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Peer-reviewed article

The effects of psilocybin therapy versus escitalopram on cognitive bias: A secondary analysis of a randomized controlled trial.

Henry J, Giribaldi B, Nutt DJ, Erritzoe D, Carhart-Harris RiD, Lyons TiD

European neuropsychopharmacology : the journal of the European College of NeuropsychopharmacologyJun 23, 2025United Kingdom, United States2 citationsDOI: 10.1016/j.euroneuro.2025.06.003

Abstract

<h4>Background</h4>Patients with Major Depressive Disorder (MDD) have more dysfunctional attitudes than healthy individuals and these pessimistic biases are correlated with depression severity. Psilocybin has demonstrated sustained remission in depression.<h4>Methods</h4>Secondary analysis of a two-arm randomized controlled trial assessing the effect of psilocybin therapy versus escitalopram on 'maladaptive' cognitive biases relevant to the construct of depression. Primary outcomes were post-treatment changes in biases at six weeks compared with baseline, as measured using three validated psychological scales.<h4>Findings</h4>Fifty-nine MDD patients were randomly allocated to the psilocybin (n = 30) or escitalopram (n = 29) groups. Self-reported optimism showed a large increase six-weeks after psilocybin treatment (M<sub>diff</sub>=6·63 p < 0·0001; 95 % CI [4·06, 9·20], d = 1·1), whereas there was no change following escitalopram (M<sub>diff</sub>=1·52, p = 0·205; 95 % CI [-0·59, 3·62], d = 0·4). Behavioral results found that patients were more optimistic about desirable life events after psilocybin treatment (M<sub>diff</sub>=0·16, p = 0·0002; 95 % CI [0·08, 0·23], d = 1·1), but they were also less pessimistic about negative life events after escitalopram treatment (M<sub>diff</sub>=0·07, p = 0·018; 95 % CI [0·01, 0·13], d = 0·5). We found improvements in all three domains of dysfunctional attitudes following psilocybin treatment: achievement (M<sub>diff</sub>=10·37, p < 0·0001; 95 % CI [6·38, 14·53], d = 1·0); dependency (M<sub>diff</sub>=7·97, p < 0·0001; 95 % CI [4·00, 11·93], d = 0·9) and self-control (M<sub>diff</sub>=6·40, p = 0·0006; 95 % CI [2·60, 10·20], d = 0·8)), whereas only the achievement domain improved after escitalopram (M<sub>diff</sub>=4·10, p = 0·005; 95 % CI [1·35, 6·86], d = 0·6).<h4>Interpretation</h4>These results suggest that two high-dose sessions with psilocybin therapy are superior to a six-week daily course of a selective serotonin-reuptake inhibitor antidepressant, in remediating negative cognitive biases in depression.

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PsilocybinDepression

Keywords

Escitalopram

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