Researchers dispute the therapeutic mode of action of a ketamine metabolite

A study in Nature contradicts a previous report on synaptic NMDAR inhibition by a ketamine metabolite, a potential antidepressant.

Illustration of brain synapse

Scientists are trying to develop treatments that harness the rapid depression-relieving effects of ketamine without the risk of unwanted side effects, such as hallucinations and loss of memory.

Previous research in mice found that a ketamine metabolite, known as (2R,6R)-HNK, can exert antidepressive effects similar to ketamine independently of the synaptic N-methyl-D-aspartate receptor (NMDAR) and that this might result in fewer side effects.

In a new study, researchers studied the effect of the metabolite on directly measured synaptic currents in vivo. Using a higher dose than that explored by the other researchers, they showed that the metabolite does block the NMDAR, resulting in a downstream cascade that has been reported responsible for the antidepressant effects of ketamine.

Reporting in Nature
(online, 21 June 2017), the team say their findings contradict those of their colleagues and indicate that blocking NMDAR is likely to be the mechanism by which (2R,6R)-HNK exerts its long-lasting antidepressant effects.


[1] Suzuki K, Nosyreva E, Hunt K et al. Effects of a ketamine metabolite on synaptic NMDAR function. Nature 2017;56:E1–E3. doi: 10.1038/nature22084

Last updated
The Pharmaceutical Journal, Researchers dispute the therapeutic mode of action of a ketamine metabolite;Online:DOI:10.1211/PJ.2017.20203196

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