Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression

Kim, Yong-Ku; Na, Kyoung-Sae

doi:10.1016/j.pnpbp.2016.03.009

Cited by 84Treatment of Major DepressionTryptophan and brain disordersNeuroscience and Neuropharmacology Research

Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression

Kim, Yong-Ku, Na, Kyoung-Sae·2016·Progress in Neuro-Psychopharmacology and Biological Psychiatry

DOI 10.1016/j.pnpbp.2016.03.009

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Abstract

Treatment-resistant depression (TRD) causes substantial socioeconomic burden. Although a consensus on the definition of TRD has not yet been reached, it is certain that classic monoaminergic antidepressants are ineffective for TRD. One decade ago, many researchers found ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, to be an alternative to classic monoaminergic antidepressants. The major mechanisms of action of ketamine rapidly induce synaptogenesis in the brain-derived neurotrophic factor (BDNF) pathway. Although excessive glutamatergic neurotransmission and consequent excitotoxicity were considered a major cause of TRD, recent evidence suggests that the extrasynaptic glutamatergic receptor signal pathway mainly contributes to the detrimental effects of TRD. Glial cells such as microglia and astrocytes, early life adversity, and glucocorticoid receptor dysfunction participate in complex cross-talk. An appropriate reuptake of glutamate at the astrocyte is crucial for preventing 'spill-over' of synaptic glutamate and binding to the extrasynaptic NMDA receptor. Excessive microglial activation and the inflammatory process cause astrocyte glutamatergic dysfunction, which in turn activates microglial function. Early life adversity and glucocorticoid receptor dysfunction result in vulnerability to stress in adulthood. A maladaptive response to stress leads to increased glutamatergic release and pro-inflammatory cytokines, which then activate microglia. However, since the role of inflammatory mediators such as pro-inflammatory cytokines is not specific for depression, more disease-specific mechanisms should be identified. Last, although much research has focused on ketamine as an alternative antidepressant for TRD, its long-lasting effectiveness and adverse events have not been rigorously demonstrated. Additionally, evidence suggests that substantial brain abnormalities develop in ketamine abusers. Thus, more investigations for ketamine and other novel glutamatergic agents are needed.

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Excessive glutamate release can induce neurotoxic effects, including excessive activation of NMDA receptors and oxidative stress, contributing to the development of depression-like behaviors.
“Excessive glutamate release can induce neurotoxic effects, including excessive activation of NMDA receptors and oxidative stress, contributing to the development of depression-like behaviors”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [51]
Treatment with the rapidly acting antidepressant ketamine was able to increase plasma BDNF levels to the level of healthy controls.
“Treatment with the rapidly acting antidepressant ketamine was able to increase plasma BDNF levels to the level of healthy controls [71, 72].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [72]

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Authors: Kim, Y.-K., & Na, K.-S.
Affiliations: Korea University Ansan Hospital (KR)
Gachon University Gil Medical Center (KR)
Corresponding author: Na, Kyoung-Sae
ORCID: Kim, Yong-Ku
Na, Kyoung-Sae
Venue: Progress in Neuro-Psychopharmacology and Biological Psychiatry
Publisher: Elsevier BV
Published: 2016-10
Volume: 70
Pages: 117-126
ISSN: 0278-5846 (ISSN-L)
DOI: 10.1016/j.pnpbp.2016.03.009
OpenAlex: W2332640807
Cited by: 84
References: 167
Citations by year: 2026: 7 · 2025: 10 · 2024: 13 · 2023: 7 · 2022: 6 · 2021: 2 · 2020: 9 · 2019: 9 · 2018: 15 · 2017: 4 · 2016: 2
FWCI: 1.14
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: treatment-resistant depression, glutamate receptors, extrasynaptic NMDA receptors, microglia, astrocytes, brain-derived neurotrophic factor, ketamine, glutamatergic neurotransmission, excitotoxicity, childhood adversity, inflammatory cytokines, neuroinflammation, stress response, glutamate uptake, antidepressant mechanism
MeSH terms: Animals, Humans, Neuroglia, Receptors, Glutamate, Depressive Disorder, Treatment-Resistant

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Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression

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