All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants.

Treatment-resistant depression (TRD) represents a major clinical challenge. Affecting about 30 % of major depressive disorder (MDD) patients, effective treatments for TRD are urgently needed. While depression research and antidepressant (AD) development have long centred on monoaminergic targets, research over the past 35 years has increasingly explored glutamatergic mechanisms. Here we present an extended discussion on developments in glutamatergic drug discovery, focusing on mechanistic convergence between NMDA and AMPA receptor signalling. Beyond established rapid-acting antidepressants (RAADs), such as (es)ketamine and dextromethorphan/bupropion (AXS-05), we highlight novel therapeutic directions involving esmethadone (REL-1017), nitrous oxide, and positive allosteric modulators (PAMs) of NMDA receptors (e.g. rapastinel, zelquistinel, and apimostinel). Moreover, we discuss forward-looking strategies using AMPA receptor PAMs (e.g. osavampator and tulrampator) and targeting of AMPA receptor-interacting proteins. By integrating recent clinical evidence with molecular and physiological findings, we highlight a convergent mechanism across these compounds. This involves increased AMPA receptor activation, triggering BDNF release and mTOR signalling, promoting synaptic strengthening through enhanced AMPA receptor trafficking and dendritic spine formation. Together, targeting glutamatergic signalling represents a transformative path for TRD treatment with high efficacy by more directly modulating pathologically affected signalling modules. These developments place glutamatergic agents at the forefront of next-generation AD strategies.