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 language | English (US) |
|---|---|
| Pages (from-to) | 907-924 |
| Number of pages | 18 |
| Journal | Journal of Neural Transmission |
| Volume | 121 |
| Issue number | 8 |
| DOIs | |
| State | Published - Dec 8 2013 |
| Externally published | Yes |
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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 journal › Article
}
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 -