Adenosine signalling drives antidepressant actions of ketamine and ECT

Summary

Adenosine signaling is identified as the central mechanism underlying the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT). Experiments in mice using genetically encoded adenosine sensors and real-time optical recordings show that both therapies cause strong adenosine surges in mood-regulatory brain regions such as the medial prefrontal cortex and hippocampus. Disrupting A1 and A2A adenosine receptors genetically or pharmacologically abolishes the therapeutic effects, establishing adenosine's essential role. Ketamine increases adenosine by modulating cellular metabolism without causing neuronal hyperactivity. Newly developed ketamine derivatives that enhance adenosine signaling show improved antidepressant efficacy with fewer side effects. Acute intermittent hypoxia, a non-pharmacological intervention, also increases brain adenosine and produces antidepressant effects, paralleling ketamine and ECT.

Study at a glance

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.