A commentary published in Brain Medicine by Drs. Julio Licinio and Ma-Li Wong examines groundbreaking research identifying adenosine signaling as the convergent mechanism underlying rapid-acting antidepressant therapies. The analysis synthesizes the recent Nature study by Yue and colleagues led by Professor Min-Min Luo, which unified the therapeutic effects of ketamine, electroconvulsive therapy, and acute intermittent hypoxia through adenosine surges in mood-regulatory brain circuits. The commentary explores how this metabolic mechanism operates independently of NMDA receptor antagonism, potentially enabling improved derivatives with better therapeutic indices. Most intriguingly, it raises questions about caffeine consumption patterns in treatment-resistant depression, distinguishing between potentially protective effects of chronic coffee drinking and possible interference from acute pre-treatment consumption. This provides a framework for understanding how disparate interventions achieve rapid antidepressant effects.