Mutant Gene Linked to Treatment-Resistant Depression
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 University announced their
findings in the January 2005 Neuron, published online in
"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.
NIMH and NHLBI are part of the National Institutes of Health (NIH),
the Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and
To learn more, visit the following links:
Bipolar Disorder: http://www.nimh.nih.gov/healthinformation/bipolarmenu.cfm
PubMed abstract of July 9, 2004 Science article: