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NIMH Researchers Identify Genes Associated With Response to Antidepressant Celexa

Depression patients with variations in two genes – GRIK4 and HTR2A – are more likely to respond to the medication citalopram (Forest’s Celexa) than are people without the variations, a study by the National Institute of Mental Health has found.
“The increased likelihood was small, but when people had both [the GRIK4] variation and one in a different gene [HTR2A] shown to have a similarly small effect in an earlier study, [patients] were 23 percent more likely to respond to citalopram than were people with neither variation,” NIMH said in a release this week.
Gonzalo Laje, a clinical research fellow working in the Genetic Basis of Mood and Anxiety Disorders program at NIMH, told Pharmacogenomics Reporter this week that the research is perhaps too early to determine whether a diagnostic may result. However, “I think we are on the right track and this is a good step forward,” Laje said.
Prior to developing a diagnostic, the researchers will have to perform whole-genome studies and analyze other genetic variations and predictors of outcome, such as copy number variations, other polymorphisms, and epigenetics. “We are still a ways away from having antidepressant diagnostics,” Laje said.
According to Laje, several companies have expressed interest in taking the study findings further. “We have been approached by industry but these markers have not yet been licensed,” Laje added. He would not say which companies had contacted NIMH.
In the study, published in the August issue of the American Journal of Psychiatry, researchers examined the DNA of 1,816 patients who had participated in the Sequence Treatment Alternatives to Relieve Depression study, or STAR*D, a seven-year, $31 million study across 41 sites in the US looking at non-psychotic major depression.
The STAR*D trial found that depressed patients who don’t benefit from the first medication prescribed to them may have a chance of benefiting from subsequent treatments. 
Initially, researchers identified 68 candidate genes thought to be involved in depression from 1,297 patients who participated in the STAR*D trial. Researchers compared DNA for those who responded to citalopram and those who had not, and found that many of the responders had a variation in the HTR2A gene. These results were published in May 2006.
In the newest study, researchers “discovered that people with the variation in the GRIK4 gene had a higher likelihood of response, and again found that the variation in the HTR2A gene also made people more likely to respond. The results were reproduced, strengthening their validity,” NIMH said in a statement.
The protein produced by HTR2A acts as a receptor on brain cells for serotonin. “The discovery that a variation in a serotonin-related gene could affect response to citalopram was not entirely surprising, since the serotonin system is known to be involved in depression,” NIMH said in a statement. However, GRIK4 makes a protein that acts as a receptor in the glutamate system.
According to Laje, current research is uncovering more and more data supporting the involvement of glutamate to antidepressant treatment. This current NIMH study implicates the glutamate gene.

“We have been approached by industry but these markers have not yet been licensed.”

“HTR2A „Ÿ that is a serotonin 2A receptor gene „Ÿ is also present in glutamate terminals in the prefrontal cortex, an area associated with depression in imaging studies,” Laje said. “This gene and this receptor seem to regulate the release of glutamate. We’re learning more and more about the links between serotonin and glutamate, and also the relevance of glutamate in response.”
In a statement, lead researcher Francis McMahon explained that “the 23 percent increase in likelihood of response to citalopram occurred in people who carried the favorable variations in both copies of both of the genes.
“People with fewer of the favorable variations didn't have as high a response rate, but still were more likely to respond than were people with none of the favorable variations,” he said.
Genotyping was performed using Illumina’s microarray technology and confirmatory testing for the SNPs was performed with Applied Biosystem’s TaqMan technology.
Citalopram, developed by the Danish pharmaceutical firm H. Lundbeck AS and marketed by Forest Laboratories, is the fastest-growing SSRI in the United States and is the top-selling antidepressant in 13 countries, according to Forest.
In STAR*D, when at one stage everyone received Celexa without differentiating based on genetics, approximately 50 percent of 4,000 enrolled patients responded to the drug. Response, according to Laje, meant that patients got at least 50 percent better.
“One of the complexities we have in pharmacogenomics is [that] in order to do these studies we need very large samples of patients. This is really the first time that we have a sample of such size from STAR*D,” he added.
Scientists from the National Human Genome Research Institute, the National Institute on Alcohol Abuse and Alcoholism, Mount Sinai School of Medicine, and University of Texas Southwestern Medical Center also contributed to the research.
"We're moving steadily closer to being able to personalize treatments based on patients' genetic variations. This is a crucial need for the millions of Americans who suffer from depression," said NIMH Director Thomas Insel in a statement. "New techniques have led to advances that would have been inconceivable a few years ago and are making individualized treatment an achievable goal."

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