatrist.

Genetic Study

"So what we did was to look at 68 genes, and we found two genes that essentially tell us a lot about who would be at risk for developing these suicidal thougts when they are taking antidepressant medications," Laje says.

To study a rare effect takes large numbers of patients. So Laje and his team turned to a study in which large numbers of patients contributed DNA samples-- the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, also funded by NIMH.

"This study was done at 41 centers around the country, took seven years and it cost about $35 million," says Leje. "It had multiple levels of treatment, and the first level, everybody was treated with citalopram
(an SSRI-- selective serotonin reuptake inhibitor). So these results really only reflect citalopram treatment."

None of the 4000-plus patients in the trial actually committed suicide. Of the 1950 patients who contributed DNA samples, fifty percent reported suicidal thoughts before treatment, while six percent reported such thoughts only after starting the drug. The gene markers were much more common in this group, and having more than one of them greatly increased the risk. But that group was small-- just one percent of 1950 people.

As the researchers wrote in The American Journal of Psychiatry, the study had limitations. A major one is that it's not known if it applies to other antidepressants. And for a genetics study, the 120 patients who reported suicidal ideation is still a small sample size.

"When we're looking at genetics, studies will usually require that the samples are very large," Laje says.

And Laje emphasizes that the markers still need to be validated. "While our results are significant, these results need to be replicated in an independent sample. And that is going to be hard given the size of sample that we need to study this phenomenon," he says. "Our findings if replicated will certainly bring us closer to the possibility of doing genetics testing with some predictive value to assess who's at risk for developing treatment-emergent suicidal thoughts. But until then, our findings are preliminary."

And scientists still don't know the role of these genes in suicidal thinking, or, for that matter, whether suicidal ideation is a predictor of suicide attempts or actual suicide.

"This research doesn't tell us the mechanism by which treatment-emergent suicidal ideation happens, it doesn't tell us if there's an increase for suicide itself. But these are important questions that we are very interested in following up."

Hype and Hope

Follow-up might come from an independent company called Neuromark -- which jumped on the anticipated publicity from the publication to announce that it has already licensed the agency's patents on the two markers, plus a couple of additional markers that NIMH researchers have not yet published (more on that below), and will immediately begin offering a test for them to physicians. In its press statement, the company also invited "physicians and patients across the country to participate in prospectively collecting data to confirm and extend the predicted risk of the Mark-C test."

A couple of other things would strengthen these findings. One would be discovering the function of the genes flagged by these markers.

"These two genes are involved in the [neurotransmitter] glutamate pathway , and we know that the glutamate pathways have been associated with antidepressant outcomes," says Laje. "So we have seen a link between glutamate and depression and the treatment of depression. [But] we don't know exactly what these changes actually do in the cell yet. We're working on that."

And since 41 percent of patients with treatment emergent suicidal thinking lacked either of the two published markers, there must be other genes, or environmental factors, involved.

In fact, Lajes says his team has already discovered and patented a couple of as-yet unpublished markers. "We will be presenting some additional findings where we linked two other genes to treatment emergent suicidal ideation, and these genes taken together give us a more specific and sensitive way to test for risk for developing this unusual but serious side effect," he says.

The STAR*D study also revealed that the drug was much less effective for patients who had treatment emergent suicidal ideation. So, says Laje, the work could eventually help predict which antidepressant will work best for individual patients.

"We're a step closer to being able to tell who is at a higher risk of developing suicidal ideas when they're taking antidepressants, as well as a step closer to knowing who will respond to an antidepressant, " he says.
"A test might be around the corner, if you will, but we still need to look further into these results to make sure that the phenomenon that we're describing is actually related to the genes that that we found."

This research will be published in The American Journal of Psychiatry, October 2007, and is funded by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH).

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