Towards a glutamate hypothesis of depression

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.

The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives

“…The so-called ‘tripartite' glutamate synapses encompass presynaptic and postsynaptic neurons and glia, and include several targets involved in the regulation of synaptic and extrasynaptic glutamate levels such as: excitatory amino acid transporters; postsynaptic density proteins; AMPA receptors; N-methyl- D -aspartate (NMDA) receptors; kainate receptors; and cognate metabotropic glutamate receptors [131,132]. Targets of the ‘tripartite glutamate synapse' have been implicated in the pathophysiology of mood disorders [24,132]. Recent trials have tested candidate glutamate modulators for TRD.…”

“…For instance, some glutamatergic compounds (e.g. ketamine) [24,25] as well as scopolamine (an anticholinergic agent) [26] have been tested with encouraging results in recent RCT. In addition, inflammatory and oxidative pathways are showing promise as novel treatment targets [27], with agents as diverse as pioglitazone [28], minocycline [29], celecoxib [28], N-acetylcysteine [28] and aspirin [30] showing evidence of utility.…”

Restraint stress differentially regulates inflammation and glutamate receptor gene expression in the hippocampus of C57BL/6 and BALB/c mice

“…Glutamate neurotransmission in the hippocampus is altered by stress exposure and produces behavioral changes relevant to psychiatric disorders (Sanacora et al, 2012). Here, stress differentially regulated the different classes of glutamate receptors in the two strains.…”

The role of the neuroendocrine and immune systems in the pathogenesis of depression

“…To summarize, the above results indicate that the 334 autoimmune response directed against 5-HT leads to sensitization [6,59,26]. 404 The release of these factors by monocytes has been described in 405 scientific publications by many authors [60][61][62] …”