ArticleMolecular psychiatry2016
Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation.
Article in Molecular psychiatry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02892916 (The Prevention of Post Operative Cognitive Dysfunction by Ketamine), which is not on this map. Cited by 43 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Prevention of Post Operative Cognitive Dysfunction by Ketamine: a Prospective Multicenter Randomized Blinded Placebo-controlled Trial in Elderly Patients Undergoing Elective Orthopaedic Surgery
Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity.Frontiers in psychiatry · 2022Pooled it
- Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2020Trial
- Esketamine/Ketamine: Dual-Action Mechanisms and Clinical Prospects beyond Anesthesia in Psychiatry, Immunology, and Oncology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.Cell reports · 2025Article
- Implications of neurogenesis in depression through BDNF: rodent models, regulatory pathways, gut microbiota, and potential therapy.Molecular psychiatry · 2025Review
- Differential effects of statins on the anti-dyskinetic activity of sub-anesthetic ketamine.Neuroscience letters · 2025Article
- Differential effects of opioid receptor antagonism on the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine treatment in a preclinical model.Neuropharmacology · 2024Article
- Article
- Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival.Cell death & disease · 2024Article
- TBL1X: At the crossroads of transcriptional and posttranscriptional regulation.Experimental hematology · 2022Review
- The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model.Translational psychiatry · 2022Review
- A high-affinity cocaine binding site associated with the brain acid soluble protein 1.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.Haematologica · 2021Article
- Glucose metabolic crosstalk and regulation in brain function and diseases.Progress in neurobiology · 2021Review
- miR-129-5p Ameliorates Ischemic Brain Injury by Binding to SIAH1 and Activating the mTOR Signaling Pathway.Journal of molecular neuroscience : MN · 2021Article
- Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule.World journal of psychiatry · 2021Review
- Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis.PloS one · 2021Article
- (2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy.Neuropsychiatric disease and treatment · 2021Article
- Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant.Frontiers in pharmacology · 2021Review
- Case Report: Repeated Series of Ketamine Infusions in Patients With Treatment-Resistant Depression: Presentation of Five Cases.Frontiers in psychiatry · 2021Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
As traditional antidepressants act only after weeks/months, the discovery that ketamine, an antagonist of glutamate/N-methyl-D-aspartate (NMDA) receptors, elicits antidepressant actions in hours has been transformative. Its mechanism of action has been elusive, though enhanced mammalian target of rapamycin (mTOR) signaling is a major feature. We report a novel signaling pathway wherein NMDA receptor activation stimulates generation of nitric oxide (NO), which S-nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb, a small G protein that activates mTOR. Siah1 degrades Rheb leading to reduced mTOR signaling, while ketamine, conversely, stabilizes Rheb that enhances mTOR signaling. Drugs selectively targeting components of this pathway may offer novel approaches to the treatment of depression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.