title: 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.affiliation: Department of Psychiatry, Clinical Neuroscience Research Unit, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Sanacora
authors.forename: Giulia
authors.initials: G
authors.lastname: Treccani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Popoli
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D005938:Glucocorticoids / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D019964:Mood Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D005938:Glucocorticoids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid