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.
Comparable studies
Other observational and cohort studies on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Patients with treatment-resistant depression | 2017 | Observational cohort | n = 19 |
| Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression Patients with treatment-resistant depression and healthy controls | 2017 | Observational cohort | n = 33 |
| More Realistic Forecasting of Future Life Events After Psilocybin for Treatment-Resistant Depression Patients with treatment-resistant depression (TRD) | 2018 | Observational cohort | n = 15 |
| Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression. 17 patients with treatment-resistant depression and 18 untreated age-matched healthy... | 2018 | Observational cohort with machine learning classification | n = 35 |
| Brain dynamics predictive of response to psilocybin for treatment-resistant depression. Responders and non-responders to psilocybin therapy for depression | 2024 | Observational cohort |