The mystery of why ketamine and electroconvulsive therapy work so rapidly for severe depression may finally be solved, with profound implications for developing safer treatments that bypass ketamine's dissociative effects and ECT's cognitive disruption. Using real-time brain imaging in mouse models, researchers discovered that both interventions trigger massive adenosine surges specifically in the medial prefrontal cortex and hippocampus—regions critical for mood regulation. When adenosine A1 and A2A receptors were blocked genetically or pharmacologically, both treatments lost their antidepressant power entirely, confirming adenosine as the essential mediator. The prefrontal cortex emerged as the key target, with adenosine activity in this region alone sufficient to drive therapeutic effects. Ketamine achieves this through a previously unknown metabolic pathway that boosts intracellular adenosine without the neuronal hyperexcitation typically associated with its mechanism. This discovery enabled the team to engineer ketamine derivatives with enhanced adenosine signaling that showed superior antidepressant efficacy at lower doses with fewer side effects. Perhaps most intriguingly, they demonstrated that controlled intermittent hypoxia—brief, carefully managed reductions in oxygen—similarly elevates brain adenosine and produces antidepressant effects comparable to ketamine and ECT. This adenosine-centered understanding represents a potential paradigm shift in depression treatment, moving beyond the serotonin hypothesis that has dominated for decades. The metabolic approach could lead to treatments that harness the brain's natural adenosine systems without ketamine's abuse potential or ECT's memory effects, offering hope for millions with treatment-resistant depression.