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 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.

• Authors: Mark J Niciu, Dawn F Ionescu, Erica M Richards, Carlos A Zarate Jr
• Journal: Journal of neural transmission (Vienna, Austria : 1996) (J Neural Transm (Vienna)) Vol. 121 Issue 8 Pg. 907-24 (Aug 2014) ISSN: 1435-1463 [Electronic] Austria
• PMID: 24318540 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antidepressive Agents
• Biomarkers, Pharmacological
• Excitatory Amino Acid Agents
• Receptors, Glutamate
• Glutamic Acid
• Ketamine

Topics

• Animals
• Antidepressive Agents (pharmacology, therapeutic use)
• Biomarkers, Pharmacological (metabolism)
• Depressive Disorder, Major (drug therapy, genetics, immunology, physiopathology)
• Excitatory Amino Acid Agents (pharmacology, therapeutic use)
• Glutamic Acid (metabolism)
• Humans
• Ketamine (pharmacology, therapeutic use)
• Receptors, Glutamate (metabolism)