Ketamine is an NMDA receptor antagonist that elicits rapid antidepressant responses in patients with treatment-resistant depression. However, it has adverse side effects, which has drawn clinicians to investigate whether the clinically tolerated NMDAR antagonist memantine can also elicit fast antidepressant action. However, memantine does not trigger rapid antidepressant action for reasons which remain unclear. Here, the authors reconstitute the ketamine and memantine clinical findings in animal models and, combined with the analysis of synaptic function and subsequent intracellular signaling, demonstrate significant differences between the efficacies of ketamine and memantine on NMDAR-mediated neurotransmission and downstream intracellular signaling. They discuss potential mechanisms for the earlier clinical observations.
Gideons ES, Kavalali ET and Monteggia LM: Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc. Natl. Acad. Sci. USA 111(23): 8649-8654 (2014).

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