Adenosine signalling drives antidepressant actions of ketamine and ECT
Chenyu Yue, Nan Wang, Haojiang Zhai, Zhengwei Yuan, Yuting Cui, Jing Quan, Yu Zhou, Xiaofeng Fan, Hongshuang Wang, Zhao-Fa Wu, Huijie Mi, Woo-Ping Ge, Yulong Li, Xiaohui Wang, Minmin Luo
Nature November 5, 2025 DOI: 10.1038/s41586-025-09755-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study (mouse models) Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine electroconvulsive therapy ketamine derivatives acute intermittent hypoxia |
| Topics | Esketamine Ketamine |
| Citations | 22 |
| Key findings | Adenosine signaling is a central mediator of the antidepressant effects of ketamine and electroconvulsive therapy. |
Abstract
Ketamine and electroconvulsive therapy (ECT) achieve rapid remission in treatment-resistant depression. However, their mechanisms of action—the understanding of which is essential for refining therapeutic precision—remain unclear1, 2–3. Here, using mouse models, we identify adenosine signalling as a central pathway that underlies the antidepressant effects of these interventions. Results from genetically encoded adenosine sensor experiments and real-time optical recordings reveal that both therapies induce strong adenosine surges in key mood-regulatory regions, including the medial prefrontal cortex and the hippocampus. Genetic or pharmacological disruption of A1 and A2A adenosine receptors abolishes their therapeutic effects, which establishes the essential role of adenosine signalling in antidepressant efficacy. Notably, adenosine signalling specifically in the medial prefrontal cortex drives antidepressant actions. Ketamine increases adenosine by modulating cellular metabolism to increase intracellular adenosine levels without causing neuronal hyperactivity. Leveraging this mechanism, we develop ketamine derivatives that enhance adenosine signalling and exhibit improved antidepressant efficacy with reduced side effects at therapeutic doses. Furthermore, acute intermittent hypoxia, a non-pharmacological intervention involving controlled reductions in oxygen levels, increases brain adenosine levels and produces antidepressant effects, paralleling the actions of ketamine and ECT. Our findings establish adenosine as a pivotal mediator of rapid-acting antidepressants and a tractable target for scalable, noninvasive therapeutics in major depressive disorder. Adenosine signalling is identified as the central mechanism of action of the antidepressant effects of ketamine and electroconvulsive therapy, and newly developed analogues of ketamine exhibit improved antidepressant efficacy with reduced side effects.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| 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 Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 13
- Adenosine as the metabolic common path of rapid antidepressant action: The coffee paradox. Brain medicine December 31, 2025
- Ketamine as a Rapid-Acting Antidepressant: A Scoping Review of Mechanisms and Efficacy in Treatment-Resistant Depression. Psychopathology March 27, 2026
- Ketamine for comorbid treatment-resistant depression and substance use disorders: balancing risks and opportunities Pharmacological Reports March 11, 2026
- Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy Frontiers in Molecular Neuroscience October 21, 2026
- Psychoplastogens to Reduce Persistent Cognitive Symptoms for Traumatic Brain Injury as a Chronic Condition Journal of Neurotrauma October 19, 2026
and 8 more in the library
Cites 13
- 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
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
and 8 more in the library