Adenosine as the metabolic common path of rapid antidepressant action: The coffee paradox.
Brain medicine : from neurons to behavior and better health – December 31, 2025
Source: PubMed
Summary
A unifying mechanism for rapid-acting antidepressants has been uncovered: adenosine signaling. Ketamine, ECT, and acute intermittent hypoxia all trigger adenosine surges by activating A1 and A2A receptors in mood-regulating brain circuits. This suggests ketamine's antidepressant effects stem from mitochondrial metabolism modulation, not just NMDA receptor antagonism, paving the way for improved therapies for depression. The findings also prompt critical questions about how chronic caffeine or coffee consumption might impact treatment response or offer protection in treatment-resistant depression.
Abstract
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.