Ketamine and psilocybin both provide rapid relief from major depressive disorder by enhancing synaptic plasticity in mood-regulating circuits, but through distinct initial mechanisms: ketamine blocks NMDA receptors while psilocybin primarily activates 5-HT2A receptors. A shared downstream pathway involves BDNF-TrkB signaling, which promotes spinogenesis and synaptogenesis critical for sustained antidepressant effects. The review also discusses 5-HT2A receptor biased agonism as a potential strategy to separate therapeutic benefits from hallucinogenic effects. Understanding how serotonergic, glutamatergic, and neurotrophic systems converge may guide development of fast-acting, durable, and non-hallucinogenic antidepressants.
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.