Effects of psilocybin-assisted therapy on neural signatures of cognitive flexibility in treatment-resistant depression

Abstract

Major Depression has been conceptualized as a disorder of inflexible higher-order beliefs about the self in its environment and reduced bottom-up integration of unexpected new information (Barrett et al., 2016; Kiverstein et al., 2020; Kube et al., 2020; Magaraggia et al., 2021). Psilocybin-assisted therapy, a promising approach for treatment-resistant depression (TRD) (Haikazian et al., 2023, Goodwin et al., 2022, Carhart-Harris et al., 2016), might address this issue. According to the Relaxed Beliefs under Psychedelics model, psychedelics weaken rigid higher-order beliefs via their agonistic action at the 5-HT2A receptor in cortical association areas and increase bottom-up sensitivity for prediction errors (Carhart-Harris & Friston, 2019). In line with this, previous studies using reversal learning paradigms have reported increased cognitive flexibility during acute psychedelic action in mice and humans (Kanen et al., 2022; Torrado Pacheco et al., 2023) and one week after psychedelic administration in mice (Šabanović et al., 2024). In depressed individuals, psilocybin-assisted therapy was associated with increased cognitive flexibility in a set shifting task 1 and 4 weeks after treatment, with increased neural flexibility 1 week after treatment (Doss et al., 2021), and with heightened psychological flexibility up to 3 months after treatment (Sloshower et al., 2024). Here, we aim to investigate the sub-acute and post-acute effects of psilocybin-assisted therapy on cognitive flexibility and its neural correlates in patients with TRD who took part in the bi-centric, double-blind, randomized controlled EPIsoDE trial (EudraCT:2019-003984-24; NCT04670081). Patients performed a probabilistic instrumental reversal learning paradigm during functional magnetic resonance imaging (fMRI) ~1 week before (baseline), ~1 week after, and ~6 weeks after dosing. We will model patients’ behavior during reversal learning using the Hierarchical Gaussian Filter (HGF) (Mathys et al., 2014), allowing us to derive measures of cognitive flexibility and their neural correlates. Our findings will contribute to a better understanding of the mechanisms of action of psilocybin-assisted therapy in TRD.

Topics & conditions

Detected automatically by Psychedelic Commons from the title and abstract, not labels from the source. They may be incomplete.

Keywords