Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin

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.

Study at a glance

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.