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

Publication date: Jun 23, 2025

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. 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. 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=6.63 p < 0.0001; 95 % CI [4.06, 9.20], d = 1.1), whereas there was no change following escitalopram (M=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=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=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=10.37, p < 0.0001; 95 % CI [6.38, 14.53], d = 1.0); dependency (M=7.97, p < 0.0001; 95 % CI [4.00, 11.93], d = 0.9) and self-control (M=6.40, p = 0.0006; 95 % CI [2.60, 10.20], d = 0.8)), whereas only the achievement domain improved after escitalopram (M=4.10, p = 0.005; 95 % CI [1.35, 6.86], d = 0.6). 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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