Abstract
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.
Highlights
Major depressive disorder (MDD) is a debilitating psychiatric disorder and one of the leading causes of disability worldwide
The monoaminergic hypothesis of depression dominated the field for several decades, research in the past two decades demonstrates that the glutamatergic system plays a central role in the pathophysiology of MDD [1]
Despite the failure of rapastinel in phase 3 clinical trials, it will be interesting to understand the key mechanisms underlying the actions of these NMDAR PAMs considering the fact that high placebo response is associated with intravenous administration of rapastinel in clinical trials and currently orally administered NMDAR PAMs like AGN-241751 are in phase II clinical trials [4]
Summary
Major depressive disorder (MDD) is a debilitating psychiatric disorder and one of the leading causes of disability worldwide. Low subanesthetic doses of the N-methyl-Daspartate (NMDA) receptor antagonist ketamine exerts rapid and sustained antidepressant effects in both clinical and preclinical studies [2,3]. An NMDA receptor positive allosteric modulator (NMDAR-PAM), rapastinel has received attention as a rapid acting antidepressant, in particular it lacks the side effects of ketamine.
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