Our understanding of ketamine’s MOA is flawed
What has brought about the revision of our views on ketamine? It appears that our understanding of how ketamine exerted its antidepressant effects was flawed. It was thought that ketamine worked by directly inhibiting the N-methyl-D-aspartate glutamate receptor (NMDAR). However, other NMDAR inhibitors could never generate ketamine’s depth of antidepressant effect. This suggests there was something special about ketamine’s mode of action. By examining what happens to ketamine as it is metabolised in depressed mice, National Institute of Health (NIMH) researchers have uncovered something quite new.1
Metabolism of (R,S)-ketamine to (2R,6R)-HNK generates antidepressant effects in rodents
The NIMH group have shown that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential to promote antidepressant effects. And just one form of HNK - the (2R,6R)-HNK enantiomer - exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. Importantly, if ketamine metabolism is blocked, the anti-depressant effects of ketamine do not occur. This suggests that the metabolite and not ketamine itself is responsible for these beneficial effect.
But it may be even better. Firstly, (2R,6R)-HNK exerted its anti-depressive effects without generating any of the unwanted cognitive and motor side-effects normally observed with ketamine in rodent studies.
(2R,6R)-HNK acts on AMPA not NMDA receptors
The reason for the lack of side-effects is thought to be because (2R,6R)-HNK doesn’t act on NMDA but on another glutamate receptor - the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Experiments have shown that if the AMPA receptors are blocked, so are the antidepressant effects of (2R,6R)-HNK.
Just like ketamine, a single dose of (2R,6R)-HNK promotes long-lasting antidepressant effects in treated mice. Finally, the ketamine metabolite appears not to be addictive. When mice were allowed to ‘self-administer’ the two compounds, they only helped themselves to ketamine and not to (2R,6R)-HNK.
Uncovering the mechanism behind ketamine’s actions may open the way for the development of specific rapid and long-acting antidepressants. Human studies are planned to start next year and, not surprisingly, are generating considerable interest. At long last, ketamine’s press coverage is positive.