Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin
OpenAlex – May 30, 2025
Source: OpenAlex
Summary
Ketamine offers rapid relief for Major Depression, often within a single day, unlike traditional monoaminergic antidepressants requiring weeks. Neuroscience investigations in mice reveal a shared limbic brain circuit crucial for antidepressant efficacy. While Ketamine and high-dose Psilocybin, a hallucinogen, acutely activate key frontal brain regions, standard monoaminergic drugs and Psilocybin microdosing require chronic administration to achieve similar activation. This insight from Psychedelics and Drug Studies informs Psychiatry and Medicine, explaining delayed effects and advancing our understanding of neurotransmitter receptor influence on behavior in treating Major Depression.
Abstract
Abstract Ketamine has transformed depression treatment by providing therapeutic relief within a single day, unlike monoaminergic antidepressants that require weeks to take effect. Here, we conducted whole-brain screening in mice to compare drug-evoked c-fos expression—acting as a marker of brain activity leading to protein synthesis-dependent forms of plasticity—following treatment with monoaminergic antidepressants, ketamine and psilocybin. Our findings reveal a shared limbic brain circuit comprising subcortical and frontal cortical regions, with a key distinction: c-fos-based activity in the prelimbic and infralimbic frontal cortex—areas strongly implicated in depression—was acutely induced by ketamine and high-dose psilocybin, but emerged only after chronic dosing with the selective serotonin reuptake inhibitor fluoxetine or psilocybin microdosing. These results suggest the existence of a core limbic subcortico-cortical circuit underlying antidepressant efficacy, provide mechanistic insight into the delayed therapeutic effects of monoaminergic antidepressants, and reveal a close similarity in brain activity evoked by monoaminergic antidepressants and psilocybin microdosing.