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

This preprint (2022) reanalysed fMRI data from a previous open-label study where psilocybin was used in the treatment of treatment-resistant depression (TRD). After using whole-brain models to fit the spatiotemporal brain dynamics, dynamic sensitivity analysis identified brain regions in transition from a depressive brain state to a healthy one. The identified regions correlate with in vivo density maps of serotonin receptors 5-HT_2A and 5-HT_1A, providing further evidence for the role of serotonergic signalling in the recovery of depression via psilocybin.

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 healthy 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-HT_2A and 5-HT_1A, for 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.”

Authors: Jakub Vohryzek, Joana Cabral, Louis-David Lord, Henrique M. Fernandes, Leor Roseman, David J. Nutt, Robin Carhart-Harris, Gustavo Deco & Morten L. Kringelbach