NMDA antagonists under investigation for the treatment of major depressive disorder

Mood disorders, including depression, are becoming increasingly prevalent in the developed world. Furthermore, treatment of depression therapeutics, mainly influencing the serotonergic and adrenergic systems, is considered insufficient. The original NMDA-glutamate hypothesis mechanism of antidepressant action was first proposed ∼ 20 years ago. Since then, a number of preclinical and clinical studies have examined its rationale.

This review highlights the recent clinical evidence for the use of functional NMDA receptor antagonists as antidepressants. Furthermore, the authors present the mechanism(s) of antidepressant action derived mostly from preclinical paradigms.

Currently, clinical studies mostly use ketamine (a noncompetitive high-potency NMDA antagonist) as an agent for rapid relief of depressive symptoms. However, due to the ketamine-induced psychotomimetic effects, new NMDA receptor antagonists (modulators) are continuously being introduced for rapid antidepressant action, especially for use in treatment-resistant patients. Recent clinical reports for the use of CP-101,606, MK-0657 (selective GluN2B subunit NMDA receptor antagonists), GLYX-13 and d-cycloserine (glycine site partial agonists) are optimistic but await further support.