|Gene Influences Antidepressant Response
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
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 several 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,
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
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.
Everyone inherits two copies of the serotonin 2A receptor gene, one from each
parent. A tiny glitch in the gene’s chemical sequence results in some people
having an adenine (A) at the same point that other people have a guanine (G).
So an individual can have gene types AA, AG or GG. Overall, the prevalence of
the A version was 38 percent, compared to 62 percent for the G version in this
sample. Fourteen percent had AA gene type, 43 percent AG and 43 percent GG. Since
the site of variation is located in a stretch of genetic material with no known
function, the researchers suspect that it may be just a marker for a still-undiscovered
functional variation nearby in the gene.
Based on scores on a depression rating scale, close to 80 percent of patients
who had AA responded to the antidepressant, compared to about 62 percent of those
with GG. Thus, patients with the AA gene type were 16-18 percent more likely
to benefit from the medication. Even patients with AG showed some increased benefit.
But this only applied to white patients, in whom the A version was more than
six times more frequent than in black patients. There was no significant association
between gene type and treatment outcome in black patients, who tended to fare
less well in the trial overall.
“We now have to consider genetic factors as well as psychosocial issues in our
attempts to explain why antidepressants do not help our black patients as much
as they should,” McMahon said. “The new findings help make a compelling case
for a key role of the serotonin 2A receptor in the mechanism of antidepressant
Also participating in the study were: A. John Rush and Madhukar Trivedi, University
of Texas Southwestern Medical Center; Gonzalo Laje, NIMH; Dennis Charney, Mount
Sinai Hospital; Robert Lipsky, National Institute on Alcohol Abuse and Alcoholism
(NIAAA); Alexander Wilson, Alexa Sorant, and George Papanicolaou, National Human
Genome Research Institute (NHGRI); Maurizio Fava, Massachusetts General Hospital;
and Stephen Wisniewski, University of Pittsburgh.
NIMH, NIAAA and NHGRI are part of the National Institutes of Health (NIH),
the Federal Government's primary agency for biomedical and behavioral research.
NIH and CDC are components of the U.S. Department of Health and Human Services.
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 http://www.nih.gov.