The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity
M. J. Kang, Emily R. Hawken, Gustavo Vazquez
Frontiers in Psychiatry April 25, 2022 DOI: 10.3389/fpsyt.2022.860882 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Patients with major depressive disorder or bipolar disorder, including treatment-resistant depression, plus animal models and cell cultures |
| Topics | Esketamine Ketamine Neuroplasticity |
| Key findings | Accumulating evidence supports that ketamine induces increases in molecules involved in modulating neuroplasticity, paired with rapid antidepressant effects. |
Abstract
The mechanism of action underlying ketamine’s rapid antidepressant effects in patients with depression, both suffering from major depressive disorder (MDD) and bipolar disorder (BD), including treatment resistant depression (TRD), remains unclear. Of the many speculated routes that ketamine may act through, restoring deficits in neuroplasticity may be the most parsimonious mechanism in both human patients and preclinical models of depression. Here, we conducted a literature search using PubMed for any reports of ketamine inducing neuroplasticity relevant to depression, to identify cellular and molecular events, relevant to neuroplasticity, immediately observed with rapid mood improvements in humans or antidepressant-like effects in animals. After screening reports using our inclusion/exclusion criteria, 139 publications with data from cell cultures, animal models, and patients with BD or MDD were included (registered on PROSPERO, ID: CRD42019123346). We found accumulating evidence to support that ketamine induces an increase in molecules involved in modulating neuroplasticity, and that these changes are paired with rapid antidepressant effects. Molecules or complexes of high interest include glutamate, AMPA receptors (AMPAR), mTOR, BDNF/TrkB, VGF, eEF2K, p70S6K, GSK-3, IGF2, Erk, and microRNAs. In summary, these studies suggest a robust relationship between improvements in mood, and ketamine-induced increases in molecular neuroplasticity, particularly regarding intracellular signaling molecules.
Comparable studies
Other systematic reviews and meta-analyses on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics Systematic review of 20 studies (16 preclinical, 4 clinical) | 2021 | Systematic review | |
| Neurobiological Changes Induced by Mindfulness and Meditation: A Systematic Review. | 2024 | Systematic review | |
| Mindfulness-Based Cognitive Therapy in Clinical Practice: A Systematic Review of Neurocognitive Outcomes and Applications for Mental Health and Well-Being. | 2025 | Systematic review | |
| Psychedelic-Induced Neural Plasticity: A Comprehensive Review and a Discussion of Clinical Implications. | 2025 | Systematic review | |
| Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD. | 2025 | Systematic review |
Citations in the library
Cited by 46
- Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment‐resistant depression Bipolar Disorders January 13, 2023
- Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. International Journal of Molecular Sciences December 5, 2024
- 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
- The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine International Journal of Molecular Sciences November 23, 2022
- Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine-A 10-Year Systematic Review. Pharmaceuticals May 18, 2025
and 41 more in the library
Cites 61
- 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
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- 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 56 more in the library