Possible Pathway Discovered for Ketamine’s Antidepressant Effects

Numerous studies have suggested that a single dose of the anesthetic ketamine can reduce symptoms of depression within a matter of hours, but the medication’s dissociative and euphoric properties have raised questions about its viability as a long-term depression medication. A study published last month in Nature has now found that treating animals with a metabolite created when the body breaks down ketamine is able to reverse depression-like behaviors without the side effects commonly 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,” Carlos Zarate, M.D., chief of the Experimental Therapeutics and Pathophysiology Branch and Section on the Neurobiology and Treatment of Mood Disorders at the National Institute of Mental Health, said in a press statement.

While researchers believed that ketamine produces its antidepressant effects by blocking N-Methyl-D-aspartic acid (NMDA) glutamate receptors, other NMDA receptor antagonists have failed to produce ketamine’s rapid and sustained antidepressant effects.

To determine whether NMDA receptor inhibition is the main mechanism underlying the antidepressant effects of ketamine, Zarate along with other scientists and clinicians from the National Institutes of Health, University of Maryland School of Medicine, and University of North Carolina School of Medicine compared the antidepressant effects of two enantiomers (2S, 6S)-hydroxyketamine (HNK) and (2R, 6R)-HNK, which are byproducts of metabolized ketamine.

For the study, the researchers measured acute (one hour) and sustained (24 hour) antidepressant response in mice that were administered a single 10 mg/kg dose of ketamine, (2S, 6S)-HNK, or (2R, 6R)-HNK. Antidepressant response was measured by the mouse forced swim test and learn helplessness test.

The researchers found that administration of (2R, 6R)-HNK elicited acute and sustained antidepressant-like effects similar to that of ketamine, whereas (2S, 6S)-HNK did not. The antidepressant actions induced by (2R, 6R)-HNK were found to be independent of NMDA receptor inhibition, but were associated with early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA).

“These findings reveal that production of a distinct metabolite of ketamine is necessary and sufficient to produce the ketamine antidepressant actions,” the researchers noted.

Additional analysis revealed (2R, 6R)-HNK did not induce changes in locomotor activity and motor coordination in the mice, nor did the animals self-administer (2R, 6R)-HNK, as was seen in the animals given access to ketamine.

“The current findings are encouraging and exciting news,” Zarate told Psychiatric News.

“Hopefully these findings will open the gate for other researchers trying to tap into AMPA activation for creation of new compounds for depression.”

This research was supported by the National Institutes of Health. ■

An abstract of “NMDAR Inhibition-Independent Antidepressant Actions of Ketamine Metabolites” can be accessed here.