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Genes Might Predispose Antidepressant Users to Suicidal Thoughts

THURSDAY Sept. 27, 2007 -- Variations in two genes may help spur suicidal thinking in individuals taking a commonly prescribed antidepressant, research suggests.

Although preliminary, the findings could pave the way for genetic testing to determine which patients with depression are likely to have this unusual but dangerous side effect.

"These findings, if replicated, would provide a way to have a genetic test that would tell us who is at a higher risk of developing suicidal ideation when taking antidepressants," said Dr. Gonzalo Laje, lead author of the study and associate clinical investigator at the U.S. National Institute of Mental Health. "Our long-term goal is to make sure that people with depression can take antidepressants, because treating depression is the best way to avoid suicide," he said.

Other experts stressed the need for more studies before getting too excited about the finding.

"The real key is, does it replicate in another data set? . . . [because] replicating results is rare," said Dr. Michael Slifer, assistant professor of medicine at the University of Miami Institute for Human Genomics. "It's a very important topic," said Slifer, who was not involved in the study. "Nobody has really looked into what might be different about the background of these folks that have such a difficult time in treatment and get suicidal thoughts. This is a first step, but it's only a first step."

There is some evidence that people starting antidepressant medication can develop suicidal ideation, or suicidal thoughts and ideas, although this notion remains controversial.

In 2004, the U.S. Food and Drug Administration (FDA) recommended that the class of drugs known as selective serotonin reuptake inhibitors (SSRIs) carry a strong "black box" warning on the label outlining the possibility of an increase in suicidal ideation. SSRIs include widely used drugs such as Celexa, Paxil, Prozac and Zoloft.

The black box warning was based on studies that found that 4 percent of the group taking SSRIs had suicidal ideation, compared with 2 percent of the group taking a placebo.

"It is a severe side effect, but it is unusual," Laje stated. "Given the warnings by regulatory agencies, we thought this would be a very important side effect to look at."

The current study was part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the largest trial to date to look at depression in real-world settings. Participants in STAR*D were treated with the SSRI citalopram (Celexa) for up to 14 weeks.

For this study, Laje and colleagues analyzed DNA samples from 1,915 participants, looking for associations between reports of suicidal ideation at 768 sites in 68 genes.

Versions of two genes involved with cellular glutamate receptors, which have been implicated in depression, were more prevalent in participants reporting suicidal thinking.

While overall about 6 percent of the patients reported suicidal thoughts when taking Celexa, 36 percent of patients who carried both of the gene variations reported suicidation. Overall, 59 percent of those who reported suicidal ideation had at least one of the suspect gene types.

One percent of the participants had a version of the kainate receptor gene (GRIK2) that increased the risk of suicidal thinking more than eightfold.

Forty-one percent had a version of the AMPA receptor gene (GRIA3) that almost doubled the odds.

Eleven participants, or one-half of one percent, had both versions which resulted in a 15-fold increase in risk.

Since the researchers only looked at Celexa, it's unknown if the findings extend to other antidepressants, even those in the same class of SSRIs.

This study, which is published in the October issue of the American Journal of Psychiatry, is the first to find a significant association between a genetic marker and suicidal ideation.

Researchers elsewhere are working to further clarify the links, if any, between antidepressant use and suicide ideation.

On Thursday, scientists led by Dr. John March, chief of child and adolescent psychiatry at Duke University Medical Center, announced the launch of a large-scale safety registry tracking antidepressant use by children and youth.

In its first study, the Child and Adolescent Psychiatry Trials Network (CAPTN) hopes to follow the outcomes of 2,420 children and adolescents prescribed either an SSRI or another type of drug, a serontonin-norepinephrine reuptake inhibitor (SNRI) to help treat depression, anxiety disorders, and other psychiatric woes. A subset study will examine gene variants associated with an increase in either the benefits or side effects of psychiatric medicines in young users.

The CAPTN effort is funded by the U.S. National Institute of Mental Health.

More information

There is more on suicide prevention at the U.S. National Institute of Mental Health.

Posted: September 2007


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