Defect In Enzyme For Serotonin Synthesis Confers Depression Risk

NEW YORK (Reuters Health) - A genetic mutation that confers a risk for major depression has been identified by researchers at Duke University Medical Center in Durham, North Carolina.

In the December 9th online edition of Neuron, Dr. Xiaodong Zhang and colleagues explain that the defect is a single nucleotide polymorphism in the gene for tryptophan hydroxylase-2, the rate-limiting enzyme in neuronal serotonin synthesis. The mutation, G1463A, results in an 80% loss of function in serotonin production when expressed in cultured cells.

The investigators searched for the mutation in 87 patients with unipolar major depression, 60 patients with bipolar depression, and 219 control subjects. Nine patients with unipolar depression and three control subjects, but none of the patients with bipolar disorder, carried the mutant allele.

Of the nine carriers with unipolar depression, seven had family histories of mental illness or drug and alcohol abuse, and six had exhibited suicidal behavior or made a suicide attempt.

Furthermore, seven of the carriers with unipolar disorder were unresponsive to treatment with selective serotonin reuptake inhibitors, and the other two responded only to the highest doses of these medications. This finding, the researchers say, suggests that serotonin synthesis in the brain plays a role in the efficacy of this class of drugs.

It may even be the case, they speculate, that this and similar genetic variants might be associated with the paradoxical adverse reactions that occur in some patients who take SSRIs, including suicidal behavior, mania, and psychosis.

In addition, the authors report, while the three controls with the mutation did not have unipolar major depression, one had generalized anxiety and the other two had mild depression and a family history of mental illness or drug and alcohol abuse, "suggesting a potentially higher susceptibility for certain neuropsychiatric disorders in the presence of the mutant allele."

"Clearly, further large-scale genetic studies are needed to confirm these observations and to investigate in detail the inheritance and penetrance of this functional [single nucleotide polymorphism] in unipolar major depression," they write.

In the meantime, they conclude, their discovery "suggests that a defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression."

Neuron,2004.

MeSH Headings: Polymorphism, Single Nucleotide

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