NMDAR inhibition-independent antidepressant actions of ketamine metabolites

By P. Zanos, R. Moaddel, Patrick J. Morris, Polymnia Georgiou, J. Fischell, G. Elmer, M. Alkondon, P. Yuan, H. Pribut, Nagendra S. Singh and 10 more. Nature, 2016

1,471 citations recorded by the source corpus.

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.

Subfields: Biological Psychiatry, Cellular and Molecular Neuroscience, Pharmacology

View Paper: https://www.semanticscholar.org/paper/fc5c883e59fd815bd133f88763c9ab2d3965eca9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biological Psychiatry

1. G. Sanacora
2. Michael Berk
3. C. Nemeroff
4. K. Al-Harbi

In Cellular and Molecular Neuroscience

1. G. Sanacora
2. Todd D. Gould
3. C. Nemeroff
4. K. Al-Harbi

In Pharmacology

1. G. Sanacora
2. Todd D. Gould
3. C. Nemeroff
4. K. Al-Harbi

Citations in the corpus

• Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms (2018, background): “93 for (R)-ketamine at 10 minutes postinjection (Zanos et al., 2016).”
• Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024, background): “377 Studies have suggested that ketamine can increase the synthesis of synaptic proteins through BDNF signaling dependent on the activate protein kinase B (Akt) and mammalian target of rapamycin complex 1 (mTORC1) signaling cascades.”
• Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial (2016, background): “Similarly, ketamine (the only other known acute and short-term sustained anti-depressant) is theorized to exert its anti-depressant effects via cortical AMPA activation (Zanos et al., 2016) and BDNF expression (Lepack et al.”
• Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation (2021, background): “For example, ketamineis reported toactivatehuman-recombinantm,k, andd opioid receptors (35).”
• Psychedelics Promote Structural and Functional Neural Plasticity (2018, background): “Although our group is actively investigating the psychoplastogenic properties of non-hallucinogenicanalogsofpsychedelics, othershave reported the therapeutic potential of safer structural and functional analogs of ketamine (Moskal et al., 2017; Yang et al., 2015; Zanos et al., 2016).”