The nervous system is hypothesized to compute reward prediction errors (RPEs) to promote adaptive behavior. Correlates of RPEs have been observed in the midbrain dopamine system, but the extent to which RPE signals exist in other reward-processing regions is less well understood. In the present study, we quantified outcome history-based RPE signals in the ventral pallidum (VP), a basal ganglia region functionally linked to reward-seeking behavior. We trained rats to respond to reward-predicting cues, and we fit computational models to predict the firing rates of individual neurons at the time of reward delivery. We found that a subset of VP neurons encoded RPEs and did so more robustly than the nucleus accumbens, an input to the VP. VP RPEs predicted changes in task engagement, and optogenetic manipulation of the VP during reward delivery bidirectionally altered rats' subsequent reward-seeking behavior. Our data suggest a pivotal role for the VP in computing teaching signals that influence adaptive reward seeking.

Objectives

To perform a Bayesian reanalysis of a recent trial of psilocybin (COMP360) versus escitalopram for Major Depressive Disorder (MDD) in order to provide a more informative interpretation of the indeterminate outcome of a previous frequentist analysis.

Design

Reanalysis of a two-arm double-blind placebo controlled trial.

Participants

Fifty-nine patients with MDD.

Interventions

Two doses of psilocybin 25mg and daily oral placebo versus daily escitalopram and 2 doses of psilocybin 1mg, with psychological support for both groups.

Outcome measures

Quick Inventory of Depressive Symptomatology-Self-Report (QIDS SR-16), and three other depression scales as secondary outcomes: HAMD-17, MADRS, and BDI-1A.

Results

Using Bayes factors and 'skeptical priors' which bias estimates towards zero, for the hypothesis that psilocybin is superior by any margin, we found indeterminate evidence for QIDS SR-16, strong evidence for BDI-1A and MADRS, and extremely strong evidence for HAMD-17. For the stronger hypothesis that psilocybin is superior by a 'clinically meaningful amount' (using literature defined values of the minimally clinically important difference), we found moderate evidence against it for QIDS SR-16, indeterminate evidence for BDI-1A and MADRS, and moderate evidence supporting it for HAMD-17. Furthermore, across the board we found extremely strong evidence for psilocybin's non-inferiority versus escitalopram. These findings were robust to prior sensitivity analysis.

Conclusions

This Bayesian reanalysis supports the following inferences: 1) that psilocybin did indeed outperform escitalopram in this trial, but not to an extent that was clinically meaningful--and 2) that psilocybin is almost certainly non-inferior to escitalopram. The present results provide a more precise and nuanced interpretation to previously reported results from this trial, and support the need for further research into the relative efficacy of psilocybin therapy for depression with respect to current leading treatments.

Trial registration number

NCT03429075.