Underlying Mechanisms of the Treatment Efficacy of (R, S)‐Ketamine for Post‐Traumatic Stress Disorder and Depression: A Review
Medicine Advances March 27, 2026 Thomas Edward Cutting, Richard Evans Hartman
Ketamine and its stereoisomers show efficacy for PTSD and treatment-resistant depression, with (R)-ketamine having fewer side effects. The therapeutic mechanisms involve specific brain regions: the dentate gyrus, prefrontal cortex, CA3 region of the ventral hippocampus, dorsal raphe nucleus, and the prelimbic–dorsal raphe nucleus circuit. For PTSD, ketamine attenuates serotonin signaling in the dorsal raphe nucleus and activates that circuit. When given before stress, it increases purine and pyrimidine metabolism, potentiates inhibitory neurotransmitters, and dampens excitatory ones except glutamic acid. Brain-derived neurotrophic factor activation of tropomyosin-related kinase B appears necessary for treatment effects, but N-methyl-D-aspartate receptor antagonism may not be.