Towards a glutamate hypothesis of depression

By G. Sanacora, G. Treccani, M. Popoli. Neuropharmacology, 2011

1,036 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Pharmacology

View Paper: https://www.semanticscholar.org/paper/99d9a611b6ba0219e88877f5b75a316ed5e26a6e

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In Cellular and Molecular Neuroscience

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Citations in the corpus

Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments (2019, background): “Findings of abnormalities within the glutamate and GABA systems in the brains of individuals with mood disorders have led to new theories on the pathophysiology and treatment of these disorders (Abdallah et al., 2014; Fee et al., 2017; Sanacora et al., 2012) (Figure 1).”
Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications (2013, background): “The efficacy of N-Methyl-D-aspartate (NMDA) receptor antagonist drugs, such as ketamine, in rapid antidepressant responses has prompted much attention to the role of glutamate in the pathophsyiology of depression (Sanacora et al., 2012).”
Understanding resilience (2013, background): “…training can improve Frontiers in Behavioral Neuroscience www.frontiersin.org February 2013 | Volume 7 | Article 10 | 4 the quality of parenting, family function, and attachment relationship, and in turn promote adaptive functioning and resilience in children and youth (Sapienza and Masten, 2011).”