Adenosine on the common path of rapid antidepressant action: The coffee paradox
6 days ago
- #ketamine
- #adenosine
- #antidepressant
- Adenosine signaling is identified as the common mechanism underlying rapid-acting antidepressant therapies like ketamine, ECT, and acute intermittent hypoxia.
- Ketamine's antidepressant effect is primarily due to mitochondrial metabolism modulation, not NMDA receptor antagonism, suggesting potential for improved derivatives with better therapeutic indices.
- Genetically encoded sensors reveal adenosine surges in mood-regulatory circuits (mPFC and hippocampus) following ketamine, ECT, and acute intermittent hypoxia, with specific kinetics for each intervention.
- Adenosine receptor knockouts (A1 and A2A) abolish antidepressant effects, and pharmacological blockade confirms adenosine's necessity and sufficiency for rapid antidepressant action.
- Ketamine modulates mitochondrial function to increase intracellular adenosine, which exits via equilibrative nucleoside transporters (ENT1/2), without inducing neuronal hyperactivity.
- Derivatives like deschloroketamine (DCK) show stronger adenosine signals and improved therapeutic indices, dissociating NMDAR antagonism from therapeutic effects.
- ECT and acute intermittent hypoxia (aIH) also rely on adenosine signaling, with aIH offering a non-invasive, scalable alternative for low-resource settings.
- Chronic caffeine consumption may protect against depression via adenosine receptor upregulation, but acute intake could interfere with treatment response by antagonizing adenosine receptors.
- Key unanswered questions include the link between acute adenosine surges and sustained plasticity, hippocampal functional heterogeneity, and clinical heterogeneity in treatment-resistant depression.
- The study provides a framework for rational development of adenosine-targeted therapies, including optimized compounds, non-pharmacological interventions, and biomarker-driven patient stratification.