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.


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 US 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 drugs such as citalopram (Celexa), paroxetine (Paxil), fluoxetine (Prozac) and sertraline (Zoloft).

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

"It is a severe side effect, but it is unusual," Gonzalo Laje, MD, lead author of the study and associate clinical investigator at the US National Institute of Mental Health stated.

"Given the warnings by regulatory agencies, we thought this would be a very important side effect to look at," said Dr. Laje.

New Study

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 Celexa for up to 14 weeks.

For this study, Dr. Laje and colleagues analyzed DNA samples from 1.915 participants, looking for associations between reports of suicidal ideation and 68 genes.


Versions of two genes were more prevalent in participants reporting suicidal thinking.

While overall about 6% of the patients reported suicidal thoughts when taking Celexa, 36% of patients who carried both of the gene variations reported suicidal ideation. Overall, 59% 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 was associated with eight times the risk for suicidal thinking.

Forty-one percent had a version of the AMPA receptor gene GRIA3) that was associated with almost double the odds.

Eleven participants, or one-half of one percent, had both versions, which was associated with 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, published in the American Journal of Psychiatry, is the first to find a significant association between a genetic marker and suicidal ideation.


"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. Laje.

"Our long-term goal is to make sure that people with depression can taek antidepressants, because treating depression is the best way to avoid suicide," he said.

Expert Reaction

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

"It's a very important topic," said Michael Slifer, MD, an assistant professor of medicine at the University of Miami Institute for Human Genomics.

Dr. Slifer, who was not involved in the study, added, "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."

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