The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology February 1, 2026 Dongsun Park, Gwangho Lee, Bokyum Kim et al. 1 citation
Ketamine works as a rapid antidepressant by enhancing synaptic plasticity in the hippocampus, not by normalizing stress hormone systems. It acts through multiple mechanisms including blocking NMDA receptors, activating BDNF-TrkB signaling, and promoting adult neurogenesis. These hippocampal changes coordinate with other brain regions like the medial prefrontal cortex and lateral habenula. The review synthesizes evidence that ketamine's therapeutic effects are separate from HPA axis function, shifting focus from neuroendocrine models to circuit-level plasticity. This framework suggests new strategies for developing fast-acting antidepressants.