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Review
, 62 (1), 63-77

Towards a Glutamate Hypothesis of Depression: An Emerging Frontier of Neuropsychopharmacology for Mood Disorders

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Review

Towards a Glutamate Hypothesis of Depression: An Emerging Frontier of Neuropsychopharmacology for Mood Disorders

Gerard Sanacora et al. Neuropharmacology.

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'.

Figures

Figure 1
Figure 1
Summary of MRI studies measuring volumetric changes in hippocampus in major depressive disorder. Values represent the calculated Cohen’s d effect size of changes from mean total hippocampal volume. Error bars indicate 95% confidence intervals. From Koolschijn et al., 2009.
Figure 2
Figure 2
Dendritic remodeling in hippocampus (Dentate Gyrus and CA3) and prefrontal cortex in a 6 weeks chronic mild stress (CMS) protocol. These effects were reversed by treatment with different antidepressant agents (imipramine; fluoxetine; CP 156,526; SSR 149415), administered during the last 2 weeks of CMS. Three-dimensional morphometric analysis of Golgi-impregnated neurons using computer-assisted reconstructions of hippocampal and medial prefrontal cortex neurons. Representative dentate granule (a), CA3 pyramidal (b), and layer II/III pyramidal neurons from prelimbic area of medial prefrontal cortex (c). Cells are depicted in the x-y orthogonal plan. Adapted from Bessa et al., 2009.
Figure 3
Figure 3
The effects of stress and glucocorticoids on glutamate synapses and neurotransmission. Several sites/mechanisms of regulation of the glutamate synapse have been shown to be targets of stress and hormones released in the stress response (glucocorticoids): (1) presynaptic release of glutamate; (2) postsynaptic ionotropic receptors for glutamate (NMDA and AMPA receptors); (3) reuptake of glutamate by glial glutamate membrane transporters; (4) glutamate metabolism and recycling by the glutamate/glutamine cycle. Major consequences of stress/glucocorticoid exposure on these sites/mechanisms are: (1) increased glutamate release; (2) altered trafficking/expression/function of ionotropic glutamate receptors; (3) altered clearing of glutamate from the synapse; (4) reduced glutamate/glutamine cycling and glial cell density (see section 7). Adapted from Sanacora et al., 2008.

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