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 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.