Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses

Ketamine is an NMDA receptor (NMDAR) antagonist that elicits rapid antidepressant responses in patients with treatment-resistant depression. However, ketamine can also produce adverse side effects, which raised interest in whether the clinically tolerated NMDAR antagonist memantine can elicit similar fast antidepressant action. Rather surprisingly, clinical data have shown that memantine does not trigger rapid antidepressant effects for reasons that have yet to be elucidated. Here, we 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. These findings suggest a potential mechanism to explain the earlier clinical observations.