Advances in Research on eEF2 as a Potential Target for Rapid-Acting Antidepressants

Rapid-acting antidepressants (RAADs) can alleviate depressive symptoms within hours and have opened a new therapeutic avenue for major depressive disorder, particularly treatment-resistant depression. Representative RAADs, such as ketamine and esketamine, exert their rapid antidepressant effects mainly by restoring glutamatergic/GABAergic balance, enhancing AMPA receptor-related signaling, activating the BDNF-TrkB-mTORC1 pathway, and promoting synaptic plasticity. In recent years, the eukaryotic elongation factor 2 kinase (eEF2K)/eukaryotic elongation factor 2 (eEF2) axis has attracted increasing attention as a key molecular link between receptor signaling and translational elongation. Previous studies have mainly focused on the canonical model in which inhibition of eEF2K and dephosphorylation of eEF2 relieve translational repression. However, this model does not fully account for the shared features of different RAADs in translational selectivity, spatiotemporal specificity, and multi-pathway convergence. Based on a systematic overview of the clinical and mechanistic advances in RAAD research, this review proposes an eEF2-centered analytical framework and highlights the potential roles of eEF2 in local translational control, brain-region-specific plasticity, and the convergence of multiple signaling pathways. This perspective may provide a useful framework for further mechanistic studies and for the exploration of novel therapeutic strategies targeting translational regulation.