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

Yong‐Ku Kim, Kyoung-Sae Na

Progress in Neuro-Psychopharmacology and Biological Psychiatry October 3, 2016 DOI: 10.1016/j.pnpbp.2016.03.009 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Review Peer reviewed
Intervention Ketamine
Topics Depression Ketamine
Keywords Glia Glutamate receptors Neuroinflammation
Key findings The authors propose that TRD involves extrasynaptic glutamatergic signaling, glial dysfunction, early life adversity, and glucocorticoid receptor dysfunction acting in complex cross-talk, rather than excitotoxicity alone. They argue that because inflammatory mediators like pro-inflammatory cytokines are not specific to depression, more disease-specific mechanisms are needed, and that ketamine's long-lasting effectiveness and adverse events remain inadequately demonstrated.

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.

Comparable studies

Other narrative reviews on ketamine for depression, most cited first.

Study Year Design Participants
Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression 2021 Review
Ketamine: a paradigm shift for depression research and treatment 2019 Review
Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective 2019 Review
Ketamine: A tale of two enantiomers 2020 Review
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor 2021 Review

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