The DOI matches its Crossref record, with a small difference in title or year; 229 of the 229 references it cites were found in a registry or an index.
Towards a glutamate hypothesis of depression
Open accessAbstract
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'.
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In the citing paper
“Serotonin modulates glutamatergic transmission and might kindle N-methyl-D-aspartate (NMDA) receptor dependent plasticity (Bennett, 2010;Sanacora et al., 2012).”
From Serotonin and neuroplasticity – Links between molecular, functional and structural pathophysiology in depression (2017) · cites this paper as Sanacora et al., 2012
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“There are three broad disease models proposed by the literature to explain treatment resistance, summarised in Figure 5 (see eAppendix 3 for search details). 48–51”
From Treatment resistance in psychiatry: state of the art and new directions (2022) · cites this paper as [50]
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“There has been suggestion that glutamatergic neurotransmission is dysregulated in MDD.83,84”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [83]
In the citing paper
“Stress-induced dysfunction in forebrain excitatory transmission has led to the development of the excitatory synaptic transmission hypothesis of depression (22, 32, 33).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [32]
In the citing paper
“Interestingly, antidepressants are believed to exert one of the therapeutic effects by modulating the extracellular availability of this neurotransmitter [122,123,124,125].”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [123]
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“Altogether, there are substantial evidence that P2X7R modulates 5-HT, NA, glutamate, GABA and NO release, which are mechanisms consistently involved in stress and depression [123,129,130].”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [123]
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The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission
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Metadata
- Authors
- Sanacora, G., Treccani, G., & Popoli, M.
- Affiliations
- Yale University (US)
- University of Milan (IT)
- Corresponding author
- Popoli, Maurizio
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 62
- Issue
- 1
- Pages
- 63-77
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC3205453
- OpenAlex
- W72199885
- Cited by
- 1,036
- References
- 229
- Citations by year
- 2026: 48 · 2025: 61 · 2024: 66 · 2023: 74 · 2022: 80 · 2021: 80 · 2020: 89 · 2019: 67 · 2018: 62 · 2017: 66 · 2016: 83 · 2015: 90 · 2014: 71 · 2013: 55 · 2012: 38
- FWCI
- 6.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH081211, K02MH076222)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- depression, glutamate hypothesis, glutamatergic system, monoamine hypothesis, mood disorders, anxiety disorders, environmental stress, dendritic remodeling, synaptic loss, neuroplasticity, antidepressant mechanism, treatment-resistant depression, glutamate metabolism, limbic system
- MeSH terms
- Animals, Antidepressive Agents, Brain, Drug Evaluation, Preclinical, gamma-Aminobutyric Acid, Glucocorticoids, Humans, Synaptic Transmission, Magnetic Resonance Spectroscopy, Receptors, N-Methyl-D-Aspartate, Glutamic Acid, Mood Disorders
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