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Ketamine lifts depression via a byproduct of its metabolism

A chemical byproduct, or metabolite, created as the body breaks down ketamine likely holds the secret to its rapid antidepressant action, National Institutes of Health (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 Carlos Zarate, M.D. of the NIH’s National Institute of Mental Health (NIMH), 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 Todd Gould, M.D. of the University of Maryland School of Medicine, in collaboration with Zarate and other colleagues, report on their findings May 4, 2016 in the journal Nature. The team also included researchers at the NIH’s National Center for Advancing Translational Sciences (NCATS) and National Institute on Aging (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.

In hopes of finding leads to a more practical treatment, the research team sought to pinpoint the exact mechanism by which ketamine relieves depression. Ketamine belongs to a class of drugs that block cellular receptors for glutamate, the brain’s chief excitatory chemical messenger. Until now, the prevailing view was that ketamine produced its antidepressant effects by blocking N-methyl-D-aspartic acid (NMDA) glutamate receptors.

However, human trials of other NMDA-receptor blockers failed to produce ketamine’s robust and sustained antidepressant effects. So the team explored the effects of ketamine on antidepressant-responsive behaviors in mice. Ketamine harbors two chemical forms that are mirror images of each other, denoted (S)- and (R)-ketamine. The investigators found that while (S)-ketamine is more potent at blocking NMDA receptors, it is less effective in reducing depression-like behaviors than the (R) form.