Treatment of depression with psilocybin or escitalopram leads to different hierarchical reconfigurations of the brain

Depression is one of the most common mental disorders, affecting approximately 300 million people worldwide. Although there are currently many pharmacological treatments for depression, the impact of these different treatments on the brains of the patients to whom they are administered is not yet fully understood.

Selective serotonin reuptake inhibitors (SSRIs) are among the most widely recognized antidepressants in the world. SSRIs can increase the activity of the neurotransmitter serotonin, which plays a key role in regulating sleep, mood, appetite, and learning.

A more recently explored treatment option for depression is psilocybin, a naturally occurring psychedelic compound found in “magic mushrooms.” This compound has also been found to interact with serotonin receptors in the brain, which can improve individuals’ moods after consuming it.

Researchers from Pompeu Fabra University, Oxford University and other European institutes recently conducted a study on the effects of these two different types of treatments on the brains of people diagnosed with depression, particularly on the hierarchical organization of the brain after taking these drugs. Their article, published in Nature Mental Healthsuggests that these two treatment options result in very different hierarchical brain reconfigurations.

“We have long been interested in the orchestration of brain hierarchy across many different brain states and have been able to demonstrate in numerous papers that the human brain is organized hierarchically, orchestrating global dynamics to perform distributed computations efficiently,” Gustavo Deco and Morten L. Kringelbach, co-authors of the paper, told Medical Xpress.

“We were interested in how the hierarchy evolves in treatment-resistant depression. Thanks to a recent randomized controlled trial, we were able to study two different pharmacological treatments.”

In their recent study, the researchers compared the effects of psilocybin to those of escitalopram, one of the most commonly prescribed SSRI medications. All study participants received two doses of psilocybin three weeks apart. For a period of six weeks, one group of participants also received a daily dose of escitalopram, while the other group was given a placebo (i.e., a neutral substance with no psychoactive effects).

“Our main idea was to study the reconfiguration of the hierarchical organization of the brain in depression after different pharmacological treatments,” Deco and Kringelbach said. “The experimental data were obtained from a two-arm, double-blind, phase II randomized controlled trial comparing psilocybin therapy (22 patients) to escitalopram (20 patients) by co-author Professor Carhart-Harris.”

The researchers recorded clinical outcomes of the two treatment plans that the participants followed. They also collected images of the patients’ brains using functional magnetic resonance imaging (fMRI) at the start of the study and after the patients completed the 6-week treatment period.

“We used advanced whole-brain modeling, which fits a personalized computational model to the patient’s empirical functional brain scans,” Deco and Kringelbach explain. “We designed a framework to assess hierarchical reconfiguration by the global level of directionality of the generative effective connectivity (GEC) matrix underlying the whole-brain model. The GEC reflects the underlying anatomical structure and dynamic functional activity in an asymmetric matrix that captures the hierarchical organization.”

Using machine learning algorithms, Deco, Kringelbach, and their colleagues were able to extract hierarchical features of the brain from the scans they collected. To support their findings, they used a theoretical construct known as the “trophic coherence” framework, which in ecology describes the hierarchical food chain (i.e., carnivores eating herbivores, which in turn eat plants).

“According to this framework, a flat hierarchy is characterized by equal trophic levels and low directionality, which reflects low asymmetry in a network,” Deco and Kringelbach said. “In contrast, a strong hierarchy is associated with high directionality and strong asymmetric connections in a multi-layered network.”

The researchers found that the hierarchical organization of brain dynamics is a very accurate measure of change following treatments. In their study, they used the trophic coherence framework to determine how the two treatments they evaluated reorganized the brain dynamics of patients who received them.

“This approach has allowed us to better understand the underlying mechanisms of depression and could ultimately lead to even more effective interventions,” Deco and Kringelbach said. “Our results also support the hypothesis that problems in key regions of the global workspace orchestrating brain dynamics may be the primary cause of neuropsychiatric disorders. Future larger studies should further investigate this hypothesis by focusing on different neuropsychiatric diseases.”

Essentially, the results gathered by these researchers suggest that while psilocybin and escitalopram may be effective treatments for depression, the two compounds resulted in significantly different reconfigurations of the brain hierarchy. Using computer models based on machine learning, the team was also able to predict patients’ responses to treatment with an impressive 85% accuracy.

Overall, the results of this study show that SSRIs and psilocybin rebalance brain dynamics in completely different ways. In the future, the results obtained could inform pharmacological and psychiatric studies, thus contributing to the improvement of therapeutic interventions against depression.

“We now plan to use this new framework to understand the orchestration of the brain hierarchy in any brain state, as this would allow us to find new ways to rebalance the brain in disease,” Deco and Kringelbach added.

“The current whole-brain modeling framework could be used for treatment studies using any type of effective intervention, whether pharmacological, electrical, or behavioral. We also plan to use this methodology to study hierarchical reconfiguration in cognitive/behavioral tasks and different brain states in healthy participants.”

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