Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin
bioRxiv (Cold Spring Harbor Laboratory) May 30, 2025 Pavel Osten, K Sunny Joseph, Jane Collins et al. preprint
Ketamine relieves depression within a day, whereas standard monoaminergic antidepressants take weeks. In mice, whole-brain mapping of the activity marker c-fos after treatment with monoaminergic antidepressants, ketamine, and psilocybin revealed a shared limbic circuit involving subcortical and frontal cortical regions. Ketamine and high-dose psilocybin acutely activated the prelimbic and infralimbic frontal cortex—areas linked to depression—while the selective serotonin reuptake inhibitor fluoxetine and psilocybin microdosing activated these regions only after chronic dosing. This suggests a common limbic subcortico-cortical circuit underlies antidepressant efficacy, explains the delay of monoaminergic drugs, and shows that monoaminergic antidepressants and psilocybin microdosing evoke similar brain activity.