Specific variations in two genes are linked to suicidal thinking that sometimes occurs in people taking the most commonly prescribed class of antidepressants, according to a large study led by scientists at the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH).
Depending on the particular mix inherited, these versions increased the likelihood of such thoughts from 2- to15-fold, the study found. About 1 percent of adult patients were deemed to be at high genetic risk, 41 percent at elevated risk and 58 percent at lower risk.
If confirmed, the findings may hold promise for genetic testing, as more such markers are identified.
Risk increased proportionately if a participant had two, as opposed to just one of the suspect versions. Both genes code for components of the brain's glutamate chemical messenger system, which recent studies suggest is involved in the antidepressant response.
Overall, about 6 percent of 1,915 patients with depression reported that they started to have suicidal thoughts while taking an antidepressant. This rate soared to 36 percent among the few patients with both of the suspect gene versions; 59 percent of the patients who had suicidal thoughts had at least one of the versions.
Francis J. McMahon, M.D., Gonzalo Laje, M.D., NIMH Mood and Anxiety Disorders Program, and colleagues at the National Human Genome Research Institute (NHGRI), Mount Sinai School of Medicine, and the University of Texas Southwestern Medical Center, report on their findings in the October, 2007 issue of The American Journal of Psychiatry.
“These data suggest that genetics may soon help us in our quest to individualize treatments for depression,” said NIMH Director Thomas R. Insel, M.D.
“In the future, we hope that genetic testing will help doctors identify those few patients who are at high risk for suicidal thinking during antidepressant therapy and need close monitoring or alternative treatments,” said McMahon. “This should help allay concerns for the vast majority of patients. The best way to prevent suicide is to treat depression.”
In the most comprehensive study of its kind to date, McMahon and colleagues screened genetic material from 1,915 adult participants with major depression in level one of the NIMH-funded STAR*D (Sequenced Treatment Alternatives for Depression) trial. Study participants were treated with the selective serotonin reuptake inhibitor (SSRI) citalopram. The researchers looked for associations between self-reports of suicidal thinking and more than 700 sites in 68 suspect genes where letters in the genetic code vary across individuals, creating different versions of the same gene.
The researchers found that certain versions of two genes that code for glutamate receptors – the receiving stations for the neurotransmitter's chemical messages – were more prevalent in patients with suicidal thinking. How the newly identified versions affect the workings of glutamate receptors to confer increased risk remains to be discovered. It's also not yet known whether the findings generalize to other antidepressants.
One percent of the study participants had a version of the kainate receptor gene, GRIK2, that increased the odds for suicidal thinking more than 8-fold. Forty-one percent of participants had a version of the AMPA receptor gene, GRIA3, that raised the odds nearly 2-fold. About one-half of 1 percent of participants had both high risk gene versions, boosting the odds 15 fold – but this was the case for only 11 participants, of whom four developed suicidal thinking.
Neither version was related to self-reported history of suicide attempts. This suggests that the versions are specific to suicidal thoughts that occur during antidepressant treatment, rather than the much more common suicidal thoughts and behavior that occur outside of the treatment setting.