Retiring brain network dynamics with psilocybin: a pharmaco-imaging study on the efficacy of psychedelics in treatment-resistant depression
Progetto Treatment-resistant depression (TRD) affects 30% of subjects with Major
Depressive Disorder (MDD) worldwide, producing a severe impact on quality of life and social functioning. Conceptualizing depression as a disorder resulting from the disruption of brain network dynamics, a growing body of evidence has highlighted the potential role of psiJocybin as a radically innovative intervention for TRD. However, long-term efficacy has not been fully proven. The drug's antidepressant mechanisms of action are still unclear, although preliminary resulu indicate its capacity to modulate brain networks. Notably, biomarkers that can predict the individual response to psilocybin are also still largely unknown. We intend to fill these knowledge gaps regarding the long-term neural and clinical effects of psilocybin in TRD.
To that aim, the project will consist of a multicentric, double-blind, placebo- controlled, pharmaco-imaging trial with a six-month follow-up period. Fifty TRD patients will be randomized (1:1) and administrated either psilocybin (25 mg) or placebo as an add-on to their current therapy.
Hence, the project will assess 1) long-term efficacy and safety profiles of a 3 month treatment; 2) mechanisms of action through the investigation of drug- induced changes of functional connectivity [assessed with electroencephalography (EEG) and functional magnetic resonance imaging (fMRI)], and variations of local cerebral blood perfusion [assessed with arterial spin labeling (ASL)]; 3) psilocybin capacity of counteracting synaptic impairment and neural loss in TRD; 4) profiles of central and peripheral biomarkers that can identify subsets of responders.
Breaking and rewiring TRD-related brain network dynamics through psilocybin, we hypothesize a substantial reduction of depressive symptoms along with a significant increase in cortico-cortical connections and a re- modulation of thalamocortical synchronization. Breaking new grounds about the treatment of a seriously disabling disorder, this project has the potential to innovate future clinical approaches, as well as to expand current knowledge about the pathophysiology of MDD.