Ketamine and the Disinhibition Hypothesis: Neurotrophic Factor-Mediated Treatment of Depression.
Pharmaceuticals (Basel, Switzerland) May 12, 2023 Philip Borsellino, Reese I Krider, Deanna Chea et al.
Ketamine offers rapid and enduring relief for major depressive disorder and treatment-resistant depression, unlike standard antidepressants. This narrative proposes that depression stems from neuronal atrophy and synaptic disconnection rather than a monoamine imbalance. Ketamine, its enantiomers, and metabolites act through multiple pathways, including NMDAR inhibition and enhanced glutamatergic signaling. The disinhibition hypothesis suggests ketamine causes excitatory cortical disinhibition, releasing neurotrophic factors like BDNF, VEGF, and IGF-1, which repair neuro-structural abnormalities. Ketamine's efficacy is revolutionizing psychiatric treatment and understanding of mental illness.