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A mutant gene that
starves the brain of serotonin, a mood-regulating
chemical messenger, has been discovered and found
to be 10 times more prevalent in depressed patients
than in control subjects, report researchers funded
by the National Institutes of Health’s
National Institute of Mental Health (NIMH) and
National Heart Lung and Blood Institute (NHLBI).
Patients with the mutation failed to respond well
to the most commonly prescribed class of
antidepressant medications, which work via
serotonin, suggesting that the mutation may
underlie a treatment-resistant subtype of the
illness.
The mutant gene codes
for the brain enzyme, tryptophan hydroxylase-2,
that makes serotonin, and results in 80 percent
less of the neurotransmitter. It was carried by
nine of 87 depressed patients, three of 219 healthy
controls and none of 60 bipolar disorder patients.
Drs. Marc Caron, Xiaodong Zhang and colleagues at
Duke Unversity announced their findings in the
January 2005 Neuron, published online in
mid-December.
“If confirmed,
this discovery could lead to a genetic test for
vulnerability to depression and a way to predict
which patients might respond best to
serotonin-selective antidepressants,” noted
NIMH Director Thomas Insel, M.D.
The Duke researchers
had previously reported in the July 9, 2004 Science
that some mice have a tiny, one-letter variation in
the sequence of their tryptophan hydroxylase gene
(Tph2) that results in 50-70 percent less
serotonin. This suggested that such a variant gene
might also exist in humans and might be involved in
mood and anxiety disorders, which often respond to
serotonin selective reuptake inhibitors (SSRIs)
— antidepressants that block the re-absorption
of serotonin, enhancing its availability to
neurons.
In the current study,
a similar variant culled from human subjects
produced 80 percent less serotonin in cell cultures
than the common version of the enzyme. More than 10
percent of the 87 patients with unipolar major
depression carried the mutation, compared to only
one percent of the 219 controls. Among the nine
SSRI-resistant patient carriers, seven had a family
history of mental illness or substance abuse, six
had been suicidal and four had generalized
anxiety.
Although they fell
short of meeting criteria for major depression, the
three control group carriers also had family
histories of psychiatric problems and experienced
mild depression and anxiety symptoms. This points
up the complexity of these disorders, say the
researchers. For example, major depression is
thought to be 40-70 percent heritable, but likely
involves an interaction of several genes with
environmental events. Previous studies have linked
depression with the same region of chromosome 12
where the tryptophan hydroxylase-2 gene is located.
Whether the absence of the mutation among 60
patients with bipolar disorder proves to be
evidence of a different underlying biology remains
to be investigated in future
studies.
The researchers say
their finding provides a potential molecular
mechanism for aberrant serotonin function in
neuropsychiatric disorders.
Also participating in
the study were: Raul Gainetdinov, Jean-Marin
Beaulieu, Tatyana Sotnikova, Lauranell Burch,
Redford Williams, David Schwartz, and Ranga
Krishnan, Duke University.
In addition to grants
from NIMH and NHLBI, the study was also funded by
the Human Frontiers Science Program and the
Canadian Institute of Health
Research.
To learn more, visit
the following links:
- Depression
- Bipolar
Disorder
- PubMed abstract
of July 9, 2004 Science article
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