NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses

By Anita E. Autry, M. Adachi, E. Nosyreva, E. Na, M. Los, Peng Cheng, E. Kavalali, L. Monteggia. Nature, 2011

1,847 citations recorded by the source corpus.

Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

Subfields: Biological Psychiatry, Cellular and Molecular Neuroscience, Pharmacology

View Paper: https://www.semanticscholar.org/paper/f5a1bffc20a06ac7d306b7bc163eeb3fce36a18c

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Citations in the corpus

Psychedelics Promote Structural and Functional Neural Plasticity (2018, background): “, 2015), paradigms for which ketamine has also been shown to be effective (Autry et al., 2011; Girgenti et al., 2017; Li et al., 2010).”
BDNF — a key transducer of antidepressant effects (2015, background): “…rapid increase in BDNF protein expression while required, was not maintained at 24 h after ketamine treatment, suggesting that BDNF working through TrkB was triggering intracellular signaling, and possibly synaptic plasticity effects, required for the antidepressant response (Autry et al., 2011).”
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial (2013, neutral): “It is interesting that a recent study of patients with major depressive disorder found that carriers of the Val66Met (rs6265) single nucleotide polymorphism—representing an attenuation of BDNF functioning—had a smaller antidepressant response to ketamine (36), in line with findings in animal models ”
Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders (2012, background): “Our laboratory has demonstrated that this drug may elevate protein levels of BDNF through a translational mechanism involving the eukaryotic elongation factor-2 pathway (Autry et al., 2011).”
Towards a glutamate hypothesis of depression (2011, background): “Lastly, a very recent study suggests the effects of ketamine are mediated through inhibition of spontaneous NMDA-RemEPSCs, leading to a rapid decrease in elongation factor 2 kinase activity permitting rapid increases in Brain Derived Neurotrophic factor (BDNF) translation (Autry et al., 2011).”
Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression (2012, positive): “While the riluzole for relapse prevention strategy was based on potential synergy between ketamine and riluzole involving modulation of glutamate signaling, the recent identification of additional signaling pathways implicated in the antidepressant action of ketamine suggests new targets for synergy”