Increased global integration in the brain after psilocybin therapy for depression

Abstract

Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose (NCT03429075). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.

Neuroimaging in psychedelic drug development: Past, present, and future

“…Modularity was assessed in two groups; patients from the initial open-label study 37 and patients from a double-blind study where psilocybin was compared with the selective serotonin reuptake inhibitor (SSRI) escitalopram 39 . Changes in modularity were related to change in clinical outcome scores in both studies, while escitalopram produced no such effects 44 . These findings are consonant with the disruptive effects on network function seen in the acute-challenge studies, and suggest that these effects might be central to psilocybin's rapid anti-depressant effects 45 .…”

“…The third "pillar" (pharmacologic activity; does the drug cause downstream effects on physiology, brain activity, or some other relevant measure?) can be assessed in a number of ways, most obviously in the current case, putative biomarkers of psychedelic response such as brain network segregation/modularity measured with fMRI 20,44 and/or PET neuroplasticity changes. In addition to being consistent with general procedures carried out in clinical development, this workflow may provide us with key insights into the unique molecular and functional effects of these novel compounds for use in basic-science research and the future development of pharmaceutical drug candidates.…”

Dysfunctional cortical gradient topography in treatment resistant major depression

“…The pervasive correlation between nodal degree and nodal dispersion in our patient sample suggests that TRD impacts cortical hierarchies by driving hyper-modularity within several brain networks (46). Other neuropsychiatric conditions have been shown to impact cortical connectivity gradients.…”

Unraveling the Mysteries of Mental Illness With Psilocybin

“…Recent work supports this hypothesis. Using functional magnetic resonance imaging (fMRI), one study found that psilocybin may reduce the hyperconnectivity in the DMN thought to be the result of depression, and consequently enhance connectivity in other brain functional networks, leading to a more “globally” integrated brain [ 97 ]. The study was an extension of previous work [ 79 , 98 ] and used two groups; one diagnosed with treatment-resistant depression (TRD) and a second diagnosed with MDD.…”

“…The psilocybin-induced brain network changes correlated well with the decreases in BDI score. Interestingly, increased global brain network connectivity, suggesting better integration, was not observed in the escitalopram treatment group [ 97 ]. This study is of increased interest because it is the first RCT with psilocybin against a previously studied antidepressant medication that reported greater treatment efficacy for the psychedelic while also suggesting a possible mechanistic explanation for the observed outcome differences.…”