Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders.

Abstract

Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'.

• Authors: Gerard Sanacora, Giulia Treccani, Maurizio Popoli
• Journal: Neuropharmacology (Neuropharmacology) Vol. 62 Issue 1 Pg. 63-77 (Jan 2012) ISSN: 1873-7064 [Electronic] England
• PMID: 21827775 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antidepressive Agents
• Glucocorticoids
• Receptors, N-Methyl-D-Aspartate
• Glutamic Acid
• gamma-Aminobutyric Acid

Topics

• Animals
• Antidepressive Agents (pharmacology, therapeutic use)
• Brain (drug effects, metabolism)
• Drug Evaluation, Preclinical
• Glucocorticoids (metabolism)
• Glutamic Acid (metabolism)
• Humans
• Magnetic Resonance Spectroscopy
• Mood Disorders (drug therapy, metabolism, pathology)
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Synaptic Transmission (drug effects)
• gamma-Aminobutyric Acid (metabolism)