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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