Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression
August P. M. Lullau, E. Haga, E. Ronold, G. Dwyer
Frontiers in Neuroscience August 8, 2023 DOI: 10.3389/fnins.2023.1223145 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Longitudinal Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Esketamine Ketamine |
| Key findings | The authors propose that depression involves four interacting neuroprogressive elements—stress, inflammation, neurotoxicity, and neurodegeneration—and argue that ketamine acts on all of these levels, producing rapid and potent reductions in depressive symptoms while increasing stress resilience, modulating inflammation, attenuating neurotoxic processes, and facilitating synaptogenesis. They caution that ketamine's mechanisms and the durability of its effects remain insufficiently understood. |
Abstract
Concurrent with recent insights into the neuroprogressive nature of depression, ketamine shows promise in interfering with several neuroprogressive factors, and has been suggested to reverse neuropathological patterns seen in depression. These insights come at a time of great need for novel approaches, as prevalence is rising and current treatment options remain inadequate for a large number of people. The rapidly growing literature on ketamine’s antidepressant potential has yielded multiple proposed mechanisms of action, many of which have implications for recently elucidated aspects of depressive pathology. This review aims to provide the reader with an understanding of neuroprogressive aspects of depressive pathology and how ketamine is suggested to act on it. Literature was identified through PubMed and Google Scholar, and the reference lists of retrieved articles. When reviewing the evidence of depressive pathology, a picture emerges of four elements interacting with each other to facilitate progressive worsening, namely stress, inflammation, neurotoxicity and neurodegeneration. Ketamine acts on all of these levels of pathology, with rapid and potent reductions of depressive symptoms. Converging evidence suggests that ketamine works to increase stress resilience and reverse stress-induced dysfunction, modulate systemic inflammation and neuroinflammation, attenuate neurotoxic processes and glial dysfunction, and facilitate synaptogenesis rather than neurodegeneration. Still, much remains to be revealed about ketamine’s antidepressant mechanisms of action, and research is lacking on the durability of effect. The findings discussed herein calls for more longitudinal approaches when determining efficacy and its relation to neuroprogressive factors, and could provide relevant considerations for clinical implementation.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| 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 Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 18
- Rapid and sustained antidepressant effects of intravenous ketamine in treatment-resistant major depressive disorder and suicidal ideation: a randomized clinical trial. BMC Psychiatry May 7, 2024
- Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression. Pharmacological Research 2025
- Treatment-resistant depression and intranasal esketamine: Spanish consensus on theoretical aspects Frontiers in Psychiatry August 4, 2025
- Lessons learned from the regulatory alignment in ketamine, esketamine and arketamine clinical trials: A cross-sectional analysis of protocols from ClinicalTrials.gov. Psychiatry Research August 1, 2025
- Can ketamine therapy overcome treatment-resistant depression in Alzheimer's disease and older adults? Preclinical and clinical evidence. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 1, 2025
and 13 more in the library
Cites 39
- 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
- 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
- The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis American Journal of Psychiatry October 3, 2017
- A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists Philosophical transactions of the Royal Society of London. Series B, Biological sciences July 23, 2012
and 34 more in the library