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 preprint DOI: 10.64898/2026.06.22.733731 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort with pre- and post-treatment brain imaging |
|---|---|
| Population | Individuals with major depressive disorder (MDD) |
| Interventions | Psilocybin Escitalopram |
| Topics | Psilocybin Depression |
| Keywords | Escitalopram Depression economics Human brain Amygdala Psychological intervention Neuroimaging Rat model Central nervous system Brain mapping |
| Key findings | Global brain network reconfiguration under perturbation increases after psilocybin and decreases after escitalopram treatment. |
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.