Mutation that suppresses serotonin synthesis is tied to severe depression resistant to therapy with selective serotonin reuptake inhibitors
A mutation that decreases serotonin synthesis
by 80 percent is far more common in depressed patients and is linked
with disease resistant to therapy with selective serotonin reuptake
inhibitors, according to an article published online in mid-December
by the journal Neuron.
The mutation in the gene for the enzyme tryptophan
hydroxylase-2, which
makes serotonin, was found in 9 of 87 depressed patients, 3 of 219
healthy controls and none of 60 bipolar disorder patients.
"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 Thomas Insel, MD,
of the National Institutes of Health.
The same American research group had reported in a July issue of
Science that they had identified a single-nucleotide variation in
the tryptophan hydroxylase gene (Tph2) of mice that resulted in
50-70 percent less serotonin. This finding suggested that such a
variant might also exist in humans and might be involved in mood
and anxiety disorders that often respond to serotonin selective
reuptake inhibitors (SSRIs).
In the current study, a similar variant isolated 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 with only 1 percent of 219 controls.
Among the
9 SSRI-resistant patient carriers, 7 had a family history of mental
illness or substance abuse, 6 had been suicidal, and 4 had generalized
anxiety.
Although they fell short of meeting criteria for major depression,
the 3 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 had linked depression with the same region of
chromosome 12 where the tryptophan hydroxylase-2 gene is located.
Whether the absence of the mutation among the 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."
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