NMDAR modulators as rapid antidepressants: Converging and distinct signaling mechanisms

Dysregulation of the glutamatergic system underlies the pathophysiology of depression. Both negative and positive modulation of NMDARs exert rapid and sustained antidepressant effects by reversing the dysregulated glutamatergic system. Research in the past decades has identified key signaling pathways activated by these rapid acting antidepressants. Here, we review the converging signaling mechanisms shared by rapid acting antidepressants and discuss the recent progress on distinct actions of NMDAR antagonists and NMDAR positive modulators to trigger rapid antidepressant actions.