NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

Abstract

Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate receptor (NMDAR) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder (MDD), although the underlying mechanism is unclear1-3. Depressed patients report alleviation of MDD symptoms within two hours of a single low-dose intravenous infusion of ketamine with effects lasting up to two weeks1-3, unlike traditional antidepressants (i.e. serotonin reuptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current MDD therapies, leaving a need for faster acting antidepressants particularly for suicide-risk patients3. Ketamine's ability to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. We show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models that depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). We find that ketamine-mediated NMDAR blockade at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII) resulting in reduced eEF2 phosphorylation and desuppression of BDNF translation. Furthermore, we find inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings suggest that protein synthesis regulation by spontaneous neurotransmission may serve as a viable therapeutic target for fast-acting antidepressant development.

Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

“…Since the delay to reach efficacy with current antidepressants is a major drawback, particularly for suicide risk patients, the development of fast-acting antidepressants represents a significant advance for the treatment of depression [7]. Interestingly, in recent preclinical and clinical reports ketamine emerges as a novel rapid-acting antidepressant agent [8][9][10]. However, the mechanisms of action implicated in the ketamine antidepressant-like effect are not well established.…”

Blocking NMDA receptor at rest: a possible alleviation of depression

“…Therefore, fast-acting antidepressants are urgently needed for clinical treatment of depression. Autry et al reported in a recent issue of Nature that N-methyl-D-aspartate receptor (NMDAR) antagonists could be such candidates by triggering rapid behavioural antidepressant responses [4] .…”

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

“…These results are consistent with previous studies [12,13], in which (R)-ketamine appeared to be a more potent, long-lasting, and safe antidepressant than (S)-ketamine. MK-801, another NMDAR antagonist, also has rapid antidepressant effects but they are not maintained [14,15]. These findings raise doubts about the NMDAR-dependent antidepressant responses to ketamine.…”

“…The antidepressant effects of ketamine require the activation of several intracellular signaling pathways [15,23,24] and the enhancement of AMPAR-mediated synaptic plasticity [20,25]. The authors examined the biochemical profiles of ketamine and (2R,6R)-HNK in the hippocampus and medial prefrontal cortex, two moodrelated brain regions.…”