Therapeutic modulation of glutamate receptors in major depressive disorder

Brittany A. Jaso, Mark J. Niciu, Nicolas D. Iadarola, Niall Lally, Erica M. Richards, Minkyung Park, Elizabeth D. Ballard, Allison C. Nugent, Rodrigo Machado-Vieira, Carlos A. Zarate

Research output: Contribution to journalReview articlepeer-review

76 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)57-70
Number of pages14
JournalCurrent Neuropharmacology
Issue number1
StatePublished - 2017


  • Antagonist
  • Glutamate
  • Major depressive disorder (MDD)
  • Metabotropic
  • N-methyl-D-aspartate (NMDA)
  • Negative allosteric modulator
  • Positive allosteric modulator
  • α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA)

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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