Journal of Neural Transmission

, Volume 121, Issue 8, pp 907–924 | Cite as

Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder

  • Mark J. Niciu
  • Dawn F. Ionescu
  • Erica M. Richards
  • Carlos A. ZarateJr.
Psychiatry and Preclinical Psychiatric Studies - Review article


Monoaminergic neurotransmitter (serotonin, norepinephrine and dopamine) mechanisms of disease dominated the research landscape in the pathophysiology and treatment of major depressive disorder (MDD) for more than 50 years and still dominate available treatment options. However, the sum of all brain neurons that use monoamines as their primary neurotransmitter is <20 %. In addition, most patients treated with monoaminergic antidepressants are left with significant residual symptoms and psychosocial disability not to mention side effects, e.g., sexual dysfunction. In the past several decades, there has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of MDD. Although several preclinical and human magnetic resonance spectroscopy studies had already implicated glutamatergic abnormalities in the human brain, it was rocketed by the discovery that the N-methyl-d-aspartate receptor antagonist ketamine has rapid and potent antidepressant effects in even the most treatment-resistant MDD patients, including those who failed to respond to electroconvulsive therapy and who have active suicidal ideation. In this review, we will first provide a brief introduction to glutamate and its receptors in the mammalian brain. We will then review the clinical evidence for glutamatergic dysfunction in MDD, the discovery and progress-to-date with ketamine as a rapidly acting antidepressant, and other glutamate receptor modulators (including proprietary medications) for treatment-resistant depression. We will finally conclude by offering potential future directions necessary to realize the enormous therapeutic promise of glutamatergic antidepressants.


Major depressive disorder Glutamate Glutamate receptor NMDA receptor antagonist Ketamine 



Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services (IRP-NIMH-NIH-DHHS) and by a NARSAD Independent Investigator and the Brain and Behavior Mood Disorders Research Award (CAZ).

Conflict of interest

Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the U.S. government, but will share a percentage of any royalties that may be received by the government.


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Copyright information

© Springer-Verlag Wien (outside the USA) 2013

Authors and Affiliations

  • Mark J. Niciu
    • 1
  • Dawn F. Ionescu
    • 1
  • Erica M. Richards
    • 1
  • Carlos A. ZarateJr.
    • 1
  1. 1.Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, Department of Health and Human ServicesNational Institute of Mental Health, National Institutes of HealthBethesdaUSA

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