Ketamine's mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine's antidepressant effects?
Brandi Quintanilla, Carlos A. Zarate, Anilkumar Pillai
Molecular Psychiatry September 1, 2024 DOI: 10.1038/s41380-024-02507-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Esketamine |
| Keywords | Mental health Immunology |
| Citations | 17 |
| Key findings | Ketamine's rapid antidepressant effects may involve regulation of neuroinflammation through the complement system, linking complement component 3 and glutamatergic modulation. |
Abstract
Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital for synaptic plasticity. The complement system has been implicated in the pathophysiology of depression, and studies have shown increases in complement component 3 (C3) expression in the prefrontal cortex of suicidal individuals with depression. Given the role of the complement system in depression, ketamine and the complement system's abilities to modulate glutamatergic transmission, and our current understanding of ketamine's anti-inflammatory properties, there is reason to suspect a common link between the complement system and ketamine's mechanism of action. This review will summarize ketamine's anti- inflammatory roles in the periphery and central nervous system, with an emphasis on complement system regulation.
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 7
- Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions Journal of Anesthesia and Translational Medicine July 11, 2024
- The Effect of Ketamine on the Immune System in Patients with Treatment-Resistant Depression International Journal of Molecular Sciences August 1, 2025
- Assessment of complement cascade components in patients with major depressive disorder. Brain, Behavior, and Immunity July 1, 2025
- Narrating the psychoneuroimmunomodulatory properties of serotonin 5-HT2A receptor psychedelics from a transdiagnostic perspective. Acta Neuropsychiatrica July 25, 2025
- Correlations between major depressive disorder, splenic morphology, and immune function. BMC Psychiatry May 12, 2025
and 2 more in the library
Cites 23
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. American Journal of Psychiatry March 29, 2019
and 18 more in the library