New analyses of a large, nationwide study of antidepressant treatment have identified genetic variations linked to a controversial and concerning side effect: suicidal thinking. If confirmed, these variations could eventually provide the basis for a genetic test to predict who is most susceptible.

"We really want to be able to pick up the potential for worrisome side effects before we start treatment," says Francis McMahon, a psychiatric geneticist at the National Institute of Mental Health (NIMH), in Bethesda, MD, who led one of the studies.

In 2005, following an extensive analysis of drug trials and testimony from parents whose children had committed suicide after starting the drugs, the Food and Drug Administration (FDA) ruled to add a black-box warning--the strongest warning it issues--outlining that risk. However, previous studies have shown that antidepressant use generally lowers suicide rates, meaning that the number of suicides prevented by antidepressant treatment far outweighs the number that may be triggered by them. So psychiatrists worry that the labels will scare away patients in need of medication.

This concern was reflected in an FDA request to drug makers in May. The agency required that the age range for the black-box warning be extended to include everyone under 25. (Previously, teens and children were of most concern.) But the agency also recommended that new labels urge doctors to weigh the risk of suicide against the clinical need for the drugs.

New studies identifying genetic predictors of this risk could help clarify the issue. Scientists at NIMH and at Massachusetts General Hospital and Harvard Medical School, in Boston, have pored through genetic data collected as part of the STAR*D trial, a multicenter trial funded by NIMH to assess both the genetic and the behavioral factors that predict how patients respond to antidepressants. About 6 to 8 percent of patients in the trial report suicidal thoughts within the first month of taking citalopram, a commonly prescribed antidepressant. So far, scientists have come up with three likely candidates.

In a study of 1,879 participants, published today in Archives of General Psychiatry, Roy Perlis and his team at Harvard found a significant link between a variation in the gene CREB1 and suicidal thinking in men, but not in women. This gene has been linked to mood regulation in animal models of disease, and people who have committed suicide show altered regulation of this gene in their brains. The scientists don't yet know the role that the gene might play in suicidal thinking.

While it's difficult to unravel the risk of suicidal thoughts triggered by the disease rather than by the treatment, Perlis points out that men in the trial who carried the gene did not report thinking about suicide at the start of the trial but were more likely to do so within the first month of treatment with citalopram.