The Adenosine Pathway: a Unified Mechanism for Rapid Antidepressant Action and Precision Therapy
YUE Chenyu, LUO Minmin*
MDD (major depressive disorder) remains a major global health challenge, with conventional antidepressants often exhibiting delayed onset and limited efficacy. Rapid-acting interventions like ketamine and ECT (electroconvulsive therapy) offer promise, yet their underlying mechanisms have been unclear. The traditional hypothesis holds that ketamine acts primarily by blocking NMDA (N-methyl-D-aspartate) receptors; however, this view cannot fully explain its complex biological effects, and drug development based on this target has repeatedly encountered setbacks. Centered on a recent study published in Nature, this article systematically reviews the scientific journey toward identifying a unified mechanism for rapid antidepressant action. This work demonstrates for the first time that the rapid antidepressant effects of both pharmacological (ketamine) and physical (ECT) interventions are driven by a common downstream pathway—the adenosine signaling pathway in the mPFC (medial prefrontal cortex). This article elaborats on the key experimental evidence supporting this discovery and proposes a novel conceptual framework: ketamine acts as a “metabolic neuromodulator” that directly targets mitochondria, triggering a controlled perturbation of cellular energy metabolism. This metabolic signal is then “amplified” by the adenosine system and translated into potent neural modulation and antidepressant effects. Building on this mechanism, this article further discusses how this new understanding can guide phenotypic drug discovery and the development of non‑pharmacological intervention strategies (such as acute intermittent hypoxia) to dissociate therapeutic effects from side effects. Finally, this article offers a perspective on a future of precision MDD treatment centered on the “metabolic‑neural axis”, including the development of biomarkers, individualized neuromodulation, and integrated therapeutic paradigms.
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