Ketamine, a drug that has shown promise in quickly easing depression in people, doesn't actually do the job itself. Instead, depression relief comes from one of the drug's breakdown products, a study in mice suggests. The results, published online May 4 in Nature, identify a potential depression-fighting drug that works quickly but without ketamine's serious side effects or potential for abuse.

The discovery "could be a major turning point," says neuroscientist Roberto Malinow of the University of California, San Diego. "I'm sure that drug companies will look at this very closely."

Depression is a pernicious problem with few good treatments. Traditional antidepressants don't work for everyone, and when the drugs do work, they can take weeks to kick in. Ketamine, developed in the 1960s as a sedative and now used by veterinarians to knock out animals, can ease depression in minutes, not weeks, small studies show.

The new study suggests that a metabolite of ketamine--not the drug itself--fights depression. Inside the body, ketamine gets converted into a slew of related molecules. One of these molecules, called (2R,6R)-hydroxynorketamine, is behind the benefits, neuropharmacologist Todd Gould of the University of Maryland School of Medicine in Baltimore and colleagues find.

On its own, a single dose of (2R,6R)-HNK reduced signs of depression in mice, restoring their drive to search for a hidden platform in water, to try to escape a shock and to choose sweet water over plain. A type of ketamine that couldn't be broken down easily into HNKs didn't ease signs of depression.

Ketamine comes with serious side effects--hallucinations, floating sensations and clumsiness, for example. And at high enough doses, the drug is an anesthetic. But (2R,6R)-HNK may avoid these problems, experiments on mice movement indicate. And since ketamine has already been used to treat depression, Gould says, the breakdown product has been inside people with no apparent ill effects. He and colleagues plan to test the metabolite in clinical trials of people with depression.