Divergent changes in perturbation-induced brain reconfiguration following depression treatment with psilocybin and escitalopram
Paulina Clara Dagnino, Irene Acero-pousa, Robin Carhart‐Harris, David Erritzøe, David Nutt, Morten L. Kringelbach, Yonatan Sanz Perl, Gustavo Deco
bioRxiv (Cold Spring Harbor Laboratory) June 26, 2026 Peer reviewed DOI: 10.64898/2026.06.22.733731 via OpenAlex
Summary
The study found that major depressive disorder (MDD) patients showed increased brain reorganisation after treatment with psilocybin, while escitalopram led to decreased reorganisation. Specifically, the global brain network reconfiguration index (NRI) increased with psilocybin and decreased with escitalopram, indicating that psilocybin promotes greater brain flexibility, whereas escitalopram stabilises brain dynamics. This suggests different neural changes following each treatment approach.
Study at a glance
| Population | patients with major depressive disorder (MDD) |
|---|---|
| Key finding | Psilocybin treatment increases brain reorganisation under perturbation, while escitalopram decreases it. |
Abstract
Abstract A central challenge in neuroscience is understanding how the human brain is organised to support optimal functioning and adaptability. One approach to characterise complex brain dynamics is by artificially perturbing whole-brain models. Here, we asked whether whole-brain organisation under perturbation in major depressive disorder (MDD) changes after intervention with psilocybin and escitalopram. First, we built whole-brain models of pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) and obtained an initial generative effective connectivity (GEC) matrix for each individual. Then, we employed systematic and local artificial perturbations across intensities, re-optimised each model to create a response GEC (GECr), and assessed the extent of brain reorganisation by quantifying the brain network reconfiguration index (NRI). Our results showed that the global brain NRI increases with psilocybin and decreases with escitalopram. Across sessions and interventions, higher global NRI was related with localised perturbations in brain areas orchestrating the brain’s hierarchical dynamics. Traditional approaches complemented our investigation. Our findings suggest distinct neural changes following each treatment for MDD. The increase in brain reorganisation under perturbation following psilocybin is consistent with greater brain flexibility and changeability, whereas the decrease following escitalopram suggests more stabilised brain dynamics. Overall, perturbation-induced brain NRI may represent a useful approach for uncovering neural changes following different interventions for depression.