This interventional trial (n=12) will investigate the effect of a single 25 mg dose of psilocybin on the positive valence system in patients with treatment-resistant depression (TRD).
The study, conducted by the Centre Hospitalier Universitaire de Nîmes, aims to explore whether psilocybin reduces anhedonia and increases motivation by enhancing reward anticipation.
Functional MRI scans will measure brain activity before and after psilocybin administration, focusing on key neural circuits involved in effort evaluation and reward processing. The trial will assess correlations between brain activity changes and depression severity, behavioural activation, and anhedonia scores. Findings will contribute to understanding psilocybin’s antidepressant mechanisms and its feasibility for use in a French clinical population.
Trial Details
The study hypothesis is that the antidepressant effect of psilocybin is mediated by a normalization of the functioning of the positive valence system. Depressive states, especially moderate to severe depressions that associate a certain level of anhedonia, produce an overvaluation of the cost of efforts and an infra-evaluation of the possible rewards derived from an action. Psilocybin would reduce anhedonia and the cost of efforts, facilitating the anticipation of reward. Thus, the antidepressant effect of psilocybin would be mediated by a greater anticipation of rewards (reduction of anhedonia) and a more optimistic estimation of the results of efforts (increase in motivation). Psilocybin-induced changes in the positive valence system will be observable on brain MRI images, particularly in the effort evaluation circuits: basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum (VS), ventral tegmental area (VTA). The mesolimbic circuit (VS, VTA) is the anatomical substrate of anticipation of rewarding stimuli (food, sex, drugs). The amygdala also fulfills an associative function between environmental cues and rewarding stimuli. Structural and functional alterations in this circuit are associated with depressive symptoms such as anhedonia or distortions in the perception and memories of rewards. This hypothesis will be tested on a population of patients with moderate or severe depressive symptoms who meet the criteria for TRD.Trial Number NCT06650800