Distinct brain responses to psilocybin and escitalopram in depression captured by the Fluctuation-Dissipation Theorem
Paulina Clara Dagnino, Irene Acero-pousa, Gorka Zamora‐lópez, Anira Escrichs, David Erritzøe, David Nutt, Robin Carhart‐Harris, Yonatan Sanz Perl, Morten L. Kringelbach, Gustavo Deco
bioRxiv (Cold Spring Harbor Laboratory) June 16, 2026 Peer reviewed DOI: 10.64898/2026.06.12.731811 via OpenAlex
Summary
Psilocybin and escitalopram produced opposite changes in brain dynamics in patients with major depressive disorder (MDD). The study used resting-state functional magnetic resonance imaging (fMRI) to analyze brain activity before and after treatment, revealing that the deviation from the fluctuation-dissipation theorem could help differentiate the effects of these treatments. Additionally, baseline measures were effective in distinguishing responders from non-responders for each treatment.
Study at a glance
| Design | double-blind randomized controlled trial |
|---|---|
| Population | patients with major depressive disorder |
| Key finding | The deviation of the fluctuation-dissipation theorem may serve as a marker for differentiating the effects of psilocybin and escitalopram in MDD treatment. |
Abstract
Abstract In recent decades, the psychedelic psilocybin has been studied as a potential treatment for major depressive disorder (MDD), offering an alternative to traditional antidepressants. However, the brain changes underlying the clinical effects of different interventions remain unclear. Here, we investigated the effects of psilocybin and a conventional antidepressant, escitalopram, from the double-blind randomised controlled trial (DB-RCT) - NCT03429075 - on the brain’s hierarchical organisation. Using pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) we built whole-brain models and obtained a generative effective connectivity (GEC) matrix for each patient. Based on the GEC, we measured the level of non-equilibrium brain dynamics by quantifying the deviation from the fluctuation-dissipation theorem (FDT) and performed complementary analysis on brain segregation and asymmetry. Our results showed opposite reconfigurations of the hierarchical non-equilibrium brain dynamics following each treatment. Additionally, baseline measures effectively distinguished responders from non-responders within each treatment. These findings suggest that the deviation of the FDT may serve as a marker for differentiating the effects of psilocybin and escitalopram in MDD treatment, overall, contributing to the understanding of therapeutic mechanisms of depression.