A Major Breakthrough In Treating Depression With Ketamine

A newly discovered compound might hold the key to safer treatment

Illustration: R. A. Di Ieso
May 04, 2016 at 5:58 PM ET

Ketamine, first used as an anesthetic then as a psychedelic club drug, has gotten a new kind of attention in recent years for its possible role as a miracle treatment for depression. Psychiatrists and patients alike have used the drug to relieve the most severe symptoms of depression, and to do so much more quickly than typical antidepressants like Prozac. In some tests, a small dose of ketamine left patients feeling good for up to seven days.

It hasn’t yet been approved by the FDA to treat depression, but some clinicians are already prescribing it off-label, and treatment centers have sprung up to offer infusions for patients to relieve their symptoms.

But like most medications for mental illness, scientists weren’t quite sure why it worked, the mechanisms by which ketamine affected the brain. Now a new study conducted on mice and published in Nature shows that it’s not the ketamine itself that treats the symptoms of depression—it’s one of its molecular components released as the body breaks it down.

Despite patients’ enthusiasm for ketamine, some researchers have expressed concern. Even at the low doses needed to treat depression—far lower than a recreational dose—the drug can make some patients feel detached or distort their perceptions. Plus, if history tells us anything, the drug would lend itself to abuse, making it a potential liability for mental health professionals to prescribe.

This fact inspired researchers to look for a version of the drug that wouldn’t induce the side effects that party-goers know and love. In the study, the researchers took plasma and brain samples from mice that had recently been given a dose of ketamine to identify the drug’s metabolites, which are the molecules created when the body breaks it down. They expected to find compounds that affect a particular receptor in the brain called the NMDA, since past studies have found that it is associated with depression and that ketamine affects it.

But that’s not what they found at all. In a series of experiments, researchers tested traditional antidepressants, ketamine, and its metabolites on groups mice that showed behavior and biochemical signs characteristic of depression. Based on measurements of brain waves and the chemicals in the mice’s brains, the researchers discovered that one of the metabolites, hydroxynorketamine, was the one reducing the mice’s depressive symptoms. The majority of the mice that received hydroxynorketamine showed reduced signs of depression, and didn’t have any of the side effects that make ketamine unappealing to clinicians.

When the researchers also allowed the mice to self-administer—a common lab test that can indicate how habit forming a substance is—doses of ketamine and hydroxynorketamine, the mice only dosed themselves with ketamine, indicating to the researchers that hydroxynorketamine may not be addictive.

Hydroxynorketamine still hasn’t been tested on humans, and there’s no telling whether the results will be similarly impressive. And even if hydroxynorketamine works as well in humans as it does in mice, it wouldn’t be a cure for depression—patients would still have to take a dose of the drug every few days or weeks.

Still, other researchers are impressed with the findings, calling it a “major advance,” buoying hopes that a ketamine-derived, FDA-approved treatment for depression might not be far off.

The researchers next plan to test hydroxynorketamine for safety and toxicity before beginning clinical trials in humans.