NMDAR inhibition-independent antidepressant actions of ketamine metabolites
This review (2106) explores findings from rodent studies that examined whether a ketamine-metabolite (HNK) with fewer side effects is sufficient to induce antidepressant effects using a range of measurement techniques. Results indicated that the metabolite could exert antidepressant effects through early activation of glutaminergic AMPA receptors, independent of NMDA receptor inhibition typically induced by ketamine.
Abstract
Introduction
Major depressive disorder afflicts ~16 per cent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients.
Methods
Here we show that the metabolism of 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 actions in vivo.
Results
Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition.
Discussion
These findings have relevance for the development of next-generation, rapid-acting antidepressants.
Research Summary of 'NMDAR inhibition-independent antidepressant actions of ketamine metabolites'
Introduction
Major depressive disorder is common and existing monoaminergic antidepressants typically require weeks to produce clinical improvement, leaving an unmet need for faster-acting therapies. Sub-anaesthetic doses of (R,S)-ketamine produce rapid and sustained antidepressant effects in treatment-resistant unipolar and bipolar depression, but its clinical use is limited by dissociative side effects and abuse liability. The conventional mechanistic explanation holds that ketamine's antidepressant actions arise from direct inhibition of N-methyl-d-aspartate receptors (NMDARs), yet other selective NMDAR antagonists have failed to reproduce ketamine's robust and enduring clinical profile, prompting uncertainty about the underlying mechanism. Zanos and colleagues set out to test whether metabolism of ketamine to downstream hydroxynorketamine (HNK) metabolites is necessary for its antidepressant-like effects and to characterise the pharmacology of the HNK enantiomers. The study examines behavioural antidepressant readouts in mice, compares stereoisomers and metabolites, probes receptor-level actions (NMDAR versus AMPAR), measures electrophysiological and electroencephalographic biomarkers, and evaluates side-effect and abuse-related outcomes. Their central aim was to determine whether a specific ketamine metabolite can produce antidepressant actions independently of NMDAR inhibition and with an improved side-effect profile.
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Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., Dossou, K. S. S., Fang, Y., Huang, X., Mayo, C. L., Wainer, I. W., Albuquerque, E. X., Thompson, S. M., Thomas, C. J., Zarate Jr, C. A., & Gould, T. D. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533(7604), 481-486. https://doi.org/10.1038/nature17998
References (1)
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