Current pharmacotherapies for major depressive disorder (MDD) have a
distinct lag of onset that can prolong distress and impairment for patients, and realworld
effectiveness trials further suggest that antidepressant efficacy is limited in
many patients. All currently approved antidepressant medications for MDD act
primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or
antagonists with varying affinities for serotonin, norepinephrine, or dopamine.
Glutamate is the major excitatory neurotransmitter in the central nervous system, and
glutamate and its cognate receptors are implicated in the pathophysiology of MDD,
as well as in the development of novel therapeutics for this disorder. Since the rapid
and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist
ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD.
These have been associated with relatively modest antidepressant effects compared to ketamine, but some
have shown more favorable characteristics with increased potential in clinical practice (for instance, oral
administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion
liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators
with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine,
memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP-
101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX-
13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant).
Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that
have yet to be studied clinically, are also briefly discussed; these include α-amino-3-hydroxyl-5-methyl-4-
isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists.