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Potential Genetic Basis for Suicidal Ideation, SSRI Link Identified
> 10/1/2007 10:49:36 AM

Suicide rates rose after the FDA slapped blackbox warnings on antidepressants. For months, evidence has been piling up that Selective Serotonin Reuptake Inhibitors (SSRIs) should not be blamed for suicides. The statistical link was poorly constructed and there is no conclusive evidence that the suicidal ideation supposedly increased by medication actually leads to suicidal behavior. The FDA acted irresponsibly, but it is possible that their concerns have some small basis in reality. A genetic test, published in the current issue of The American Journal of Psychiatry, suggests that a tiny sub-population of depressed patients carry genes that predispose them to adverse reactions to SSRIs.

Dr. Gonzalo Laje suspected that the anecdotal reports of suicidal ideation surging in the first stage of treatment might sometimes be caused by rare genes rather than paranoid doctors. To test his hypothesis, he turned to the vast database of information collected by the STAR*D trial (suicidal ideation increases are so rare, around 4%, that large pools of data are required in order to attain statistical validity). Dr. Laje focused on the citalopram trial because citalopram is a representative and widely prescribed SSRI. He also narrowed his focus to the 68 genes that seemed most likely to contain genetic markers relevant to depression treatment. �

Two genes, GRIA3 and GRIK2, did contain markers that were closely correlated to suicidal ideation. Both of these genes regulate glutamate, a neurotransmitter thought to be crucial in SSRI treatment. While this study has some limitations, such as an examination of only one SSRI and a reliance on another study that was not specifically tailored to collect information on suicidal ideation, it is sound enough to warrant attention. The statistical analysis is particularly rigorous; the link between genes and ideation was filtered through many different population groupings to make sure that no hidden associations were confounding the results. For example, researchers made sure that the genetic link maintained statistical significance inside of each racial group to rule out the possibility that some groups responded more negatively to treatment for extraneous reasons.

The discovery of more genes that influence depression treatment is incredibly important. In a June article, we expressed our excitement about the progress being made towards predicting how individuals will react to depression medication with a genetic test. These tests should be able to predict the likelihood of positive reactions (a reduction in depression symptoms) and negative reactions (suicidal ideation). Many patients have to try multiple antidepressants before they find one that is effective for them. Genetic tests, now possible because of discoveries like the neurotrophic factor that Dr. Francis Lee proved responsible for unresponsiveness to some SSRIs, hold out the possibility of replacing arduous trial-and-error with a quick and sure genetic test. In that June article, we pointed out the tantalizing evidence put forth by Dr. Roy Perlis that there was a link between suicidal ideation and the CREB1 gene. While Dr. Perlis� study was small and preliminary, it combines with the more recent work of Dr. Laje to create a solid foundation for genetic testing. It seems likely that psychiatrists will soon be able to identify patients most at risk for adverse reactions, and then either prescribe alternative medication or protect those endangered patients with heightened monitoring.

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