This secondary analysis of an RCT (n=59) comparing two doses of psilocybin (25mg) plus placebo versus two doses of 1mg psilocybin plus daily escitalopram found that both treatments produced comparable reductions in negative bias in facial expression recognition, though decreased misclassification of positive faces as negative was associated with lower depression scores only in the escitalopram group.
Abstract of Negative affective bias in depression following treatment with psilocybin or escitalopram
“Recent clinical trial data suggests that ratings on depression scales are lowered after psilocybin therapy compared to placebo, though it is unclear what neuropsychological mechanisms underpin these effects. This study compared psilocybin, with an established antidepressant, escitalopram, to investigate whether there are shared or distinct effects on emotional information processing. Patients with long-standing moderate-to-severe depression were randomly and double-blindly assigned in a 1:1 ratio to receive either 1) two doses of 25 mg of psilocybin, 3-weeks apart, plus 6-weeks of daily placebo (psilocybin group N = 30); or 2) two doses of 1 mg of psilocybin 3-weeks apart plus 6-weeks of daily oral escitalopram (escitalopram group N = 29); all patients received the same psychological support. Behavioural measures of affective bias as well as subjective measures of depression were collected at baseline and at the primary 6-week endpoint, using an established computerised task (Facial Emotion Recognition Task) and Quick Inventory of Depressive Symptomatology, respectively. Change in affective bias was further correlated with change in depression scores measured concurrently as well as at 1-month post-trial follow-up (week-10), corrected for baseline depression severity. Negative bias in facial expression recognition decreased after both treatments to a comparable level. Concurrently, change in negative affective bias was not associated with change in depression. Longitudinally, a decrease in the misclassification of positive faces as negative was associated with a decrease in depression scores at week-10 for the escitalopram group only. Therefore, a more positive behavioural bias in emotional processing was seen following psilocybin and citalopram compared to baseline. This highlights the potential for at least some overlap in cognitive mechanisms across two distinct treatments, which is noteworthy given the short dosing regimen with psilocybin.“
Authors: Marieke A. G. Martens, Bruna Giribaldi Cunha, David Erritzoe, David Nutt, Robin Carhart-Harris & Catherine J. Harmer
Summary of Negative affective bias in depression following treatment with psilocybin or escitalopram
The introduction sets the context for why new treatments for depression are needed. The authors explain that while widely used antidepressants such as selective serotonin reuptake inhibitors (SSRIs) can be effective, they often come with limitations, including side-effects, incomplete symptom relief, and a relatively slow onset of therapeutic benefit. Because of this, there is increasing interest in novel treatment approaches that act more rapidly and target alternative neuropsychological mechanisms. Psychedelics, particularly psilocybin, have emerged as a promising candidate. Psilocybin is described as a pro-drug, meaning it is converted within the body into an active compound—psilocin—which binds to a serotonin receptor called the 5-HT2A receptor. This receptor has a central role in mood regulation and has long been implicated in depression. The introduction highlights that psilocybin’s mechanism of action appears distinct from that of SSRIs, despite both acting upon serotonin systems.
Previous studies, including earlier clinical trials and meta-analyses, are summarised to show accumulating evidence that psilocybin-assisted therapy can lead to substantial reductions in depressive symptoms. Some studies have involved comparison with inactive control conditions, whereas others have compared different doses of psilocybin. In the larger trial from which this secondary analysis is drawn, psilocybin and escitalopram were previously found to reduce depression severity to similar extents across a six-week period. Nevertheless, the authors note that it remains unclear how psilocybin exerts its psychological and neurobiological effects, and whether its influence on emotional processing resembles or diverges from those of SSRIs.
The authors then introduce the concept of emotional processing, which refers to how people perceive, interpret, and remember emotional information. This is relevant because depression is associated with a “negative affective bias”—a tendency to interpret social or emotional cues more pessimistically or more sensitively to threat. For example, people with depression often recognise fewer happy facial expressions and over-recognise negative ones. According to long-standing cognitive models of depression, such biases can maintain depressive symptoms by reinforcing negative interpretations of the world. A related cognitive neuropsychological model suggests that antidepressants act partly by shifting emotional biases in a more positive direction, sometimes even before subjective mood improves. This shift may eventually lead to clinical improvement as patients interact with their environment in ways shaped by these new, more optimistic tendencies.
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https://doi.org/10.1038/s41398-025-03693-w
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Cite this paper (APA)
Martens, M. A., Cunha, B. G., Erritzoe, D., Nutt, D., Carhart-Harris, R., & Harmer, C. J. (2025). Negative affective bias in depression following treatment with psilocybin or escitalopram–a secondary analysis from a randomized trial. Translational Psychiatry
Study details
Compounds studied
Psilocybin
Topics studied
Depression
Study characteristics
Original Re-analysis
Double-Blind
Longitudinal
Randomized
Participants
59
Humans
Compound Details
The psychedelics given at which dose and how many times
Psilocybin 25 mg | 2x