Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment.
International journal of molecular sciences December 20, 2024 Zuzanna Antos, Xawery Żukow, Laura Bursztynowicz et al. 14 citations
Ketamine shows rapid antidepressant effects primarily by blocking NMDA receptors, which reduces GABAergic inhibition and increases glutamate release. This activates AMPA receptors and downstream BDNF-TrkB and mTOR pathways, promoting synaptic growth and regeneration. Neuroimaging reveals changes in the Default Mode, Central Executive, and Salience networks—brain networks often disrupted in depression. The opioid system may play a permissive role in ketamine's effects, though ketamine is not a direct opioid agonist. Significant gaps remain in understanding its full mechanisms, safety, long-term efficacy, and how genetic factors like BDNF polymorphisms influence treatment response.