Brain dynamics predictive of response to psilocybin for treatment-resistant depression

Psilocybin therapy for depression shows promise, but how it works is unclear. By comparing responders (those with >50% reduction in symptoms) to non-responders after 10mg and 25mg doses, whole-brain modeling identified specific brain regions whose dynamics shift from a depressive to a healthy state. These regions overlap with maps of serotonin 5-HT2A and 5-HT1A receptors, which psilocin—the active metabolite of psilocybin—activates. The findings provide causal evidence linking serotonergic transmission and recovery from depression via psilocybin.

Study at a glance

Abstract

Abstract Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (> 50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT2A and 5-HT1A, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.