|Success or Failure of Antidepressant Citalopram
Predicted by Gene Variation
A variation in a gene called GRIK4 appears to make people
with depression more likely to respond to the medication citalopram
(Celexa) than are people without the variation, a study by the
National Institute of Mental Health (NIMH), part of the National
Institutes of Health, has found. The increased likelihood was small,
but when people had both this variation and one in a different
gene shown to have a similarly small effect in an earlier study,
they were 23 percent more likely to respond to citalopram than
were people with neither variation.
The finding addresses a key issue in mental health research: the
differences in people’s responses to antidepressant medications,
thought to be based partly on differences in their genes. Some
patients respond to the first antidepressant they attempt, but
many don’t. Each medication takes weeks to exert its full effects,
and patients’ depression may worsen while they search for a medication
that helps. Genetic studies, such as the one described here, may
lead to a better understanding of which treatments are likely to
work for each patient.
Results of the study are in the August issue of the American
Journal of Psychiatry, reported by lead researcher Francis
J. McMahon, MD, Silvia Paddock, Ph.D., of NIMH, and colleagues.
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 R. Insel, MD. “New techniques have led to advances
that would have been inconceivable a few years ago and are making
individualized treatment an achievable goal.”
The researchers studied DNA provided earlier by patients participating
in a recently completed NIMH clinical trial, the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) study. The trial showed
that depressed patients who don’t benefit from the first medication
they try have a fair chance of being helped by others.
After the trial, researchers spelled out the DNA codes contained
in 68 genes suspected of being involved in depression, collected
from 1,297 of the patients who had participated in STAR*D. The
genetic material included the occasional variations that occur
from person to person. Comparing the DNA codes of those who had
responded to citalopram and those who hadn’t, the scientists found
that responders were more likely to have a variation in a gene
called HTR2A. Results of that study were published in
In the newest study, researchers examined the genetic material
of more of the patients who had participated in STAR*D, for a total
of 1,816 samples, and repeated the comparison of DNA from citalopram
responders and nonresponders. They 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.
The protein produced by HTR2A acts as a receptor on brain
cells for the chemical messenger serotonin, one of several neurotransmitters
that enable the cells to communicate with each other. 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. Citalopram targets
But GRIK4 makes a protein that acts as a receptor in
a different neurotransmitter system, the glutamate system. Recent
studies suggest that the glutamate system also is involved in depression,
an assertion supported by the new finding.
“We know that a number of biological mechanisms underlie depression
and affect treatment. Findings like this one are building a picture
of what they are and how they interact, and can reveal potential
molecular targets for faster-acting and more effective medications,” said
Both of the genes consist of two copies each. 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.
By using a recent technique called “SNP tags,” the researchers
used fewer resources, in less time, than usually required for these
kinds of studies. SNP tags eliminated the need to compare all of
the millions of structural units that comprise even a tiny segment
of DNA — a resource — and time-intensive process — by
organizing the units into more manageable blocks of information.
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH website: http://www.nimh.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.