Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action

In this article, we first review current knowledge of the AMPA and NMDA glutamate receptors, their physiological properties and functions and their regulation by signaling cascades. We then discuss our hypothesis that the therapeutic effects of monoaminergic antidepressants and ketamine, an NMDA receptor antagonist, may be mediated by increased AMPA to NMDA throughput in critical neuronal circuits. We hypothesize that ketamine mediates this throughput directly, thus resulting in rapid antidepressant effects whereas monoaminergic antidepressants work indirectly and gradually; this may explain, in part, the delayed onset of several weeks to months that is observed with traditional antidepressants.