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

BackgroundPatients with Major Depressive Disorder (MDD) have more dysfunctional attitudes and pessimism than healthy individuals and these biases are correlated with depression severity. Psilocybin has demonstrated sustained remission in MDD. MethodsSecondary analysis of a two-arm, randomized controlled trial (ClinicalTrials.gov Identifier: NCT03429075) assessing the effect of psilocybin therapy versus escitalopram on maladaptive cognitive biases relevant to the construct of depression. Psilocybin group participants received two 25mg doses and escitalopram group received three weeks of daily 10mg, increased to 20mg for a following three weeks. Primary outcomes in this analysis were post-treatment changes in biases at six weeks compared with baseline, as measured using three validated psychological scales. FindingsFifty-nine MDD patients were randomly allocated to the psilocybin (n=30) or escitalopram (n=29) groups. Self-reported optimism showed a large and significant increase six-weeks after psilocybin treatment (Mdiff=6{middle dot}63 p<0{middle dot}0001; 95% CI [4{middle dot}06, 9{middle dot}20], d=1{middle dot}1), whereas there was no change following escitalopram (Mdiff=1{middle dot}52, p=0{middle dot}205; 95% CI [-0{middle dot}59, 3{middle dot}62], d=0{middle dot}4). Behavioral results found that patients were more optimistic about desirable life events after psilocybin treatment (Mdiff=0{middle dot}16, p=0{middle dot}0002; 95% CI [0{middle dot}08, 0{middle dot}23], d=1{middle dot}1), but they were also less pessimistic about negative life events after escitalopram treatment (Mdiff=0{middle dot}07, p=0{middle dot}018; 95% CI [0{middle dot}01, 0{middle dot}13], d=0{middle dot}5). We found improvements in all three domains of dysfunctional attitudes following psilocybin treatment: achievement (Mdiff=10{middle dot}37, p<0{middle dot}0001; 95% CI [6{middle dot}38, 14{middle dot}53], d=1{middle dot}0); dependency (Mdiff=7{middle dot}97, p<0{middle dot}0001; 95% CI [4{middle dot}00, 11{middle dot}93], d=0{middle dot}9) and self-control (Mdiff=6{middle dot}40, p=0{middle dot}0006; 95% CI [2{middle dot}60, 10{middle dot}20], d=0{middle dot}8)), whereas only the achievement domain improved after escitalopram (Mdiff=4{middle dot}10, p=0{middle dot}005; 95% CI [1{middle dot}35, 6{middle dot}86], d=0{middle dot}6). InterpretationThese 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. FundingSupported by a private donation from the Alexander Mosley Charitable Trust and by the founding partners of Imperial College Londons Centre for Psychedelic Research. Author ContributionRCH conceptualized the study design and RCH and DJN oversaw the trial. TL plotted and analysed the data. TL and JH interpreted the data. JH wrote the manuscript and TL and RCH provided edits. Transparency DeclarationThe lead author and manuscript guarantor affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Research Material AvailabilityResearch materials are available from the corresponding author, [JH], upon reasonable request.