NMDAR inhibition-independent antidepressant actions of ketamine metabolites
P. Zanos, R. Moaddel, Patrick J. Morris, Polymnia Georgiou, J. Fischell, G. Elmer, M. Alkondon, P. Yuan, H. Pribut, Nagendra S. Singh, K. S. Dossou, Yuhong Fang, Xi-ping Huang, Cheryl L. Mayo, I. Wainer, E. Albuquerque, S. Thompson, Craig J. Thomas, C. Zarate, T. Gould
Nature April 24, 2016 Peer reviewed DOI: 10.1038/nature17998 via Semantic Scholar 1,602 citations
Summary
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
Study at a glance
| Design | preclinical study |
|---|---|
| Population | mice |
| Key finding | The (2R,6R)-HNK enantiomer of ketamine's metabolite exerts antidepressant-related actions in mice independently of NMDAR inhibition but through AMPAR activation, and lacks ketamine-related side effects. |
Abstract
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.