Whether depressed patients will respond to an antidepressant depends, in part, on which version of a gene they inherit, a study led by scientists at the National Institutes of Health (NIH) has discovered.
Having two copies of one version of a gene that codes for a component of the brain's mood-regulating system increased the odds of a favorable response to an antidepressant by up to 18 percent, compared to having two copies of the other, more common version.
Since the less common version was over 6 times more prevalent in white than in black patients - and fewer blacks responded - the researchers suggest that the gene may help to explain racial differences in the outcome of antidepressant treatment. The findings also add to evidence that the component, a receptor for the chemical messenger serotonin, plays a pivotal role in the mechanism of antidepressant action. The study, authored by National Institute of Mental Health (NIMH) researchers Francis J. McMahon, M.D., Silvia Buervenich, Ph.D., and Husseini Manji, M.D., along with collaborators at the National Human Genome Research Institute (NHGRI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and other institutions, was posted online March 8 and will appear in the May, 2006 American Journal of Human Genetics.
"This discovery brings us closer to the day when clinicians will be able to offer treatment options and medications that are tailored and personalized to be optimally effective for individual patients," said NIH Director Elias A. Zerhouni, M.D.
However, the findings cannot yet guide treatment decisions.
"To our knowledge, this is the first demonstration of significant, replicated association between genetic variation and outcome of antidepressant treatment," added Manji, director of the NIMH's Mood and Anxiety Disorders Program.
In the initial phase of the NIMH-funded STAR*D (Sequenced Treatment Alternatives for Depression) trial, about 47 percent of the 2,876 participants experienced some improvement with the serotonin selective reuptake inhibitor (SSRI) citalopram (Celexa). The NIH scientists set out to find genetic factors that might help to explain why some patients fared better than others.
They screened genetic material from 1,953 of the STAR*D patients, a sample with a higher percentage of responders (69 percent), in part because patients who were doing well tended to stay in contact longer and were more likely to allow a blood sample to be drawn. The researchers looked for associations between treatment response and 768 known sites of variability in 68 suspect genes - sites where letters in the genetic code vary across individuals.
They found the strongest connection in the gene that codes for the serotonin 2A receptor, one of several proteins to which serotonin binds when brain cells communicate.
Located on cells in the brain's thinking center (cortex), the serotonin 2A receptor regulates circuits implicated in depression. Antidepressants, including citalopram, reduce the number of serotonin 2A receptors in animal cortex over the course of a few weeks - the same time-frame required for the drugs to work in humans - suggesting that the receptors are important in the drugs' mechanism of action.