Crosstalk Between Inflammation and Glutamate System in Depression: Signaling Pathway and Molecular Biomarkers for Ketamine's Antidepressant Effect.
Wenyan Cui, Yuping Ning, Wu Hong, Ju Wang, Zhening Liu, Ming Li
Molecular Neurobiology May 2019 DOI: 10.1007/s12035-018-1306-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Depression Esketamine Ketamine |
| Keywords | Biomarkers Inflammation |
| Key findings | The authors propose that inflammation contributes to depression pathogenesis by influencing glutamate release, transmission, and metabolism, causing accumulated extracellular glutamate, and that the mTOR pathway downstream of glutamate receptors mediates ketamine's antidepressant effect via improved neurogenesis and plasticity. They attribute inconsistent findings on inflammatory biomarkers of ketamine response at least partly to depression heterogeneity, limited sample size, and gene-environment interactions, and suggest targeting persistent inflammation and key mediator molecules may yield new therapeutic strategies. |
Abstract
Depression is a worldwide illness with a significant impact on both family and society. Conventional antidepressants are ineffective for more than 30% of patients. In such patients, who have what is called treatment-resistant depression (TRD), inflammatory biomarkers are expressed excessively in both the central nervous system (CNS) and the peripheral blood. Ketamine, a glutamate receptor antagonist, exerts a rapid and sustained therapeutic effect in patients with TRD. Thus, the investigation of the relations between inflammation and glutamate underlying depression has drawn great attention. Inflammation influences glutamate release, transmission, and metabolism, resulting in accumulated extracellular glutamate in the CNS. Downstream of the glutamate receptors, the mammalian target of rapamycin (mTOR) signaling pathway plays a key role in mediating ketamine's antidepressant effect by improving neurogenesis and plasticity. Based on the mechanism and clinical evidence of the inflammatory contribution to the pathogenesis of depression, extensive research has been devoted to inflammatory biomarkers of the clinical response of depression to ketamine. The inconsistent findings from the biomarker investigations are at least partially attributable to the heterogeneity of depression, limited sample size, and complex gene-environment interactions. Deep exploration of the clinical observations and the underlying mechanism of ketamine's antidepressant response can provide new insights into the selection of specific groups of depressed patients for ketamine treatment and to aid in monitoring the therapeutic effect during antidepressant medication. Further, targeting persistent inflammation in patients with TRD and the key molecules mediating ketamine's antidepressant effect may encourage the development of novel therapeutic strategies.
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 |
Citations in the library
Cited by 16
- Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature Brain Sciences June 27, 2021
- Targeting inflammation in depression: Ketamine as an anti-inflammatory antidepressant in psychiatric emergency Brain, Behavior, & Immunity - Health November 1, 2021
- Antidepressant Effect of Ketamine on Inflammation‐Mediated Cytokine Dysregulation in Adults with Treatment‐Resistant Depression: Rapid Systematic Review Oxidative Medicine and Cellular Longevity 2022
- The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics. Neurochemical Research April 1, 2023
- NMDA receptor modulation by Esculetin: Investigating behavioral, biochemical and neurochemical effects in schizophrenic mice model. Saudi Pharmaceutical Journal April 1, 2024
and 11 more in the library
Cites 19
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
and 14 more in the library