Annual Review of Medicine
September 20, 2023
Ji-Woon Kim, Kanzo Suzuki, E. Kavalali et al.
105 citations
Ketamine produces rapid and sustained antidepressant effects in patients with major depressive disorder that has not responded to conventional monoamine-based drugs. Recent preclinical studies have begun to clarify the mechanisms underlying these effects. This review compares clinical and preclinical findings to provide a broad perspective on how ketamine works as an antidepressant.
Science (New York, N.Y.)
May 8, 2025
Z Zack Ma, Natalie J Guzikowski, Ji-Woon Kim et al.
44 citations
Repeated ketamine treatment to maintain its rapid antidepressant effect can cause side effects, so extending the benefit from a single dose is an unmet need. Ketamine strengthens connections at CA3-CA1 synapses in the hippocampus, which is thought to underlie its antidepressant action. By temporarily boosting ERK activity through blocking the DUSP6 enzyme, researchers enhanced this synaptic strengthening and extended the antidepressant-like behavioral effects of a single ketamine dose in mice to up to 2 months. These effects depended on the TrkB receptor in excitatory neurons. The findings suggest that targeting downstream signaling pathways could sustain ketamine's rapid antidepressant effects without repeated dosing.
Molecular psychiatry
July 7, 2025
Dongsun Park, Gwangho Lee, Won-Gyu Lee et al.
7 citations
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.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2024
Ji-Woon Kim, Benjamin Kleinfelter, Ege T Kavalali et al.
3 citations
Ketamine, a rapidly acting antidepressant, works by restoring glutamate signaling in the hippocampus, countering the effects of a drug that induces depressed mood. Physostigmine, which triggers depression-like symptoms in humans, was found to cause long-term reduction of glutamate release in the mouse hippocampus. Ketamine rapidly re-establishes synaptic efficacy through postsynaptic signaling and masks the behavioral effects of physostigmine. The findings reveal that the synaptic mechanisms underlying mood changes differ from those behind antidepressant action, suggesting distinct pathways for neuropsychiatric disorders and their treatment.
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.