Increased global integration in the brain after psilocybin therapy for depression

This fMRI study assessed the impact of psilocybin on brain function in two clinical trials of depression. In both trials, the antidepressant response to psilocybin was rapid and sustained, correlating with decreases in fMRI brain network modularity. Network cartography analyses indicated that serotonin (5-HT) 2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after a psilocybin treatment. Together, the findings from both studies point to global increases in brain network integration as an antidepressant mechanism in psilocybin therapy.

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.”

Authors: Richard E. Daws, Christopher Timmerman, Bruna Giribaldi, James D. Sexton, Matthew B. Wall, David Erritzoe, Leor Roseman, David J. Nutt & Robin L. Carhartt-Harris

Notes

Psilocybin has demonstrated significant efficacy in alleviating the symptoms of depression. A number of theories, such as increased functional connectivity in the brain and the role of the default mode network (DMN), have been put forward to explain the antidepressant effects psilocybin has, yet the exact mechanisms underlying this effect remain speculative at best.

The present paper, from the research team at Imperial College London, assessed the effects psilocybin has on brain function using fMRI in order to better understand the mechanism through which psilocybin elucidates its antidepressant effect. The paper includes data from two separate trials exploring the effects psilocybin therapy has in depressed patients: 1) an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression (TRD) where fMRI was recorded at baseline and 1-day after the 25mg dose, and 2) a double-blind placebo-controlled trial comparing the effects of psilocybin to the SSRI escitalopram in patients with major depressive disorder (MDD). In this second trial, patients received 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) and fMRI was recorded at baseline and 3 weeks after the second psilocybin dose.

Using the Beck Depression Inventory as the primary outcome measure, the researchers hypothesized that the well-replicated finding of brain network disintegration and desegregation under psychedelics would be apparent in post-treatment fMRI data and that this effect, consistent with a flatter energy landscape, will relate to improved depression outcomes and will not be observed after a course of escitalopram.

What’s going on in the brain?

  • In the open-label trial, brain modularity decreased one day after psilocybin therapy implying that there is a global increase in functional connectivity between the brain’s main intrinsic networks. This decreased modularity was predictive of improved therapeutic outcomes for TRD.
  • In the RCT, psilocybin decreased brain modularity but escitalopram did not while the response to psilocybin correlated with enhanced network flexibility.
  • Taken together, decreased brain modularity was observed and correlated with improvements in depressive symptomatology and this may be specific to psilocybin.
  • Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after the psilocybin treatment.
  • The liberating effects of psilocybin (e.g. emotional release, increased cognitive & psychological flexibility) in depressed patients may be a result of the effect psilocybin has on cortical 5-HT2A receptors, dysregulating activity in regions rich in their expression.

Overall, the findings of the present study suggest that a global increase in brain network integration may underlie the therapeutic effects psilocybin has in people with depression. Going forward, the authors note that large scale trials are needed to establish the generalizability, reliability and specificity of psilocybin’s antidepressant response. In terms of brain imaging studies, the authors recommend the use of network modularity analysis to elegantly summarize global changes in the brain’s functional network organization. Ultimately, findings expand on the potential mechanisms through which psilocybin elicits a rapid and sustained antidepressant effect.

The findings of this paper have been covered in an article from the BBC.

A written response to this paper can be found here (earlier pre-print link here).

The main critiques presented in this response include:

  • The original studies that were analysed in the above paper original used the Quick Inventory of Depressive Symptoms (QIDS) as their primary outcome measures. However, the above study used the Beck Depression Inventory (BDI) as the primary measure. This raises issues of multiple comparisons as “psilocybin was not found to outperform citalopram on the QIDS in the more recent trial, but its superiority to citalopram was more apparent on the BDI.”
  • The use of a one-tailed test in the statistical analysis does not provide adequate statistical power to infer psilocybin induces global increases in network integration.
  • In terms of changes in modularity, regression to the mean may have a role to play which underlines the important clarifying role of a placebo intervention.
  • Inconsistency within the open-label datasets. In the original report, psilocybin therapy increased default mode network (DMN) functional connectivity whereas Daws et al. reported in these same data a decrease in DMN connectivity using a different measure.
  • The omission of the only other published fMRI investigation of the effects of psilocybin therapy in patients with depression. “Consistent with the findings of the prior study, Daws et al. find post-psilocybin increases in their measure of neural flexibility and speculate that these increases could be related to enhanced cognitive flexibility.

The original authors have responded to these critiques. Check it out here.

Study details

Compounds studied
Psilocybin

Topics studied
Depression Neuroscience

Study characteristics
Double-Blind Open-Label

Participants
59 Humans

Authors

Authors associated with this publication with profiles on Blossom

Leor Roseman
Leor Roseman is a researcher at the Centre for Psychedelic Research, Imperial College London. His work focussed on psilocybin for depression, but is now related to peace-building through psychedelics.

Robin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.

David Erritzoe
David Erritzoe is the clinical director of the Centre for Psychedelic Research at Imperial College London. His work focuses on brain imaging (PET/(f)MRI).

Chris Timmermann
Chris Timmerman is a postdoc at Imperial College London. His research is mostly focussed on DMT.

Institutes

Institutes associated with this publication

Imperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.