NMDA Receptor Antagonists & Clinical Applications

Introduction

• NMDA receptor antagonists inhibit the N-methyl-D-aspartate subtype of the ionotropic glutamate receptor — the substrate of slow excitatory transmission, synaptic plasticity (LTP) and glutamate-mediated excitotoxicity.
• The class is therapeutically heterogeneous; only two agents are in mainstream use — ketamine (anaesthesia, analgesia, depression) and memantine (Alzheimer's) — with amantadine, nitrous oxide (N₂O), dextromethorphan and the prototype drug-of-abuse phencyclidine (PCP) as additional channel-blocking members.
• Unifying lesson: broad NMDA blockade has been therapeutically disappointing because glutamate is ubiquitous — flooding the brain with an antagonist causes dissociation/hallucination before benefit. The successful agents block the channel with kinetics that let physiological signalling escape (memantine) or exploit the dissociative state itself (ketamine).
• The topic spans three therapeutic contexts united by one receptor: (1) dissociative anaesthesia (ketamine, N₂O); (2) neurodegeneration/excitotoxicity (memantine in AD, amantadine in PD/dyskinesia); (3) rapid-acting antidepressants (esketamine, dextromethorphan-bupropion).