Brain dynamics predictive of response to psilocybin for treatment-resistant depression

Summary & key facts

The study compared people who responded to psilocybin therapy for depression with those who did not. Participants received two doses (10 mg and 25 mg) one week apart. Before treatment, researchers used brain models of resting activity to find which areas could be pushed from a "depressive" pattern toward a "healthy" pattern. The brain regions identified matched maps of serotonin receptors (5-HT2A and 5-HT1A), which psilocin—the active form of psilocybin—binds to. The authors report this as mechanistic evidence linking those regions and receptors to recovery after psilocybin.

Key facts:

• Participants received psilocybin at two doses: 10 mg and 25 mg, given 7 days apart.
• The study defined treatment responders as people with more than a 50% reduction in depressive symptoms.
• Researchers fitted large-scale models to resting-state brain dynamics measured before treatment for both responders and non-responders.
• A dynamic sensitivity analysis of those models identified a subset of brain regions where simulated perturbation pushed brain activity from a depressive-like state toward a healthier state.
• The brain regions implicated in that simulated transition correlated with in vivo maps of serotonin receptors 5-HT2A and 5-HT1A.
• Psilocin, the active metabolite of psilocybin, has appreciable affinity for 5-HT2A and 5-HT1A receptors and can act as a full-to-partial agonist at these sites.
• The authors describe these findings as providing causal mechanistic evidence for how specific brain regions and serotonergic receptors may be involved in recovery from depression after psilocybin therapy.
• The analysis split the sample into responders and non-responders, which simplifies outcomes into two groups rather than showing a continuous range of change.

Abstract

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression-to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression, and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

Topics

Functional Brain Connectivity Studies Mental Health Research Topics Psychedelics and Drug Studies

Categories

Clinical Psychology Psychology Social Sciences

Tags

Anhedonia Depression (economics) Dopamine Economics Hallucinogen Internal medicine Macroeconomics Medicine Neuroscience Psilocybin Psychiatry Psychology Receptor Serotonergic Serotonin

Substances

Psilocybin

Conditions & symptoms

Depression Sadness or low mood