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

Mark J. Niciu, Dawn F. Ionescu, Erica Richards, Carlos A. Zarate

Research output: Contribution to journalArticle

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 Nmethyl- 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.

Original languageEnglish (US)
Pages (from-to)907-924
Number of pages18
JournalJournal of Neural Transmission
Volume121
Issue number8
DOIs
StatePublished - Dec 8 2013
Externally publishedYes

Fingerprint

Major Depressive Disorder
Glutamate Receptors
Antidepressive Agents
Treatment-Resistant Depressive Disorder
Neurotransmitter Agents
Brain
Ketamine
D-Aspartic Acid
Suicidal Ideation
Electroconvulsive Therapy
Therapeutics
Glutamic Acid
Dopamine
Serotonin
Norepinephrine
Magnetic Resonance Spectroscopy
Neurons
Research

Keywords

  • Glutamate
  • Glutamate receptor
  • Ketamine
  • Major depressive disorder
  • NMDA receptor antagonist

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. / Niciu, Mark J.; Ionescu, Dawn F.; Richards, Erica; Zarate, Carlos A.

In: Journal of Neural Transmission, Vol. 121, No. 8, 08.12.2013, p. 907-924.

Research output: Contribution to journalArticle

Niciu, Mark J. ; Ionescu, Dawn F. ; Richards, Erica ; Zarate, Carlos A. / Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. In: Journal of Neural Transmission. 2013 ; Vol. 121, No. 8. pp. 907-924.
@article{e62e2f653c494f1eade6162f2ca40273,
title = "Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder",
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 Nmethyl- 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.",
keywords = "Glutamate, Glutamate receptor, Ketamine, Major depressive disorder, NMDA receptor antagonist",
author = "Niciu, {Mark J.} and Ionescu, {Dawn F.} and Erica Richards and Zarate, {Carlos A.}",
year = "2013",
month = "12",
day = "8",
doi = "10.1007/s00702-013-1130-x",
language = "English (US)",
volume = "121",
pages = "907--924",
journal = "Journal of Neural Transmission",
issn = "0300-9564",
publisher = "Springer Verlag",
number = "8",

}

TY - JOUR

T1 - Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder

AU - Niciu, Mark J.

AU - Ionescu, Dawn F.

AU - Richards, Erica

AU - Zarate, Carlos A.

PY - 2013/12/8

Y1 - 2013/12/8

N2 - 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 Nmethyl- 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.

AB - 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 Nmethyl- 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.

KW - Glutamate

KW - Glutamate receptor

KW - Ketamine

KW - Major depressive disorder

KW - NMDA receptor antagonist

UR - http://www.scopus.com/inward/record.url?scp=84908454316&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908454316&partnerID=8YFLogxK

U2 - 10.1007/s00702-013-1130-x

DO - 10.1007/s00702-013-1130-x

M3 - Article

C2 - 24318540

AN - SCOPUS:84908454316

VL - 121

SP - 907

EP - 924

JO - Journal of Neural Transmission

JF - Journal of Neural Transmission

SN - 0300-9564

IS - 8

ER -