Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression

OBJECTIVE: Psilocybin is an emerging intervention for depression that may be at least as effective as selective serotonin reuptake inhibitors (SSRIs), but effects of the two treatments on the neural correlates of emotional processing have never been directly compared. METHODS: The authors assessed neural responses to emotional faces using blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) in two groups with major depression. One group (N=25; 9 women and 16 men) received two dosing sessions with 25 mg psilocybin plus 6 weeks of daily inert placebo, and the second group (N=21; 6 women and 15 men) received 6 weeks of escitalopram plus two dosing sessions with a nonpsychoactive (placebo) dose of 1 mg psilocybin. Both groups had equal psychological support throughout: 3 hours of preparation, one in-person integration session following the psilocybin dosing sessions, and two further integration sessions conducted via video call or telephone. An emotional face fMRI paradigm was completed before treatment and at the 6-week posttreatment primary end point (3 weeks following psilocybin dosing sessions). RESULTS: Patient group (psilocybin versus escitalopram) interacted with time point (before versus after treatment) on a distributed set of cortical regions. Post hoc within-condition analyses showed that posttreatment BOLD responses to emotional faces of all types were significantly reduced in the escitalopram group, with no change or a slight increase in the psilocybin group. Analyses of amygdala responsivity showed a reduction of response to fearful faces in the escitalopram group, but lesser effects for the psilocybin group. CONCLUSIONS: Despite large improvements in depressive symptoms in the psilocybin group, psilocybin therapy had only a minor effect on brain responsiveness to emotional stimuli. These results are consistent with prior findings that the antidepressant action of SSRIs is often accompanied by a reduction in emotional responsiveness, but this effect may not occur in psychedelic therapy.