Role of mTOR1 signaling in the antidepressant effects of ketamine and the potential of mTORC1 activators as novel antidepressants.
Taro Kato
Neuropharmacology February 1, 2023 DOI: 10.1016/j.neuropharm.2022.109325 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Antidepressants Glutamatergic signaling Mtorc1 |
| Key findings | The authors argue that mTORC1 signaling and the resulting increase in synapse formation in the medial prefrontal cortex play a key role in ketamine's rapid antidepressant effects, and propose that mTORC1 signaling itself could be a drug discovery target. |
Abstract
Conventional antidepressant medications act on monoaminergic systems and have important limitations, including a therapeutic delay of weeks to months and low rates of efficacy. Recently, clinical findings have indicated that ketamine, a dissociative anesthetic that blocks N-methyl-d-aspartate receptor channel activity, causes rapid and long-lasting antidepressant effects. Although the exact mechanisms underlying the antidepressant effects of ketamine are not fully known, preclinical studies have demonstrated a key role for mechanistic target of rapamycin complex 1 (mTORC1) signaling and a subsequent increase in synapse formation in the medial prefrontal cortex. In this review, we discuss the role of mTORC1 and its subsequent signaling cascade in the antidepressant effects of ketamine and other compounds with glutamatergic mechanisms of action. We also present the possibility that mTORC1 signaling itself is a drug discovery target.
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 9
- Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care. Anesthesiology August 1, 2024
- Early psilocybin intervention alleviates behavioral despair and cognitive impairment in stressed Wistar rats Progress in Neuro-Psychopharmacology and Biological Psychiatry 2025
- Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 8, 2024
- Psilocybin mitigates behavioral despair and cognitive impairment in treatment-resistant depression model using wistar kyoto rats. Scientific Reports May 26, 2025
- Ketamine - precursor of a new generation antidepressant drugs Farmacja Polska April 17, 2024
and 4 more in the library
Cites 23
- 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
- Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics Annual Review of Medicine October 23, 2014
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
and 18 more in the library