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

Mark J Niciu; Dawn F Ionescu; Erica M Richards; Carlos A Zarate Jr

doi:10.1007/s00702-013-1130-x

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

Journal article

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Peer reviewed

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

Mark J Niciu, Dawn F Ionescu, Erica M Richards and Carlos A Zarate Jr

Journal of neural transmission (Vienna, Austria : 1996), Vol.121(8), pp.907-924

08/2014

DOI: 10.1007/s00702-013-1130-x

PMCID: PMC4048804

PMID: 24318540

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https://www.ncbi.nlm.nih.gov/pmc/articles/4048804View

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Abstract

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.

Receptors, Glutamate - metabolism

Depressive Disorder, Major - physiopathology

Humans

Depressive Disorder, Major - immunology

Antidepressive Agents - therapeutic use

Animals

Excitatory Amino Acid Agents - therapeutic use

Depressive Disorder, Major - genetics

Excitatory Amino Acid Agents - pharmacology

Antidepressive Agents - pharmacology

Glutamic Acid - metabolism

Ketamine - therapeutic use

Ketamine - pharmacology

Biomarkers, Pharmacological - metabolism

Depressive Disorder, Major - drug therapy

Details

Title: Subtitle: Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder
Creators: Mark J Niciu - Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Building 10/CRC, Room 7-5545, Bethesda, MD, 20892, USA, mark.niciu@nih.gov
Dawn F Ionescu
Erica M Richards
Carlos A Zarate Jr
Resource Type: Journal article
Publication Details: Journal of neural transmission (Vienna, Austria : 1996), Vol.121(8), pp.907-924
DOI: 10.1007/s00702-013-1130-x
PMID: 24318540
PMCID: PMC4048804
NLM abbreviation: J Neural Transm (Vienna)
ISSN: 0300-9564
eISSN: 1435-1463
Publisher: Austria
Grant note: Z99 MH999999 / Intramural NIH HHS
Language: English
Date published: 08/2014
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984003470202771

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