Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression
In 19 patients with treatment-resistant depression, a single open‑label 25 mg dose of psilocybin reduced ventromedial prefrontal cortex–right amygdala functional connectivity during fearful and neutral (but not happy) face processing and increased amygdala connectivity with occipito‑parietal cortices. The decrease in vmPFC–amygdala coupling correlated with one‑week rumination scores, consistent with the hypothesis that psilocybin restores emotional responsiveness as a key therapeutic mechanism.
Authors
- Robin Carhart-Harris
- David Nutt
- Leor Roseman
Published
Abstract
Background
Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy.
Aims
Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin.
Methods
Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week.
Results
Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing.
Conclusion
These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.
Research Summary of 'Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression'
Introduction
Serotonergic psychedelics such as psilocybin have shown therapeutic promise for conditions including depression, yet the neural mechanisms that underlie their clinical efficacy remain poorly understood. Previous work in this cohort of patients with treatment-resistant depression (TRD) identified increased right amygdala responsiveness to emotional faces one day after a high-dose psilocybin session, and this amygdala change correlated with clinical improvement. At the same time, other post-acute studies of psychedelics have reported alterations in resting-state connectivity and regional perfusion, suggesting that neural changes beyond the acute drug state may contribute to sustained symptom benefit. Mertens and colleagues set out to probe task-related functional connectivity (FC) changes that might accompany the earlier amygdala activation findings. Specifically, they tested whether psilocybin treatment leads to altered amygdala FC during an emotional face perception task, with a primary hypothesis of decreased amygdala–ventromedial prefrontal cortex (vmPFC) connectivity after treatment. The investigators also examined whether any FC changes related to clinical outcomes at one week, focusing on depressive symptoms and rumination as primary and secondary endpoints respectively.
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Study Details
- Study Typeindividual
- Journal
- Compound
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- APA Citation
Mertens, L. J., Wall, M. B., Roseman, L., Demetriou, L., Nutt, D. J., & Carhart-Harris, R. L. (2020). Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. Journal of Psychopharmacology, 34(2), 167-180. https://doi.org/10.1177/0269881119895520
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