Psilocybin and Escitalopram Affect Brain Hierarchies in Different Ways

A recent study published in the journal Nature Mental Health reveals that two pharmacological treatments for depression influence brain dynamics in fundamentally different ways.

The finding offers new insights into how the depressed brain can be rebalanced.

The brain is organized like an orchestra

Mental health disorders, such as major depressive disorder (MDD), can significantly impair a person's daily functioning. Affecting approximately 5% of adults worldwide, the condition is characterized by persistent low mood and a loss of interest or pleasure in activities. Current treatments for MDD include psychotherapy and antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs), but these options often provide only modest benefits and can be accompanied by unpleasant side effects. Problems with these treatment options highlight the need for developing newer and more effective alternatives. However, it remains unclear how brain dynamics change in patients who improve following pharmacological intervention, limiting our understanding of the mechanisms behind recovery and hindering the development of more targeted therapies.

Neuroimaging has previously been used to identify abnormal brain dynamics in patients with MDD, finding changes linked primarily to higher-order brain networks. An earlier study by Deco and Kringelbach found that the brain is organized hierarchically, similar to an orchestra, with information being integrated in a small group of "conducting" brain regions before being distributed throughout the entire brain. Their results led them to suggest that MDD may be caused by a breakdown of this structure.

More recently, psychedelic drugs like psilocybin have had positive effects in patients with treatment-resistant depression. It has been hypothesized these results may be due to a reorganization of hierarchical brain dynamics. However, full whole-brain quantification of hierarchical processing following pharmacological interventions has not yet been attempted.

“Major depression has become pervasive and is on course to become the largest contributor to the burden of disease worldwide by 2030. New and better treatments are urgently needed but to make much needed progress, we need to better understand how current, effective interventions change brain dynamics in meaningful ways,” said senior author Dr. Morten L. Kringelbach, professor of neuroscience and founding director of the Centre for Eudaimonia and Human Flourishing at the University of Oxford.

Pharmacological interventions disrupt hierarchical brain dynamics

Brain imaging data was captured using functional magnetic resonance imaging (fMRI) in 42 patients diagnosed with MDD during a two-arm, double-blind, phase II randomized controlled trial. The participants received either 2 doses of 25 mg of oral psilocybin plus 6 weeks of daily placebo in the psilocybin arm, or 2 doses of 1 mg of oral psilocybin plus 6 weeks of daily escitalopram (a common SSRI) in the escitalopram arm. fMRI scans were taken at baseline and six weeks post-treatment.

The data were then analyzed using a novel whole-brain modelling framework, which can capture the causal brain mechanisms from neuroimaging data by estimating the “generative effective connectivity” from whole-brain modelling of the resting state for each session and patient.

Effective connectivity refers to a process that is used to describe influences among brain regions and how these regions influence each other during a specific task.

The fMRI scans revealed that psilocybin and escitalopram treatments lead to significantly different hierarchical reconfigurations of whole-brain dynamics, despite both resulting in similar improvements in depressive symptoms. Treatment with psilocybin caused a general "flattening" of the hierarchical dynamics, whereas escitalopram led to an increase in hierarchical reorganization.

Psychedelics and SSRIs work in different ways

“Overall, the results demonstrate that psilocybin and escitalopram work in fundamentally different ways to rebalance brain dynamics in depression. This confirms the hypothesis that neuropsychiatric disorders could be caused by the breakdown in regions orchestrating brain dynamics from the top of the hierarchy,” said lead author Dr. Guustavo Deco, an ICREA research professor at Pompeu Fabra University.

“Our findings shed light on a major unsolved challenging problem of how the depressed brain gets rebalanced,” said Kringelbach.

Reference: Deco G, Sanz Perl Y, Johnson S, Bourke N, Carhart-Harris RL, Kringelbach ML. Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression. Nat Mental Health. 2024. doi: 10.1038/s44220-024-00298-y

This article is a rework of a press release issued by the University of Oxford. Material has been edited for length and content.