Ketamine Lifts Depression via a Byproduct of Its Metabolism

The metabolite singularly reversed depression-like behaviors in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine.

A chemical byproduct, or metabolite, created as the body breaks down ketamine likely holds the secret to its rapid antidepressant action, NIH scientists and grantees have discovered. This metabolite singularly reversed depression-like behaviors in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine.

“This discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works and holds promise for development of more robust and safer treatments,” said NIMH’s Dr. Carlos Zarate, a study co-author and a pioneer of research using ketamine to treat depression. “By using a team approach, researchers were able to reverse-engineer ketamine’s workings from the clinic to the lab to pinpoint what makes it so unique.”

NIMH grantee Dr. Todd Gould of the University of Maryland School of Medicine, in collaboration with Zarate and other colleagues, reported on the findings May 4 in Nature. The team also included researchers at NCATS, NIA and the University of North Carolina.

“Now that we know that ketamine’s antidepressant actions in mice are due to a metabolite, not ketamine itself, the next steps are to confirm that it works similarly in humans and determine if it can lead to improved therapeutics for patients,” explained Gould.

Clinical trials by Zarate and others have shown that ketamine can lift depression in hours, or even minutes—much faster than the most commonly used antidepressant medications now available, which often require weeks to take effect. Further, the antidepressant effects of a single dose can last for a week or longer. However, despite legitimate medical uses, ketamine also has dissociative, euphoric and addictive properties, making it a potential drug of abuse and limiting its usefulness as a depression medication.