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How Ketamine Cures Depression

Researchers have identified the ketamine breakdown product that gives the drug its antidepressant effects, which could lead to faster, more-effective mood stabilizers in the future.

By Kate Wheeling


A vial of ketamine. (Photo: Wikimedia Commons)

When the antidepressant effects of ketamine were first reported a decade ago, the anesthetic drug seemed likely to change the way doctors treat the most persistent cases of depression. Since 2006, the surgical drug has been shown to work in patients with treatment-resistant depression and provide relief much faster than mood stabilizers like SSRIs. But the potential hallucinogenic side effects that make ketamine a popular recreational drug today have put a damper on its clinical applications.

Now, researchers have found that a metabolite of ketamine — a substance that forms as the drug breaks down in the body — is responsible for it’s anti-depressant effects. The finding could lead to a fast-acting, metabolite-based treatment for depression that avoids the negative side effects of ketamine itself.

“As a field, we overlook that when you give a drug, you’re also giving its metabolites,” says Todd Gould, a professor at the University of Maryland School of Medicine, and principle author on the new study. “We have a tendency to assume that it’s the drug itself that’s giving its effects.”

In the new study, published today in Nature, an interdisciplinary team of researchers turned to a mouse model to discover how ketamine works to alleviate the symptoms of depression. The authors gave mice a single dose of ketamine and evaluated its antidepressant effects using a forced swim test — a standard lab experiment that places the mice in a cylindrical tub of water with no way out. The longer the mice actively try to swim and climb before giving up and passively floating, the better the antidepressant.

“We overlook that when you give a drug, you’re also giving its metabolites.”

The authors made several key observations. Among them: the drug had a more potent antidepressant effect in female mice, and the brains of female mice had approximately three times more of the ketamine metabolite (2R,6R)-hydroxynorketamine — this, despite the fact that both sexes were given equal doses of the drug. The finding suggested that (2R,6R)-HNK may have been driving the ketamine’s mood-lifting effects.

In fact, when the researchers gave mice a dose of just (2R,6R)-HNK, the metabolite had the same mood-boosting effects as ketamine — without the negative side effects. So what’s the takeaway for humans?

Ketamine is metabolized in the same way in both humans and mice, and given that ketamine has been safely administered to humans as a Food and Drug Administration-approved anesthetic for decades, its metabolites are unlikely to have unexpected and negative side effects. Still, it’s a long road from the lab to the doctor’s office.

“We’ve cured depression many thousands of times in rats and mice, and very few of those end up being successful drugs in humans,” Gould says. “But I am optimistic.”