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

Abstract

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 break-throughs in depression pharmacotherapy. The recent study in Nature by Yue and colleagues represents a signi fi cant 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 ef fi cacy 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 speci fi c 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 ef fi cacy, 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