Solving the Antidepressant Paradox

Two genes involved in chemical signaling in the brain may help explain why antidepressants increase the risk of suicide in some people, according to a new study.

Concerns about the safety of antidepressants arose a few years ago when studies began to indicate that the drugs increased the risk of suicide in some adolescents and children. British regulatory officials in 2003 banned the use in minors of several medications called selective serotonin reuptake inhibitors (SSRIs), and in 2004 the U.S. Food and Drug Administration concluded that all classes of antidepressants should carry a warning about the risk in children, adolescents, and young adults (ScienceNOW, 3 February 2004). Although the suicide link is well-established, it is not clear how antidepressants trigger suicidal behavior or thoughts in some people.

Seeking to shed some light on this question, a team of researchers led by Francis McMahon of the National Institute of Mental Health (NIMH) in Bethesda, Maryland, looked at 68 genes in 1915 adults with major depression who were treated with the SSRI citalopram. The researchers were searching for genetic variations that might be associated with suicidal thoughts, and they may have hit pay dirt.

McMahon's team reports in the October issue of The American Journal of Psychiatry that it identified two markers, or short sequences of DNA, in two genes, GRIA3 and GRIK2, that corresponded to a significantly increased risk of developing suicidal thoughts while taking citalopram. GRIA3 and GRIK2 code for receptors for glutamate, a chemical in the brain involved in learning and memory. A small DNA variation in the marker region of these genes appears to be all that separates those who develop suicidal thoughts while taking the drug from those who do not.

Participants with the GRIA3 variation had a nearly doubled risk of developing suicidal thoughts, and participants with the GRIK2 variation showed an eightfold increase in risk. Participants carrying both markers--an extremely rare phenomenon--showed a 15-fold increase in risk.

"The findings suggest part of the tendency to develop this type of reaction to antidepressants might be genetically determined, and this might be used in the future to develop genetic screening tests to identify people who might be at risk," says McMahon. Still, he notes that the work needs to be replicated and says at this point it's not clear why these particular genetic variations would contribute to suicidal thinking in people who take antidepressants.

Elliot Gershon, a psychiatric genetics researcher at the University of Chicago in Illinois, who wrote a companion editorial to the study, calls the findings promising. "They are leading the field into the potential for tailoring treatments to individual gene differences and new general targets for the treatment of depression," he says.

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