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.
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 Human Services.
To learn more, visit the following links:
Depression nimh.nih/HealthInformation/Depressionmenu.cfm
Bipolar Disorder nimh.nih/healthinformation/bipolarmenu.cfm
PubMed abstract of July 9, 2004 Science article ncbi.nlm.nih/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15247473
Contact: Jules Asher
NIMHpressnih
301-443-4536
NIH/National Institute of Mental Health
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