Psilocybin therapy is an emerging intervention for depression that may be at least as effective as standard first-line treatments i.e., Selective Serotonin Reuptake Inhibitors (SSRIs). Here we assess neural responses to emotional faces (fear, happy, and neutral) using Blood Oxygen-Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) in two groups with major depressive disorder: 1) a 'psilocybin group' that received two dosing sessions with 25mg plus six weeks of daily placebo, and 2) an 'escitalopram group' that received six weeks of the SSRI escitalopram, plus two dosing sessions with an inactive/placebo dose of 1mg psilocybin. Both groups had an equal amount of psychological support throughout. An emotional face fMRI paradigm was completed at baseline (pre-treatment) and at the six-week post-treatment primary endpoint (three weeks following psilocybin dosing sessions). An analysis examining the interaction between patient group (psilocybin vs. escitalopram) and time-point (pre- vs. post-treatment) showed a robust effect in a distributed network of cortical brain regions. Follow-up analyses showed that post-treatment BOLD responses to emotional faces of all types were significantly reduced in the escitalopram group, with no change, or even a slight increase, in the psilocybin group. Specific analyses of the amygdala showed a reduction of response to fear faces in the escitalopram group, but no effects for the psilocybin group. Despite large improvements in depressive symptoms in the psilocybin group, psilocybin-therapy had only a minor effect on brain responsiveness to emotional stimuli. We suggest that reduced emotional responsiveness may be a biomarker of SSRIs' antidepressant action that is not shared by psilocybin-therapy.

Authors MBW, LD, and NE's primary employer is Invicro LLC., a contract research organization which provides services to the pharmaceutical and biotechnology industries. RCH is a scientific advisor to Maya Health, Osmind, Beckley Psytech, Usona Institute, Mindstate, Entheos Labs, and TRYP therapeutics. DJN is a scientific advisor to Awakn Life Sciences, and Algernon pharmaceuticals, and Psyched Wellness. DE is a scientific advisor to Mindstate, Aya Biosciences, and Clerkenwell Health.

NCT03429075

This trial was funded by a private donation from the Alexander Mosley Charitable Trust, supplemented by Founders of ICL's Centre for Psychedelic Research (CPR) (https://www.imperial.ac.uk/psychedelic-research-centre/funding-partners/). Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility.

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The London - Brent research ethics committee gave ethical approval for this work.

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All data produced in the present study are available upon reasonable request to the authors