This secondary analysis of a randomised trial (n=41) found that while psilocybin therapy (2×25 mg, three weeks apart) maintained emotional responses to musical surprises and increased activation in prefrontal and sensory brain regions. Escitalopram reduced surprise-related affective responses and increased activation in memory and emotional processing areas, suggesting distinct neurological mechanisms between these treatments for depression.

Abstract of Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises

“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 greater activation in the ventromedial prefrontal cortex and sensory regions, and reduced activation in the angular gyrus. 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.“

Authors: Rebecca Harding, Neomi Singer, Matthew B. Wall, Talma Hendler, David Erritzoe, David J. Nutt, Robin L. Carhart-Harris & Leor Roseman

Summary of Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises

Harding and colleagues investigate the contrasting effects of psilocybin therapy (PT) and escitalopram (a selective serotonin reuptake inhibitor or SSRI) on how individuals with Major Depressive Disorder (MDD) process musical surprises—unexpected deviations in music that elicit emotional responses. MDD is characterised by impaired reward processing and emotional regulation, particularly the symptom of anhedonia, or the inability to experience pleasure. This dysfunction is often linked to the mesocorticolimbic pathway, a network of brain regions involved in reward evaluation and emotional integration.

Traditional treatments for MDD, such as SSRIs, frequently fall short in alleviating anhedonia and are often accompanied by emotional blunting, a side effect that diminishes emotional experiences. In contrast, PT has shown promising effects in alleviating depressive symptoms and enhancing emotional processing. Psilocybin, the active compound in PT, primarily targets 5-HT2A receptors in the brain and is thought to reduce the influence of rigid top-down predictive models that shape perception and emotional response—a concept formalised in the Relaxed Beliefs Under Psychedelics (REBUS) model. Although the acute effects of psilocybin last only a few hours, its therapeutic impact appears to be more enduring.

The study leverages music, which is deeply emotionally evocative, as a tool to assess how hedonic (pleasure-related) and predictive processing change after treatment. Musical surprises offer a naturalistic way to probe reward and emotion-related brain activity. Emotional responses to these surprises are assessed using the Geneva Emotional Music Scale (GEMS), which breaks emotions into sublimity, vitality, and unease. The authors hypothesise that PT will show greater improvement in anhedonia and enhance brain activation in reward-related regions such as the nucleus accumbens (NAc), while escitalopram might reduce hedonic responsiveness due to emotional blunting.

Materials and Methods

Study Design

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Find this paper

Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises

https://doi.org/10.1038/s41380-025-03035-8

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Cite this paper (APA)

Harding, R., Singer, N., Wall, M. B., Hendler, T., Erritzoe, D., Nutt, D., ... & Roseman, L. (2025). Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises. Molecular Psychiatry, 1-9.

Study details

Compounds studied
Psilocybin

Topics studied
Depression Neuroscience

Study characteristics
Original Re-analysis Placebo-Controlled Active Placebo Double-Blind Randomized Re-analysis Bio/Neuro

Participants
41 Humans

Institutes

Institutes associated with this publication

Imperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 25 mg | 2x

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