Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant
Songbai Xu, Xiaoxiao Yao, Bingjin Li, R. Cui, Cuilin Zhu, Yao Wang, Wei Yang
Frontiers in Pharmacology July 7, 2022 DOI: 10.3389/fphar.2021.740996 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Citations | 50 |
| Key findings | Ketamine's antidepressant-like actions may involve potentiation of AMPA receptor transmission, activation of BDNF/TrkB and mTOR pathways, and restoration of excitatory/inhibitory balance in neural circuits. |
Abstract
Major depressive disorder (MDD) is a devastating psychiatric disorder which exacts enormous personal and social-economic burdens. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been discovered to exert rapid and sustained antidepressant-like actions on MDD patients and animal models. However, the dissociation and psychotomimetic propensities of ketamine have limited its use for psychiatric indications. Here, we review recently proposed mechanistic hypotheses regarding how ketamine exerts antidepressant-like actions. Ketamine may potentiate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR)-mediated transmission in pyramidal neurons by disinhibition and/or blockade of spontaneous NMDAR-mediated neurotransmission. Ketamine may also activate neuroplasticity- and synaptogenesis-relevant signaling pathways, which may converge on key components like brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) and mechanistic target of rapamycin (mTOR). These processes may subsequently rebalance the excitatory/inhibitory transmission and restore neural network integrity that is compromised in depression. Understanding the mechanisms underpinning ketamine’s antidepressant-like actions at cellular and neural circuit level will drive the development of safe and effective pharmacological interventions for the treatment of MDD.
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 23
- Measuring acute effects of subanesthetic ketamine on cerebrovascular hemodynamics in humans using TD-fNIRS. Scientific Reports July 19, 2023
- Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD. Psychopharmacology June 1, 2025
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
- The Use of Ketamine for the Treatment of Anhedonia in Depression. CNS Drugs August 1, 2024
- A Systematic Review on Ketamine and Esketamine for Treatment-Resistant Depression and Suicidality in Adolescents: A New Hope? Children (Basel, Switzerland) June 29, 2024
and 18 more in the library
Cites 44
- 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
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
and 39 more in the library