A central mystery of mental disorders such as depression is how infinitesimal typos in the genetic blueprint for the brain can cause a predisposition to such disease. Researchers have long known that depression tends to run in families, but they have yet to pinpoint a single genetic flaw that could help explain why--until now.

In the December 2004 issue of Neuron, Marc Caron, James B. Duke Professor of cell biology, and his colleagues reported that, compared with normal people, those with major depression were more likely to show a specific variation in a gene that is the blueprint for a bit of cell machinery called an enzyme. The variation produces a flaw in the enzyme, which is a key link in the cellular production line for the brain chemical serotonin.

Serotonin is an important neurotransmitter. It is the chemical ammunition that one nerve cell fires at another to trigger a nerve impulse in the target cell. Propagation of those nerve impulses among networks of brain cells lays down the signaling pathways throughout the brain that are responsible for memory and other brain functions.

Some of the depressive patients who had the flawed gene also had a family history of mental illness, drug or alcohol abuse, suicidal behavior, or generalized anxiety symptoms, the researchers found. All of the patients with the mutant gene were unresponsive to treatment with "selective serotonin reuptake inhibitors"--a class of antidepressive drugs that includes Paxil, Zoloft, and Prozac.

The discovery of the genetic flaw is only the beginning of a massive hunt for other such crippled genes, as well as explorations of how they predispose people to depression and other mental disorders. While such studies may take many years to yield improved treatments, say Caron and his colleagues, a more immediate payoff might be a diagnostic test for an individual's tendency to depression.