Adenosine signalling drives antidepressant actions of ketamine and ECT

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.