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.
Stopping suicide: In 2005, the Food and Drug Administration added black-box labels to antidepressants, such as Paxil, warning that the drugs increase suicidal thinking in some patients. Now scientists are trying to find the genetic variations that might underlie this unexpected side effect.
“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.
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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.
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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.
In a separate study to be published in the American Journal of Psychiatry, McMahon and his colleagues assessed whether 68 genes involved in neural signaling were linked to suicidal thinking induced by citalopram. Preliminary evidence suggests that markers in two genes involved in chemical signaling by the neurotransmitter glutamate may play a role. Psychiatrists caution that both these and earlier studies assess suicidal thinking, which is much more common than suicide itself. As with all genetic studies of this type, all three candidates must be confirmed in other populations.
While the findings are promising, none of the variations uncovered to date can predict suicidality well enough to make them the basis for a clinical test. For example, according to McMahon, the two variations his group identified could predict about 60 percent of people at risk. “But we would miss 40 percent,” he says. Scientists hope that a combination of several such variants could be much more accurate, and McMahon and others are now searching through the entire genome, rather than just the candidate genes previously studied, for additional markers.
Both McMahon and Perlis are also searching for genetic variants that predict who will respond to particular drugs. “It would be best to be able to pair the two tests so you can weigh the benefits and the risks,” says David Brent, a psychiatrist at the University of Pittsburgh not involved in the study. He adds that people who are identified as at risk may not need to skip treatment altogether–they might need additional monitoring by a psychiatrist, for example.
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Scientists aren’t sure why drugs that usually reduce suicidal thoughts seem to trigger them in a small subset of people. While antidepressants can take weeks to exert their mood-lifting effects, biochemical changes occur right away. “Perhaps suddenly elevating serotonin in the brain causes imbalances in certain people that evoke symptoms like nervousness, sleeplessness, and maybe suicidal thinking,” says McMahon.
