In a double-blind, placebo-controlled crossover trial, low-dose oral ketamine was safe and well tolerated over five days in girls aged 6–12 with Rett syndrome. Twenty-three participants enrolled; one was excluded and one withdrew due to vomiting. No clinical improvement in Rett symptoms was observed with ketamine compared to placebo, despite electroencephalography showing expected increases in high-frequency brain activity, confirming the drug engaged its target. The trial was stopped after two dose cohorts (0.75 and 1.5 mg/kg twice daily) because of pandemic-related enrollment difficulties. Further research with higher doses or longer treatment is needed.
Ketamine's antidepressant effects depend on increasing brain-derived neurotrophic factor (BDNF) and activating its receptor TrkB in the hippocampus. Rett syndrome, caused by MECP2 mutations, involves reduced BDNF. In Mecp2 knockout mice, ketamine and a TrkB agonist, LM22A-4, enhance both excitatory and inhibitory synaptic plasticity through separate BDNF-TrkB pathways. MeCP2 normally stabilizes inhibitory neurotransmission; without it, ketamine causes sustained disinhibition. These findings reveal how MeCP2 shapes acute ketamine action and suggest mechanisms for ketamine-based Rett syndrome treatments.