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 preprint DOI: 10.64898/2026.06.12.731811 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind randomised controlled trial Randomized |
|---|---|
| Population | Patients with major depressive disorder |
| Interventions | Psilocybin Escitalopram |
| Topics | Default mode network Depression Psilocybin |
| Keywords | Escitalopram Depression economics Hallucinogen Placebo Psychological intervention Magnetic resonance imaging |
| Citations | 1 |
| Registration | NCT03429075 |
| Key findings | Psilocybin and escitalopram produce opposite reconfigurations of hierarchical non-equilibrium brain dynamics in major depressive disorder 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.
Comparable studies
Other randomized controlled trials on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
| Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. Adults with treatment-resistant depression | 2022 | Phase 2 double-blind randomized controlled trial | n = 233 |