Therapeutic modulation of glutamate receptors in major depressive disorder

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

Research output: Contribution to journalReview article

Abstract

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
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Major Depressive Disorder
Glutamate Receptors
Antidepressive Agents
Ketamine
N-Methyl-D-Aspartate Receptors
Glutamic Acid
Cycloserine
Dextromethorphan
Memantine
Therapeutics
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
N-Methylaspartate
Hydroxyl Radical
Glycine
Neurotransmitter Agents
Oral Administration
Dopamine
Serotonin
Norepinephrine
Central Nervous System

Keywords

  • 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)

Cite this

Jaso, B. A., Niciu, M. J., Iadarola, N. D., Lally, N., Richards, E., Park, M., ... Zarate, C. A. (2017). Therapeutic modulation of glutamate receptors in major depressive disorder. Current Neuropharmacology, 15(1), 57-70. https://doi.org/10.2174/1570159X14666160321123221

Therapeutic modulation of glutamate receptors in major depressive disorder. / Jaso, Brittany A.; Niciu, Mark J.; Iadarola, Nicolas D.; Lally, Niall; Richards, Erica; Park, Minkyung; Ballard, Elizabeth D.; Nugent, Allison C.; Machado-Vieira, Rodrigo; Zarate, Carlos A.

In: Current Neuropharmacology, Vol. 15, No. 1, 01.01.2017, p. 57-70.

Research output: Contribution to journalReview article

Jaso, BA, Niciu, MJ, Iadarola, ND, Lally, N, Richards, E, Park, M, Ballard, ED, Nugent, AC, Machado-Vieira, R & Zarate, CA 2017, 'Therapeutic modulation of glutamate receptors in major depressive disorder', Current Neuropharmacology, vol. 15, no. 1, pp. 57-70. https://doi.org/10.2174/1570159X14666160321123221
Jaso, Brittany A. ; Niciu, Mark J. ; Iadarola, Nicolas D. ; Lally, Niall ; Richards, Erica ; Park, Minkyung ; Ballard, Elizabeth D. ; Nugent, Allison C. ; Machado-Vieira, Rodrigo ; Zarate, Carlos A. / Therapeutic modulation of glutamate receptors in major depressive disorder. In: Current Neuropharmacology. 2017 ; Vol. 15, No. 1. pp. 57-70.
@article{508d62b9eef540f3acaea8e9c2e8e6d0,
title = "Therapeutic modulation of glutamate receptors in major depressive disorder",
abstract = "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.",
keywords = "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)",
author = "Jaso, {Brittany A.} and Niciu, {Mark J.} and Iadarola, {Nicolas D.} and Niall Lally and Erica Richards and Minkyung Park and Ballard, {Elizabeth D.} and Nugent, {Allison C.} and Rodrigo Machado-Vieira and Zarate, {Carlos A.}",
year = "2017",
month = "1",
day = "1",
doi = "10.2174/1570159X14666160321123221",
language = "English (US)",
volume = "15",
pages = "57--70",
journal = "Current Neuropharmacology",
issn = "1570-159X",
publisher = "Bentham Science Publishers B.V.",
number = "1",

}

TY - JOUR

T1 - Therapeutic modulation of glutamate receptors in major depressive disorder

AU - Jaso, Brittany A.

AU - Niciu, Mark J.

AU - Iadarola, Nicolas D.

AU - Lally, Niall

AU - Richards, Erica

AU - Park, Minkyung

AU - Ballard, Elizabeth D.

AU - Nugent, Allison C.

AU - Machado-Vieira, Rodrigo

AU - Zarate, Carlos A.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Antagonist

KW - Glutamate

KW - Major depressive disorder (MDD)

KW - Metabotropic

KW - N-methyl-D-aspartate (NMDA)

KW - Negative allosteric modulator

KW - Positive allosteric modulator

KW - α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA)

UR - http://www.scopus.com/inward/record.url?scp=85011771231&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011771231&partnerID=8YFLogxK

U2 - 10.2174/1570159X14666160321123221

DO - 10.2174/1570159X14666160321123221

M3 - Review article

C2 - 26997505

AN - SCOPUS:85011771231

VL - 15

SP - 57

EP - 70

JO - Current Neuropharmacology

JF - Current Neuropharmacology

SN - 1570-159X

IS - 1

ER -