Study Sheds Light on How Depression Drugs Work

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Scientists have discovered a protein in the brain called P11 that may explain how drugs like Prozac fight depression — and why they take so long to work. The finding, published in the current issue of Science, also could point the way to a new generation of drugs for depression.

Prozac and other so-called SSRI drugs are known to increase the amount of serotonin available to brain cells very quickly, says Trevor Sharp of the University of Oxford in Great Britain. "Yet it's well known from many studies that they don't relieve depression in patients until patients have been taking a course of these drugs for several weeks."

Researchers have been looking for an explanation by studying precisely how serotonin acts on brain cells.

That's hard to do in people. So a team led by Pers Svenningsson of the Karolinska Institute in Stockholm looked at mice with signs of depression. When these mice are held by their tails, for example, they struggle less than normal mice.

Svenningsson and a group of U.S. scientists found that removing P11 from the brains of mice caused them to show signs of depression. The effect that we saw in this mouse model is very dramatic," he says.

Svenningsson says P11 appears to make mouse brain cells more sensitive to the feel-good effects of serotonin.

And he says that when mice got antidepressant drugs, their levels of P11 rose. But the effect on P11 didn't happen immediately. It took place over time and at the same pace as behavior changes.

"What this discovery showed was that p11 plays a major role in mood," says Paul Greengard, a Nobel laureate from Rockefeller University. He says that's probably because P11 is helping brain cells respond to serotonin more efficiently.

Greengard says if p11 has the same effect in humans as it does in mice, that may explain why current antidepressant drugs take so long to work.

And there is evidence that P11 does play a role in human moods. Greengard says brain tissue from autopsies of people who'd been diagnosed with depression contained less p11 than normal brain samples.

"Our thinking is that many subclasses of depression might be associated with lower levels of P11 on the one hand, and that raising either the level or the functionality of the P11 would be a novel way of developing antidepressants," Greengard says.

Right now, there aren't any drugs that act directly on p11. But researchers say biotech companies are likely to start looking.

Dr. Thomas Insel, the director of the National Institute of Mental Health, says the new study "is quite important, because it now focuses on a whole new area, and a whole new part of the cascade for how information gets processed in the brain."

Insel says it's possible that drugs acting directly on p11 or some other crucial molecule could eventually make depression treatment as quick as treatment for physical pain.

"I don't know anybody with acute pain who would accept a drug that would take six to eight weeks to work," Insel says. "And certainly, we shouldn't be expecting anyone with a disease as painful as major depression to wait that long to get a response."



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