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Gene Discovery Could Change Psychiatric Care

DNA may explain varying reactions to antidepressant drugs

THURSDAY, July 8, 2004 (HealthDayNews) -- For the first time, researchers working with mice have identified a naturally occurring genetic mutation that affects brain levels of serotonin, a neurochemical linked to depression, anxiety and other psychiatric conditions.

The discovery may help explain why some patients feel much better after taking serotonin-altering antidepressants such as Paxil, Prozac and Zoloft, and why others do not.

The findings "suggest that there really are heritable differences in how the brain makes or synthesizes serotonin," said Dr. Jerrold Rosenbaum, chief of psychiatry at Massachusetts General Hospital in Boston.

"It gives us a whole new line of inquiry, both as to tailored treatment and to understanding how treatments work, and why there are differences in the response," he said.

Serotonin is a neurotransmitter, part of the chemical circuitry of the brain responsible for putting thought, emotion and action together to shape human behavior. In healthy individuals, serotonin and another neurotransmitter, dopamine, work together in a kind of "chemical balance" to keep mood and emotions relatively stable.

When that balance is upset, however, conditions such as chronic depression can result. Medications called selective serotonin reuptake inhibitors (SSRIs) work to keep serotonin at elevated concentrations, restoring that balance and elevating mood in the process.

But for years, psychiatrists have realized that SSRIs such as Celexa, Paxil, Prozac and Zoloft don't always work as expected in every patient.

In fact, "only 30 to 40 percent of people given an SSRI really get a high-quality response" from the drug, Rosenbaum said. "There are a lot of people who are getting a partial or incomplete response, or no response at all."

To better understand differences in serotonin concentrations between individuals, researchers led by Marc G. Caron, a professor of cell biology at Duke University, used mice to look closely at genes responsible for producing a brain enzyme called tryptophan hydroxylase-2 (Tph2).

Tph2 is suspected of being the main chemical instigator for serotonin production within the brain. When the Duke team focused on genes responsible for generating Tph2, they found startling differences between individual mice.

Reporting in the July 9 issue of Science, the researchers said one Tph2 gene variant was associated with normal levels of serotonin production within the mouse brain.

On the other hand, a second Tph2 gene -- varying from the first by only a single unit of DNA -- was associated with reductions in brain serotonin concentrations of between 50 percent to 70 percent.

Caron cautioned it's still not been proven that similar genetic differences will show up in humans. "We're hoping, however, that the results of our study give us a hint, a clue, as to what might be the potential differences in individuals."

But because humans tend to show much wider genetic variance than laboratory mice, Caron said he expects there will be more Tph2 gene variants in humans, not less. Studies focusing on differences in human DNA are already under way at Duke, he said.

Caron stressed that the Tph2 gene discovery marks the first time scientists have identified a "functional" gene variant linked to serotonin -- one that has a direct impact on levels of the neurotransmitter within the brain.

Although this research is in its infancy, the finding is "very exciting," he said, because it might someday help us understand "why patients have different sensitivities to various medications, or why they have varying susceptibilities to specific psychiatric conditions."

Rosenbaum said a better understanding of each patient's genetic vulnerabilities might also lead to what's known as psychiatric pharmacogenetics, "where you can screen for the presence or absence of a gene coding for one or the other of these enzymes. If there are differences between people, doctors will be able to predict in advance who'll respond to a serotonin-augmenting drug and who is less likely to do so, so you could spare the person ineffective trials or side effects."

"This is something we've always hoped to do," he said. "Rationally tailor treatment to the individual patient."

More information

To learn more about depression, visit the National Institute of Mental Health.

SOURCES: Jerrold Rosenbaum, M.D., chief, psychiatry, Massachusetts General Hospital, Boston; Marc G. Caron, Ph.D., James B. Duke professor of cell biology, Duke University, Durham, N.C.; July 9, 2004, Science
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