Depression, Personalized

Only about two-thirds of depressed people feel better while taking antidepressant medication. Currently, doctors have no way of knowing who is likely to benefit from what drug. But now researchers have identified a gene variant that appears to enhance the odds of benefiting from antidepressants known as selective serotonin reuptake inhibitors (SSRIs). It's "a step on the road to true personalized medicine," says co-author Dennis Charney, a psychiatrist at Mount Sinai Medical Center in New York City.

The findings could also help explain why blacks appear to respond less than whites to antidepressants, says the lead author, psychiatrist Francis McMahon of the National Institute of Mental Health in Bethesda, Maryland. The beneficial gene variant--for a type of serotonin receptor--is far more common in whites than in blacks.

McMahon and colleagues analyzed DNA samples from 1953 patients diagnosed with major depression who were being treated with the SSRI citalopram (Celexa). The patients were part of the largest-ever clinical trial for depression, called STAR*D. To scout out genes that might be associated with treatment response, they looked at 768 markers on 68 candidate genes. SSRIs act on the neurons that send out serotonin, a neurotransmitter that affects many things including mood and circadian rhythms. These antidepressants, which often have fewer side effects than others, prevent transmitting neurons from quickly soaking serotonin back up that has not been absorbed by receptors on other neurons, thus giving the neurotransmitter more time in the synapse to exert an effect. SSRIs also indirectly down-regulate the 2A receptor on postsynaptic (receiving) neurons, which is also necessary for the drugs to work.

It was in the gene responsible for the 2A receptor that the researchers found the only marker significantly associated with response to the drug. Everyone has two copies, or alleles, of the 2A receptor gene, one from each parent. There are two types of alleles, called A and G. Among the people with at least one A allele, 80% benefited from the drug, while only 62% of those with 2 G alleles did well. The pattern occurred only in white patients. This may be a reason why the 313 blacks in the study had poorer responses on average--only 6% of them had at least one A allele, compared with 42% of the whites. People with two A alleles (14% of whites and only 1% of blacks) did much better than those with only one, says Charney.

McMahon says that although numerous small studies have attempted to find genes implicated in antidepressant action, this is "by far the largest" as well as the first to yield a "strong and reproducible signal." It will appear in the May issue of the American Journal of Human Genetics.

"This work presages a revolutionary future for psychiatry where choice of antidepressant treatment will be determined in part on an individual patient's genotype," says psychiatrist Eric Nestler of the University of Texas Southwestern Medical Center in Dallas. McMahon expects that future research will look at the entire genome, including genes involved in drug metabolism.

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