Adenosine surges: A step forward in understanding antidepressant actions of ketamine

The discovery that a single subanesthetic dose of (R,S)-ketamine induces rapid and long-lasting antidepressant effects by a completely different mechanism represents one of the most substantial breakthroughs in depression pharmacotherapy. The recent study in Nature by Yue and colleagues represents a significant conceptual and technical advance by identifying NMDA-independent transient adenosine surges as a convergent mechanism underlying these actions [ 1 ]. For decades, the delayed onset of conventional monoaminergic antidepressants shaped both clinical expectations and mechanistic hypotheses, reinforcing the idea that meaningful antidepressant efficacy necessarily requires weeks of molecular and synaptic remodeling [ 2 ]. However, the discovery of (R,S)-ketamine’s instant antidepressant action not only addressed an unmet clinical need but also uncovered fundamental new insights into the neurobiology of depression. The role of purinergic signaling and specific receptors subtypes, including adenosine receptors, have frequently been linked with neuropsychiatric and mood disorders [ 3 , 4 ]. The prevailing model emphasizes glutamatergic disinhibition as the primary substrate of ketamine’s antidepressant efficacy, in which the blockade of NMDA receptors on inhibitory interneurons transiently reduces GABAergic tone, leading to a burst in glutamate release and increased excitatory drive [ 5 ]. This enhanced neuronal excitation promotes brain-derived neurotrophic factor (BDNF) release in the synaptic cleft, which in turn triggers downstream signaling pathways required for the formation, maturation, and function of new synapses [ 2 ]. However, in this context, it is noteworthy that disinhibitory effects like ketamine action can also be elicited by the NMDA receptor antagonist memantine without resulting in antidepressant actions [ 2 ]. There is, indeed, accumulating evidence demonstrating that ketamine’s molecular targets extend beyond the antagonism of NMDA receptors [ 2 ]. Yue and colleagues provide evidence that ketamine and ECT trigger fast surges in extracellular adenosine within the medial prefrontal cortex (PFC). While the work of Yue and colleagues identify the PFC as the primary site, clinical effects likely involves a broader network, such as the hippocampus which has previously been implicated in ketamine-mediated adenosine mechanisms [ 6 ].