Adenosine as the metabolic common path of rapid antidepressant action: The coffee paradox

Yue, Luo, and colleagues discovered that adenosine signalling is the common underlying mechanism of rapid acting antidepressant therapies, unifying the effects of ketamine, ECT and acute intermittent hypoxia. They use genetically encoded sensors, along with extensive mechanistic dissection, to show that all three induce adenosine surges in mood-regulatory circuits via A1 and A2A receptor activation. The mechanism of action of ketamine primarily involves modulation of mitochondrial metabolism as opposed to NMDA receptor antagonism, thereby presenting the possibility for improvements in derivative products with better therapeutic indices. These outcomes offer a rational framework for gauging therapeutic benefit for depression and raise vexing questions about patterns of caffeine consumption in treatment resistant depression, specifically whether the chronic use has a protective effect or whether the acute use impedes treatment response.