All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants.
Pharmacological research October 1, 2025 Florian Freudenberg, Christine Reif-Leonhard, Gerard R Dawson et al.
Treatment-resistant depression (TRD) affects about 30% of patients with major depressive disorder. While antidepressant development has long focused on monoamine targets, research over the past 35 years has increasingly explored glutamatergic mechanisms. This review discusses developments in glutamatergic drug discovery, emphasizing convergent mechanisms between NMDA and AMPA receptor signaling. Beyond established rapid-acting antidepressants like (es)ketamine and dextromethorphan/bupropion, novel directions include esmethadone, nitrous oxide, and NMDA receptor positive allosteric modulators (rapastinel, zelquistinel, apimostinel), as well as AMPA receptor PAMs (osavampator, tulrampator). The convergent mechanism involves increased AMPA receptor activation, triggering BDNF release and mTOR signaling, promoting synaptic strengthening. Glutamatergic agents represent a transformative path for TRD treatment.