Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises
Rebecca Harding, Neomi Singer, Talma Hendler, David Nutt, Leor Roseman, Matthew B. Wall, David Erritzøe, Robin Carhart-Harris
Molecular Psychiatry April 26, 2025 DOI: 10.1038/s41380-025-03035-8 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of a randomized trial Peer reviewed |
|---|---|
| Sample size | 41 |
| Population | Patients with major depressive disorder |
| Interventions | Psilocybin therapy escitalopram |
| Duration | 6-week intervention |
| Topics | Depression Psilocybin |
| Keywords | Escitalopram Audiology Clinical psychology Cognitive psychology |
| Citations | 4 |
| Key findings | Psilocybin therapy led to a greater decrease in anhedonia than escitalopram, while escitalopram reduced surprise-related affective responses to music and psilocybin therapy did not. |
Abstract
Abstract Psilocybin therapy (PT) is emerging as an effective intervention for Major Depressive Disorder (MDD), offering comparable efficacy to conventional treatments like selective serotonin reuptake inhibitors (SSRIs). Music, an emotionally evocative stimulus, provides a valuable tool to explore changes in hedonic and predictive processing mechanisms via expectancy violations, or ‘surprises’. This study sought to compare behavioural and functional magnetic resonance imaging (fMRI) responses to musical surprises in MDD patients treated with either PT or the SSRI, escitalopram. In this secondary analysis of a trial, 41 MDD patients (with usable fMRI data) were randomly assigned to either PT ( n = 22) or escitalopram ( n = 19) treatment groups. Participants listened to music during fMRI and tracked their emotional experience, both before and after a 6-week intervention. Surprise-related valence and arousal indices were calculated. Musical surprises were entered as regressors for whole-brain and region of interest fMRI analyses. PT caused a greater decrease in anhedonia scores compared with escitalopram. While escitalopram led to reductions in surprise-related affective responses, PT showed no significant change. Escitalopram was associated with increased activation in memory and emotional processing areas during musical surprises (versus control events) when compared with PT. Following PT, there was decreased activation in the ventromedial prefrontal cortex and angular gyrus, and greater activation in sensory regions. PT may allow for the subjective response to musical surprises to be maintained through a lasting reduction in the salience of prediction errors, or, alternatively, by increasing hedonic priors. Contrastingly, escitalopram may diminish hedonic priors, highlighting fundamental differences in treatment mechanisms.
Comparable studies
Other randomized controlled trials on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
| Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. Adults with treatment-resistant depression | 2022 | Phase 2 double-blind randomized controlled trial | n = 233 |
Citations in the library
Cited by 7
- Neurocognitive effects of psilocybin: A systematic and comprehensive review of neuroimaging studies in humans. Neuroscience & Biobehavioral Reviews August 1, 2025
- Temporal dynamics in neuroimaging as correlates of therapeutic response to psilocybin in major depressive disorder: A systematic review and critical appraisal Journal of Affective Disorders September 16, 2025
- Psilocybin for Anhedonia in Unipolar and Bipolar Depression: A Systematic Review of Clinical and Preclinical Evidence Journal of Psychiatric Research October 1, 2026
- Multilevel Mechanisms and Clinical Efficacy of Psilocybin in Depression Treatment: A Systematic Review International Journal of Molecular Sciences September 10, 2026
- Divergent changes in perturbation-induced brain reconfiguration following depression treatment with psilocybin and escitalopram bioRxiv (Cold Spring Harbor Laboratory) June 26, 2026
and 2 more in the library
Cites 22
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
and 17 more in the library