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Reduced brain responsiveness to emotional stimuli with escitalopram but not psilocybin therapy for depression

June 2023

DOI:10.1101/2023.05.29.23290667

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CC BY-NC-ND 4.0

Authors:

Matthew B Wall

Invicro London

Bruna Giribaldi

Imperial College London

Leor Roseman

University of Exeter

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Preprints and early-stage research may not have been peer reviewed yet.

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.

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Reduced brain responsiveness to emotional stimuli with

escitalopram but not psilocybin therapy for depression

Matthew B. Wall1,2,3, Lysia Demetriou1,2,4, Bruna Giribaldi5, Leor Roseman5, Natalie Ertl1,2,

David Erritzoe5, David J. Nutt5, Robin L. Carhart-Harris5,6.

1Invicro London, Hammersmith Hospital, UK

2Faculty of Medicine, Imperial College London, UK

3Clinical Psychopharmacology Unit, University College London, UK

4Nuffield Department of Women’s and Reproductive Health, University of Oxford

5Centre for Psychedelic Research, Division of Psychiatry, Department of Brain Sciences,

Faculty of Medicine, Imperial College London

6Psychedelics Division, Neuroscape, University of California San Francisco, USA.

Corresponding Author:

Matthew B. Wall

matt.wall@invicro.co.uk

Funding and Disclosures

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.

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.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 3, 2023. ; https://doi.org/10.1101/2023.05.29.23290667doi: medRxiv preprint

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Abstract

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.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Introduction

Major Depressive Disorder (MDD) is one of the most prevalent and debilitating psychiatric

disorders 1. Current treatment guidelines suggest psychotherapy for mild depression, with

pharmacotherapy or a combination of the two treatments recommended for moderate-to-

severe cases 2. Pharmacotherapy with Selective Serotonin Reuptake Inhibitors (SSRIs) is a

popular option. However, SSRIs are only moderately effective, take four to eight weeks to

show a meaningful therapeutic response, and have acceptability rates (indexed by

treatment discontinuation) comparable with placebo 3, i.e. around 25-30% 4.

A phenomenon commonly referred to as ‘emotional blunting’ (i.e., a restricted range or

intensity of emotional experience) has been associated with SSRI use, with one survey

suggesting a prevalence close to 50% 5. Diminished libido and sexual functioning with SSRI

treatment 6,7 and a modest impact on symptoms of anhedonia in depression 8 are also

commonly reported. One potential cause of diminished emotional responsiveness via SSRIs

may be increased 5-HT activity on inhibitory postsynaptic 5-HT1A receptors in limbic and

paralimbic circuitry implicated in affective and hedonic functioning 9,10. Specifically,

decreased amygdala responsiveness to emotional stimuli (i.e. a normalization of responses

to negative stimuli) has been found in depressed patients soon after beginning a course of

SSRIs 11,12, and similar effects have been found in healthy subjects with short-term use of

SSRIs 13,14. This emotional/amygdala blunting has been hypothesized to be central to their

therapeutic effect 15,16.

Novel treatments for major depression are generating a great deal of interest in psychiatry

17,18. Ketamine has shown potential as a rapid-acting treatment option 19, and promising

results are being seen in small clinical trials assessing psilocybin therapy for depression 20–22

and depressive symptoms 23–25. Psilocybin is a naturally occurring ‘classic’ psychedelic which

exerts its characteristic subjective effects through direct agonism of the 5-HT2A receptor 26.

Acutely a 25mg dose of psilocybin has profound effects on spontaneous brain function 27

and longer-term functional brain changes have been reported with this dose of psilocybin in

depressed 28–30 as well as in healthy individuals 31,32. In clinical use, psilocybin dosing

sessions can be combined with psychological therapy and support, before (‘preparation’

sessions), during the dosing sessions, and after (‘integration’ sessions)33.

Emotional face perception paradigms are widely used in human fMRI studies, and

particularly in depression research 34. Using this approach in a sample of patients before and

one-day after psilocybin therapy for treatment-resistant depression we previously observed

an increase in BOLD responsiveness to emotional face stimuli in depressed patients35, which

may reflect early changes in responses to treatment or ‘afterglow’ phenomena36, i.e., a sub-

acute life in mood. Despite being directionally opposite to the BOLD-reducing action of SSRIs

on emotional faces 11,12,37, this finding was predictive of longer-term treatment response 35.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

An extension of this work identified changes in amygdala connectivity that were also

associated with clinical improvements 38. In contrast to the emotional blunting associated

with SSRIs, a sense of increased emotional connection is often reported with effective

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psychedelic therapy 39. Thus, a differential effect on emotional functioning between SSRIs

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and psychedelic therapy could explain their contrasting fMRI findings in emotional

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processing paradigms.

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The aim of the present study was to directly compare the brain effects of the two

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treatments for the first time, in a double-blinded, randomized-controlled trial. We chose

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escitalopram as an active comparator for psilocybin therapy because of its high

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pharmacological selectivity as a 5-HT reuptake inhibitor and good antidepressant

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performance; in terms of both tolerability and efficacy 3,40. Psilocybin therapy was carried

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out in a manner that was generally consistent with previous studies. The clinical procedures

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are detailed below and the clinical findings are fully reported elsewhere 41. The specific

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emotional facial expression paradigm employed in this study was similar to those used in

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previous work, e.g. 11,35. The main pre-registered hypothesis for this trial was that the two

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treatments would have significantly different effects on brain responsiveness to emotional

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faces (see trial registration under identifier NCT03429075;

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https://clinicaltrials.gov/ct2/show/NCT03429075). This is therefore the first report of the

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primary study outcome.

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Methods

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This study was approved by the Brent Research Ethics Committee, with additional approvals

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from the UK Medicines & Healthcare products Regulatory Agency, the Health Research

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Authority, and Imperial College London. MRI data collection, drug storage, and dispensing

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took place at Invicro LLC, Hammersmith Hospital, London. All subjects gave written

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informed consent, and the trial was conducted under the principles of Good Clinical

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Practice.

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Design

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The full clinical study procedure is reported in 41. This was a phase II, double-blinded,

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randomized, controlled experimental medicine trial. MRI scanning was done prior to any

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therapeutic intervention (baseline) and six weeks and one day after the first dosing day. For

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the psilocybin group, they received 2 x 25mg doses of psilocybin, three weeks apart. The

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post-treatment MR scan occurred three weeks after the second 25mg dose. After the first of

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the two dosing sessions, patients in the psilocybin group were provided with a bottle of

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capsules containing microcrystalline cellulose (i.e. inert placebo capsules) and instructed to

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take one per day for the next three weeks and two per day for the final three weeks until

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scan visit two, which was the primary endpoint. Subjects in the escitalopram group received

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a 1mg dose of psilocybin on each of the two dosing visits (also three weeks apart); 1mg has

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negligible subjective effects and therefore served as a control procedure/placebo. These

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subjects were provided with encapsulated escitalopram (10mg capsules) and were

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instructed to take one capsule (10mg escitalopram) daily for the first three weeks, and two

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capsules (20mg) daily for the final three weeks. Scan visit two occurred on the day of the

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final capsule ingestion at the approximate time of peak plasma concentration, implying both

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steady state and acute presence of escitalopram for the escitalopram group.

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Clinical scales

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The primary pre-registered (https://clinicaltrials.gov/ct2/show/NCT03429075) clinical

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outcome was the Quick Inventory of Depression Score (QIDS-SR16) 42. Additional measures

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used were the Beck Depression Inventory (BDI) 43, the Warwick-Edinburgh Mental Well-

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being Scale (WEMWBS) for assessment of well-being 44, the Snaith-Hamilton Pleasure Scale

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(SHAPS) 45 for assessment of anhedonia, the Laukes Emotional Intensity Scale (LEIS) 6 for

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assessment of emotional function, and the PRSexDQ 46 for assessment of changes to sexual

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function.

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Participants and Recruitment

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For full details of the recruitment and screening procedures see 41. Participants were

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recruited using trial networks, social media, and other sources, via a recruitment website

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(https://www.imperial.ac.uk/psychedelic-research-centre). Volunteers emailed the

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recruitment coordinator, so all recruited participants were self-referred. There followed a

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multi-step screening process involving telephone and video calls, and in-person sessions

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with a trial psychiatrist.

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Inclusion criteria were: a score of at least 17 (indicating moderate-to-severe MDD) on the

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HAM-D-17 assessments which were performed on the video call, confirmation of a diagnosis

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of depression and a satisfactory medical history (obtained from the patient’s general

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physician), willingness to withdraw completely from psychiatric medication (at least two

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weeks) and psychotherapy (at least three weeks) before starting the trial, age 18-80 years,

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and sufficient competence with English. The main exclusion criteria were a history of certain

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exclusory mental or physical health conditions (both physician-assessed), pregnancy,

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previous courses of escitalopram, and drug or alcohol dependence.

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Thirty patients were randomized to the psilocybin arm of the study, and 29 were

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randomized to the escitalopram arm. However, four patients in the escitalopram arm

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discontinued treatment due to side effects and were therefore excluded in the present

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analyses. A further five subjects in the escitalopram arm did not complete the second MRI

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visit because of Covid-19 lockdowns in the UK in March/April 2020. Four subjects in the

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psilocybin arm also did not complete their second MRI scanning session also because of

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Covid-19 lockdowns. After the end of the trial, it was revealed that one subject in the

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psilocybin arm had been using cannabis regularly throughout the trial, so their data was also

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excluded. Consequently, there were N=21 subjects available for analysis in the escitalopram

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arm of the study, and N=25 in the psilocybin arm. See figure 1 for the full recruitment flow

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diagram.

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Figure 1. Recruitment flow diagram for the study.

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Task and image acquisition

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The fMRI task involved stimuli with three facial expressions: fear, happy, and neutral. These

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were selected from the Karolinska Directed Emotional Faces set 47 and presented in blocks

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of five images of the same type, with each image on-screen for 3s. Rest/baseline blocks

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were also included, which displayed a small fixation cross at the center of the screen. There

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were eight repeats of each block type presented in a pre-determined pseudo-random order,

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and 32 blocks in total (eight each of fear, happy, neutral, and rest/baseline). The total task

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time was eight minutes, plus a 10s buffer period at the end of the task to ensure the last

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response was fully captured. Two different pseudo-random orders of block presentation

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were used, and subjects saw one order on the first visit and a different order on the second

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visit. Patients passively viewed the faces.

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Data was acquired using a Siemens TIM Trio 3 Tesla MRI scanner (Siemens, Erlangen),

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equipped with a 32-channel phased-array head-coil. Anatomical images were acquired using

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the recommended parameters for MPRAGE by the ADNI-GO project 48: TE = 2.98ms, TR =

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2300ms, 160 sagittal slices, 256x256 in-plane FOV, flip angle = 9, 1mm isotropic voxels.

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. CC-BY-NC-ND 4.0 International licenseIt is made available under a

The functional (Echo-Planar-Imaging) acquisition was based on the multiband EPI WIP v012b

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provided by the University of Minnesota 49–51 using a multiband acceleration factor of 2, and

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a slice acceleration (GRAPPA) factor of 2 (TR=1250ms, TE=30ms, 44 slices, 3mm isotropic

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voxels, FOV = 192x192mm, flip angle = 70, bandwidth = 2232Hz/pixel, 392 volumes

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acquired). This was based on sequences previously tested and validated by 52.

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Data analysis

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Analysis was conducted using FSL version 5 53. Processing of the anatomical data used the

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fsl_anat script, which performs a number of processes including inhomogeneity correction

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and brain extraction using BET (Brain Extraction Tool). Pre-processing of the functional data

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included head-motion correction, smoothing (6 mm), registration to a standard template

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(MNI152) using a two-step registration using the subjects’ anatomical scans, and high-pass

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filtering (0.01 Hz).

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For the first-level analyses, a general linear model contained regressors derived from the

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occurrence of the stimuli in three (fear, happy, and neutral face blocks) separate regressors.

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These stimulus-related time-series were convolved with a standard Gamma function to

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model the hemodynamic response. An extended set of 24 head-motion regressors were also

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included as confounds, which included temporal derivatives and quadratic functions derived

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from the raw head-motion parameters. Modelling used FSL’s FILM (FMRIB’s Improved

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Linear Model) for pre-whitening and autocorrelation correction. Contrasts were computed

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that compared each stimulus condition with the fixation cross baseline condition, as well as

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a summary contrast that modelled all stimulus conditions relative to the fixation cross

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baseline.

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To visualize treatment effects, mid-level, fixed-effects, within-subjects analyses were used

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to generate comparisons between pre- and post-intervention visits for each subject. Group

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analyses were random effects (FLAME-1) models, with statistical maps thresholded at Z =

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2.3, and p < 0.05 (cluster corrected). Mean analyses including data from all subjects and all

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visits were generated to verify the success of the task paradigm in producing an expected

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pattern of brain activation, and the general acquisition and analysis procedures (see

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supplementary material for results). Between-subjects group-level analyses then used the

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results of the mid-level analyses for a comparison between the two treatment groups

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(psilocybin vs. escitalopram). These comparisons modelled both the difference between

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groups, and the difference between study visits, and therefore test an interaction effect.

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Data were extracted from functional clusters/maps in these group-level analyses and

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plotted to visualize the precise pattern of effects across the task conditions, visits, and drug

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treatment groups. Additionally, group-level analyses of pre- vs. post-treatment effects were

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also performed with an anatomical amygdala mask, derived from the Harvard-Oxford sub-

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cortical atlas, provided with FSL. The rationale for this analysis was based on previous work

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showing that amygdala connectivity and responsiveness to emotional stimuli can be

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specifically affected by psilocybin therapy 35,38 and that it is also a region of interest in

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depression research 10. Finally, a control analysis was performed that compared the pre-

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therapy (baseline) scans of the two treatment groups, to examine any potential baseline

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differences between the two groups.

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Additional exploratory analyses were conducted to examine the relationship between

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measures of clinical outcomes, and the BOLD activation data, using Pearson’s correlations

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and moderation analyses to examine the specific relationships between clinical depression

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outcomes, BOLD activation data, and a subjective measure of emotional function.

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Results

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Demographics

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Demographic and selected clinical (baseline, pre-treatment) information for this sample are

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shown in table 1. There were no significant differences at baseline between the two groups

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on any demographic or clinical measure except for the QIDS-SR-16 score, where the

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escitalopram group were somewhat higher.

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Characteristic

Escitalopram

(N=21)

Psilocybin

(N=25)

Difference

Demographic

Age: MeanSD (range)

38.1910.9 (22-60)

42.811.7(21-64)

t(44)=-1.06,

p = 0.294

Female sex: no. (%)

6 (30)

9 (36)

2 (1) = 0.287,

p = 0.592

White race: no. (%)

17 (80)

24 (96)

2 (1) = 2.67,

p = 0.102

Employment status: no. (%)

Employed

16 (76)

16 (64)

2 (2) = 3.55,

p = 0.471

Unemployed

4 (19)

7 (28)

Student

1 (5)

2 (8)

University education (%)

15 (71)

19 (76)

2 (1) = 0.12,

p = 0.725

Weekly alcohol use, UK Units:

MeanSD (range)

8.558.69 (0-30)

4.85.8 (0-20)

t(44)=-1.73,

p = 0.090

No previous psilocybin use: no. (%)

15 (71)

17 (68)

2 (1) = 0.063,

p = 0.801

Discontinued psychiatric medication

for trial: no. (%)

8 (40)

10 (40)

2 (1) = 0.00,

p = 1.0

Clinical

Duration of illness, years: MeanSD

(range)

15.311.4 (1.5-46)

21.311.0(3-44)

t(44)=-1.84,

p = 0.08

Previous psychiatric medications:

MeanSD (range)

1.951.63 (0-5)

2.21.68 (0-6)

t(44)=-0.505,

p = 0.616

Previous use of psychotherapy: no. (%)

19 (90)

23 (92)

2 (1) = 0.033,

p = 0.855

QIDS-SR-16 score at baseline:

MeanSD (range)

16.34.4 (6-22)

13.93.4 (7-19)

t(44)=2.128,

p = 0.039

BDI-1A score at baseline: MeanSD

(range)

28.06.73 (10-38)

28.76.6 (16-41)

t(44)=0.34,

p = 0.735

Table 1. Demographic information and selected baseline clinical scores for the

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sample. Pre-treatment baseline was 7-10 days before dosing day 1. All inferential

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statistics in the third column are non-significant (at an alpha value of p < 0.05) except

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the QIDS-SR-16 baseline score.

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Clinical data

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The full clinical results from the entire cohort are presented in 41, however, selected clinical

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data from the restricted cohort of n = 45 that completed the MRI scanning sessions, after

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exclusions, is presented here (baseline to six week timepoints). For the primary outcome

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measure (QIDS SR-16) a mixed-effects analysis with one between-groups factor (treatment)

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and one within-subjects factor (time) showed a significant main effect of treatment group

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(F[1,44] = 11.76, p = 0.0013) and time (F[6,251] = 26.36, p < 0.0001), but no significant

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interaction (figure 2A). A similar analysis was used for Beck Depression Inventory (BDI)

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scores, which also showed significant main effects of time (F[3,113] = 55.89, p < 0.0001),

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time (F[1,44] = 8.73, p = 0.005), and a significant interaction (F[3,127] = 6.49, p = 0.0004),

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suggesting a significantly greater decrease in BDI scores in the psilocybin group (figure 2B).

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The same analysis model applied to well-being (WEMWBS) data showed a significant main

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effect of time (F[2,92) = 20.93, p < 0.0001), a significant main effect of treatment (F[1,44) =

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12.11, p = 0.0011) and a significant interaction between the two factors (F[3,127) = 4.97, p =

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0.0027). These results suggest significantly greater improvement in well-being scores in the

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psilocybin treatment group (see figure 2C). A two-way ANOVA analysis of scores on the

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Snaith Hamilton Anhedonia Pleasure Scale (SHAPS) showed no main effect of treatment

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group (F[1,44) = 2.13, p = 0.15), but a significant effect of pre- vs. post-treatment (F[1,44) =

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79.89, p < 0.0001), and a significant interaction (F[1,44) = 7.34, p = 0.0096), again suggesting

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greater improvement in anhedonia in the psilocybin group (figure 2D). The change (pre- vs.

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post-treatment) in scores on perceived emotional responsiveness or intensity (LEIS) were

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analysed using an unpaired t-test, and showed a significant difference between the groups

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(t[44] = 5.27, p < 0.0001), i.e., there was a relative decrease in emotional-intensity in the

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escitalopram group and a relative increase in the psilocybin group (figure 2E). Finally,

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change scores on the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ)

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were also significantly different between the two treatment groups (t[44] = 3.08, p =

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0.0036) in this restricted cohort (figure 2F).

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Figure 2. Selected clinical data from the fMRI sub-sample analyzed here. Error bars

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are standard errors. A: Significant interaction between the treatment groups and

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time on Beck Depression Inventory (BDI) scores, * p = 0.0002. B. Significant main

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effect of treatment on the Quick Inventory of Depressive Symptoms (QIDS), * p =

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0.002. C: Significant differences between the treatment groups on the Warwick-

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Edinburgh Mental Well-being Scale (WEMWBS), * p = 0.0031. D: Significant

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differences between the treatment groups on the Snaith Hamilton Anhedonia

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Pleasure Scale (SHAPS), * p = 0.014. E: Significant differences between the treatment

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groups on change (pre- vs. post-treatment) scores on the Laukes Emotional Intensity

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. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Scale (LEIS), * p < 0.0001). F: Significant differences between the treatment groups

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on the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ). * p =

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0.0036. Note, higher scores on the PRSexDQ reflect greater sexual dysfunction.

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Imaging data

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Subject head-motion was assessed and no subjects were excluded on this basis. There were

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also no significant differences in head-motion between groups or across study visits; see

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supplementary material for full details. Results of an analysis modelling the mean task

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activation of all subjects from each group and all scan visits showed the predicted pattern of

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task effects, with the emotional faces activating a broad pattern of brain regions including

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primary and secondary visual cortex, amygdala, thalamus, insula, and superior frontal

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regions (see supplementary figure S1). This pattern is entirely consistent with previous work

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(e.g. 54) and therefore validates the experimental and analysis procedures.

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Results from the main analyses of treatment and drug group effects are shown in figure 3.

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This is a complex effect that models the interaction between the (within-subject) pre- and

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post-treatment factor and the (between-subjects) treatment group factor. The voxel-wise

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analyses found a large network of areas in which there was a decreased BOLD response

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post-treatment in the escitalopram group, relative to the psilocybin group. Significant

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clusters were evident in the dorsolateral pre-frontal cortex, supramarginal gyrus, mid-insula,

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and superior temporal lobe.

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Data was extracted from this set of clusters and plotted across all the stimulus conditions

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(figure 3, panels B-E). A mixed-model 2 (group) x 2 (visit) x 3 (facial expression) ANOVA

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showed a significant main effect of study visit (F[1,44] = 5.27, p = 0.027). There were also

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significant interactions between the treatment group and visit factors (F[1,44] = 10.83, p =

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0.002), and the visit and facial expression factors (F[2,86] = 10.09, p < 0.001).

336

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Follow-up comparisons revealed that in the escitalopram group there was a significant

338

reduction in responses on the second visit (six weeks) for all three individual facial

339

expressions: fear (t[20] = 2.82, p = 0.011), happy (t[20] = 3.79, p = 0.001), and neutral (t[20]

340

= 2.25, p = 0.036). This effect is also significant when collapsing across all facial expressions

341

(t[29] = 3.16, p = 0.005). All these results survive a Bonferroni-corrected p threshold of

342

0.0125, except the neutral faces result. In the psilocybin group, similar comparisons showed

343

a significant increase in responses on the post-therapy visit for the neutral facial expressions

344

(t[24] = -3.17, p = 0.004).This neutral faces result for the psilocybin group survived the

345

corrected alpha threshold (p = 0.0125). There were no other significant effects.

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. CC-BY-NC-ND 4.0 International licenseIt is made available under a

348

Figure 3. Results from the main analysis. Panel A shows results of a voxel-wise (Z>

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2.3, p < 0.05, corrected for multiple comparisons) analysis of an interaction effect

350

between the two treatment groups and study visit (psilocybin (pre- > post-

351

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

treatment) > escitalopram (pre- > post-treatment), showing a relatively greater

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activation to faces in the post-treatment scan (relative to the pre-treatment baseline

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scan) for the psilocybin group, compared with the escitalopram group. Panels B-E

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break down this high-level effect and plot ROI data from this total set of clusters for

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all task conditions, groups, and study visits. Results show that the effect is driven by

356

a decrease in response to all face types in the escitalopram group in the post-

357

treatment visit, with minimal post-treatment change in the psilocybin group. In fact,

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for neutral faces there is an increased activation post-treatment with psilocybin. * =

359

p < 0.05, see text for exact values.

360

361

Figure 4 shows the results of the analyses using a bilateral amygdala mask. These analyses

362

compared pre- vs. post-treatment effects for the various task contrasts within each group

363

and found a significant activation cluster in the right amygdala for the escitalopram group,

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with a smaller cluster in the right amygdala for the psilocybin group, both on the task

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contrast of fear > neutral faces (figure 3, panels A and C). There were no other significant

366

effects on the other task contrasts conducted in these analyses using the amygdala mask.

367

Extracting and plotting data from the relevant activation clusters (figure 3; panels B and D),

368

and comparing baseline to post-therapy responses found that there was no change in the

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psilocybin group post-treatment, however, there was a reduction in responses in the

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escitalopram group, with a significant effect for the fear faces (t[20]=2.33, p=0.031).

371

However, this effect does not survive a multiple-comparisons correction for the four tests

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conducted here.

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375

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Figure 4. Results from analyses using an anatomical amygdala mask for the

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comparison of pre- vs. post-treatment for the task contrast fear > neutral. The

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escitalopram group showed relatively large and bilateral activation clusters for this

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contrast (A) whereas the psilocybin group showed a more dorsal and smaller cluster

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only in the left amygdala (C). ROI data from these clusters revealed a significant

381

reduction in response to fear faces post-treatment in the escitalopram group, with

382

no effects seen in the psilocybin group. * = p < 0.05.

383

384

Reassuringly, in the control analysis of the pre-treatment (baseline) scans, BOLD activations

385

were not significantly different between the two groups on any task condition or contrast.

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387

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Relationships between BOLD and clinical data

389

390

Exploratory analyses were conducted to examine relationships between the ROI data

391

plotted in figure 2 and the selected clinical data presented in figure 1. Correlations were

392

calculated within each patient group comparing the change in clinical scores (i.e., score at

393

baseline, subtracted from the 6-week follow-up) with the change in BOLD activity (visit 1

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. CC-BY-NC-ND 4.0 International licenseIt is made available under a

subtracted from visit 2) from the regions identified in figure 2. There were no significant

395

correlations present in these analyses. Results can be found in the supplementary material.

396

397

Additional exploratory work used two moderation analyses to test whether the change in

398

brain activity (average of all faces) could predict the main clinical outcome (change in QIDS

399

scores from baseline to six weeks), and whether this was moderated by emotional function

400

(change in score on the LEIS). In the psilocybin group, the LEIS alone was significantly

401

predictive of QIDS outcomes (Z = -2.24, p = 0.025), but brain activity alone was not (Z = -

402

0.07, p = 0.944), and neither was the interaction between the predictor and moderator (Z = -

403

0.91, p = 0.363). For the escitalopram group, the change in brain activity was predictive of

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BDI outcomes (Z = 1.97, p = 0.048), and while the LEIS alone was not (Z = 0.36, p = 0.721);

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the interaction (i.e., a moderation of the predictive power of brain activity via LEIS) was

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strongly significant (Z = 3.14, p = 0.002).

407

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In moderation analyses, the interaction term is the most instructive result, and a significant

409

result denotes that the relationship between the predictor and the dependent variable is

410

stronger or weaker, given varying levels of the moderator. In this case, since all three

411

variables are negative (i.e. relative decreases in brain activity, decreases in depression, and

412

decreases in emotional function) it implies that - in the escitalopram group - the relationship

413

between brain function and the clinical outcome (QIDS) is stronger when patients have

414

greater levels of emotional blunting (i.e. lower scores on the LEIS). LEIS scores were

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relatively increased in the psilocybin group, meaning that the significant direct effect of the

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LEIS on clinical outcome (Z = -2.24) implies that a higher level of emotional function post-

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psilocybin-therapy relates to a greater post-treatment reduction in depression scores (i.e.

418

greater clinical effect) after the psilocybin-therapy. These analyses were also repeated with

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the BDI as the dependent variable and showed a similar pattern of results; see

420

supplementary material.

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. CC-BY-NC-ND 4.0 International licenseIt is made available under a

423

Figure 5. Results of exploratory moderation analyses examining the effects of the

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change in brain activity on the primary clinical outcome (QIDS) and its moderation by

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a measure of emotional function (LEIS). In the psilocybin group (top) emotional

426

function has a significant effect on clinical outcomes, but there is no significant effect

427

of brain activity and no interaction effect. In the escitalopram group (bottom) the

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change in brain activity has a robust effect on clinical outcome, and emotional

429

function also has a strong moderating effect, supporting mechanistic assumptions

430

about the action of the SSRI. Significant effects are denoted by a green arrow and *.

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. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Discussion

432

433

Consistent with our primary hypothesis for this comparative mechanisms trial, we found

434

significant differences in brain responsiveness to emotional stimuli after escitalopram

435

compared with psilocybin for depression. The separate examination of treatment effects

436

revealed that the between-group differences were largely driven by decreases in

437

responsiveness post-treatment in the escitalopram group. Null, or opposite (i.e., slightly

438

increased activation) effects were seen in the psilocybin group, depending on the exact face

439

type i.e., increased activations post-treatment to neutral faces was seen in the whole brain

440

analysis. Results were generally consistent whether examining whole brain activations or

441

focusing specifically on the amygdala. Exploratory moderation analyses suggested that

442

outcomes were better predicted by the change in brain activity, moderated by changes in

443

emotional function, in the escitalopram group, whereas clinical outcomes were better

444

predicted by changes in emotional function in the psilocybin group.

445

446

This study’s findings lend support to the view that psilocybin-therapy and SSRIs have distinct

447

therapeutic mechanisms of action 9. While both drugs act on the 5-HT system, SSRIs

448

increase synaptic concentrations of 5-HT by blocking its reuptake, whereas psilocybin

449

(through its main active metabolite, psilocin) acts as a direct agonist on certain 5-HT

450

receptors, with a key action on the 5-HT2A receptor subtype 26,55. Increased synaptic 5-HT

451

via SSRIs should affect all available 5-HT receptors but there is some evidence to suggest

452

that the activation of inhibitory postsynaptic 5-HT1A receptors, which are heavily expressed

453

in limbic regions 56 and implicated in emotional 57 and sexual functioning 58, play an

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important role in the action of SSRIs. The four to six week lag in antidepressant effects with

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SSRIs is thought to be due to a gradual down-regulation of inhibitory 5-HT1A pre-synaptic

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auto-receptors 59, allowing a slow disinhibition of serotonergic efflux onto postsynaptic

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targets. Although speculative, activating inhibitory postsynaptic 5-HT1A receptors in limbic

458

regions may dampen their responsiveness and account for the emotional blunting and loss

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of sexual function described by some patients receiving treatment with SSRIs 7. The

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moderation analyses provided here suggest that this reduction in brain responsiveness to

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emotion with SSRIs may be an important factor in their therapeutic action.

462

463

The results of the whole-brain between-groups contrast revealed a pattern of reduced

464

responsiveness under escitalopram in regions including the DLPFC, temporo-parietal

465

junction (TPJ), supramarginal gyrus, and secondary somatosensory cortex. These are largely

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high-level transmodal regions implicated in a broad range of processes, including social-

467

cognitive functions. They are not necessarily regions most commonly identified in emotional

468

face perception 54, however, a recent meta-analysis 60 highlighted a similar set of regions

469

involved in empathy for physical pain, emotional situations, and emotional faces. A further

470

recent meta-analysis of the neural effects of antidepressants as assessed by emotional

471

response paradigms has also identified effects in a wider set of cortical regions than just the

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amygdala 10. Although speculative, the relative preservation of responsiveness in these high-

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level cortical regions after psilocybin therapy may relate to its positive modulation of socio-

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emotional functioning 61, an assumption that might also align with the greater

475

responsiveness to neutral faces post psilocybin therapy.

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477

Psilocybin therapy is emerging as a potential paradigm-shifting62,63 treatment for depression

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and other commonly comorbid disorders64 ; paradigm-shifting because it is arguably the first

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truly effective drug-assisted psychotherapy41. This may be because psilocybin enhances

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affective psychotherapeutic processes in a different way to other compounds that have

481

been combined with psychotherapy 65 including SSRIs66. Psilocybin therapy appears to have

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an efficacy at least comparable to established treatments20,22,41, with treatment response

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rates of approximately 70% in three recent trials in MDD21,22,67, and has a favorable side-

484

effect and patient acceptance profile. The present finding of a robust difference in the

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effects of an SSRI and psilocybin therapy on brain responsiveness to emotional stimuli are

486

consistent with previous assumptions about their differential therapeutic actions9, as well as

487

this trial’s pre-registered primary mechanistic hypothesis

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(https://clinicaltrials.gov/ct2/show/NCT03429075).

489

490

A generalized emotional blunting is often associated with SSRIs5, whereas greater

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acceptance of emotions and a multi-faceted sense of reconnection39,68 is commonplace with

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psilocybin-therapy. The differing pattern of effects in the exploratory moderation analyses

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presented here also support this perspective. In the psilocybin group, the (relatively

494

increased) emotional function was shown to have a direct positive effect on clinical

495

outcome, such that higher levels of emotional function were associated with greater

496

improvements in clinical symptoms. In the escitalopram group however, the effect of

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changes in emotional function was a robust moderator of the effect of brain responses on

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the clinical outcome, but in an opposite direction. The relationship between brain function

499

(decreased responsiveness to faces) and clinical effects (decreased symptom severity) was

500

strongest for those patients who reported the largest muting of the intensity of their

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emotions (LEIS). As others have recently noted9,16 this emotional blunting associated with

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SSRIs may be a key factor in their therapeutic efficacy, and the current findings support this

503

perspective.

504

505

The importance of the 5-HT2A receptor for the action of psychedelics is well established26,

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as demonstrated for example, via a strong and selective affinity-to-potency relationship 69,

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antagonist pre-treatment blocking the psychedelic effects70, and most recently, subjective

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psychedelic effects correlating with degree of 5-HT2A receptor occupation in the human

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brain71. 5-HT2A receptors are highly expressed throughout the human cortex56,72, but

510

particularly in high-level associative/transmodal regions that undergo marked expansion

511

throughout brain development73 and have expanded most evolutionarily74,75. A growing

512

body of evidence has linked 5-HT2A receptor signaling with increases in a variety of markers

513

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

of neuroplasticity76,77. The most recent model of psychedelic therapy’s mechanism of action

514

emphasizes a role for enhanced 5-HT2AR-induced cortical plasticity; opening a window for

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healthy psychological change, guided by concomitant psychotherapy64,78. In contrast to the

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effects of SSRIs, suppressed emotional or limbic responsiveness is not a feature of the

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psychedelic therapy model. Indeed, acute emotional release during ‘the trip’79 and then

518

progress towards greater emotional acceptance and ‘reconnection’39 are thought to be

519

important components of the psychedelic therapy model. Together with the present results,

520

replicated findings of increased whole brain functional integrity after psilocybin therapy for

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depression 30, as well as increased dynamic flexibility 29, imply a different antidepressant

522

action for psilocybin relative to SSRIs.

523

524

Regarding this study’s design, it should be noted that the final post-treatment scan occurred

525

hours after the final dose for those in the escitalopram group (coinciding with peak plasma

526

concentration of the drug) but three weeks after the second of two 25mg psilocybin

527

sessions for the psilocybin group. The smaller changes in post-treatment brain functioning in

528

the psilocybin group may be due to the duration since dosing and a different result may

529

have been found had we scanned closer to the last psilocybin dosing session, as we did in

530

previous work, where we showed a relative increases in amygdala responses one-day post-

531

dosing 28. We believe that the present study’s design can be justified however, as the

532

intention was to capture the enduring antidepressant effects of psilocybin-therapy, and

533

these were robust at the 6-week endpoint (3 weeks after the final psilocybin dosing

534

session)41. Our current findings can be seen as consistent with previous work in which

535

healthy volunteers received a single-dose of psilocybin and reduced amygdala responses

536

were observed at a one-week follow-up, with responses returning to baseline after one

537

month 80. Interestingly, a distinct metric (whole-brain network modularity applied to

538

spontaneous brain activity) has been found to reliably index the antidepressant action of

539

psilocybin-therapy, but not escitalopram30. The implication is that (unlike for SSRIs11) the

540

emotional face paradigm may not be an especially sensitive marker of the antidepressant

541

action of psilocybin-therapy (on this time-scale), whereas other brain indices may be more

542

sensitive to its specific action.

543

544

Some previous work has suggested that SSRIs and related antidepressant drugs have a

545

selective action on the processing of negatively valenced emotional stimuli 12. We did not

546

replicate this result in the whole-brain analysis but we did see suggestions of less

547

suppression of amygdala responses to happy and neutral faces with escitalopram relative to

548

its effect on fearful faces. However, consistent with observations from previous work 81,82,

549

faces of a negative valence evoked the largest amygdala responses in this study (figure 3). In

550

alignment with statistical principles, one could suggest that a drug’s modulatory action

551

would be greatest in the domain of functioning that is especially sensitive under baseline

552

conditions, i.e. in this case, the negatively-valenced domain. It seems plausible therefore

553

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that this could account for SSRI’s apparent biased action on negatively-valenced emotional

554

stimuli as seen in previous studies 12.

555

556

In conclusion, consistent with the primary hypothesis for this trial, fMRI analyses revealed a

557

reduced brain responsiveness to emotional face stimuli after six weeks of daily escitalopram

558

but not three weeks after the second of two 25mg dosing sessions with psilocybin-therapy

559

for major depressive disorder. The escitalopram data is consistent with current theories on

560

the therapeutic action of SSRIs 15 and the comparison with psilocybin-therapy highlights the

561

different brain actions of these two different treatment modalities.

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. CC-BY-NC-ND 4.0 International licenseIt is made available under a

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2012;36(1):16-26. doi:10.1007/s11031-011-9238-5

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812

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Supplementary material

813

814

Head movement

815

816

Overall head-motion characteristics for all subjects were excellent. Assessment of subject

817

head-motion during the scans was performed using the displacement time-series produced

818

during preprocessing of the functional data. These were collated, and means were

819

calculated across the time-series and across the six (three translations, three rotations)

820

displacement parameters. Maximum displacement values were also assessed.

821

822

Only one subject showed a maximum displacement value greater than one voxel dimension

823

(3mm) on a single parameter, for one study visit. Inspection of this subject’s time series

824

showed a single large (~3mm) shift in position part-way through the scan. This subject’s

825

mean displacement (0.088mm) was less than 0.1mm, and was comparable to other subjects

826

in the sample. It was therefore judged to be acceptable, and the subject was included in the

827

analyses. Mean displacement across all subjects, scan sessions, and parameters was -

828

0.00058mm (SD = 0.027mm).

829

830

A 2 (treatment group) by 2 (study visit) mixed-model ANOVA was conducted to examine any

831

systematic differences in head-motion across these factors. There was no main effect of

832

treatment group (F[1,44] = 1.84, p = 0.182) and no main effect of study visit (F[1,44] = 0.11,

833

p = 0.740. There was also no interaction effect (F[1,44] = 0.077, p = 0.782).

834

835

836

837

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Group-level task results

838

839

840

Figure S1. Results from the validation analyses of mean task effects in each group.

841

842

843

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Correlation results

844

845

Correlation of BOLD* data with:

Pearson’s r

p value

Psilocybin group (N=25)

BDI change (baseline to six weeks)

0.132

0.529

WEMWBS change (baseline to 6 weeks)

-0.001

0.997

PRSEXDQ

-0.041

0.846

LEIS change (baseline to 6 weeks)

-0.07

0.762

SHAPS change (baseline to 6 weeks)

-0.001

0.998

QIDS change (baseline to 6 weeks)

0.084

0.718

Escitalopram group (N=21)

BDI change (baseline to six weeks)

0.075

0.748

WEMWBS change (baseline to 6 weeks)

-0.001

0.997

PRSEXDQ

-0.077

0.741

LEIS change (baseline to 6 weeks)

-0.022

0.927

SHAPS change (baseline to 6 weeks)

0.037

0.878

QIDS change (baseline to 6 weeks)

0.187

0.43

*All faces vs. baseline contrast, pre-treatment vs. post-treatment

846

847

Table S1. Correlation analyses between a summary measure of brain activity and key clinical

848

measures. All analyses showed non-significant/null results.

849

850

851

852

Moderation Analyses with BDI as the dependent variable

853

854

The moderation analyses were repeated with BDI change scores (baseline to six-week

855

follow-up) as the dependent variable. For the psilocybin group, this produced the same

856

pattern of results as the analysis with QIDS scores in the main text. There was a significant (Z

857

= -3.02, p = 0.003) effect of the LEIS measure on BDI scores, but no effect of brain activity (Z

858

= -0.29, p = 0.774) and no interaction effect (Z = 1.32, p = 0.187). In the escitalopram group

859

there were no main effects of either brain activity (Z = 1.49, p = 0.137) or LEIS (Z = -0.59, p =

860

0.551) on BDI change scores, but a significant interaction effect (Z = 2.38, p = 0.018).

861

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial

Article

Sep 2024

Background Psilocybin therapy (PT) produces rapid and persistent antidepressant effects in major depressive disorder (MDD). However, the long-term effects of PT have never been compared with gold-standard treatments for MDD such as pharmacotherapy or psychotherapy alone or in combination. Methods This is a 6-month follow-up study of a phase 2, double-blind, randomised, controlled trial involving patients with moderate-to-severe MDD. Participants were recruited from a hospital in the UK. Male or female patients with major depressive disorder (DSM-IV), moderate to severe depression (HAM-D ≥17), no MRI or SSRI contraindications, confirmed diagnosis by a GP or mental healthcare professional, aged 18–80, and competent in English were eligible. Patients were randomly assigned (1:1) to receive either two 25 mg doses of the psychedelic drug psilocybin administered orally combined with psychological support (‘psilocybin therapy’ or PT) and book-ended by further support or a 6-week course of the selective serotonin reuptake inhibitor (SSRI) escitalopram (administered daily at 10 mg for three weeks and 20 mg for the subsequent three weeks) plus matched psychological support (‘escitalopram treatment’ or ET). The primary outcome measure was change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16) at week 6, which has been reported previously. Herein, we present results at the 6-month follow-up time point. Measures of social functioning, connectedness, and meaning in life constituted the study's secondary outcomes during follow-up. Safety in the follow-up period was not assessed. This trial is registered at ClinicalTrials.gov, NCT03429075. Findings Between January 15th, 2019 and March 20th, 2020, 59 patients were enrolled and 30 (11 females [37%] and 19 males [63%]) were assigned to the psilocybin group and 29 (9 females [31%] and 20 males [69%]) to the escitalopram group. 25 participants in the PT group and 21 in the ET group completed the 6-month follow-up. At the 6-month follow-up, both PT and ET conditions yielded sustained improvements in depressive symptom severity. The mean between-condition difference in QIDS-SR-16 scores at 6-months was 1.51 (95% CI: −1.35, 4.38; p = 0.311). Secondary outcomes demonstrated that PT had greater mean between-condition differences in functioning (WSAS: −7.46; 95% CI: −12.4, −2.47; p < 0.001), psychological connectedness (WCS: 11.02; 95% CI: 1.25, 20.83; p = 0.033), and meaning in life (MLQ: 4.86; 95% CI: 0.67, 9.05; p = 0.021) compared to ET. Interpretation Six-week intensive treatments with either psilocybin or escitalopram (with psychological support) for MDD were associated with long-term improvements in depressive symptom severity. The greater degree of improvement in the PT arm at follow-up on psychosocial functioning, meaning in life, and psychological connectedness suggests warrant future research. However, these results are descriptive and should be interpreted with caution. Key limitations of the study include its suboptimal power to detect small but meaningful differences between treatments, missing data, the potential use of additional interventions during the follow-up period, and reliance on self-reported treatment assessments. These factors may affect the interpretation of the study findings and should be considered when evaluating the results.

Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression

Article

Full-text available

Aug 2024

Effective interventions for neuropsychiatric disorders may work by rebalancing the brain’s functional hierarchical organization. Here we directly investigated the effects of two different serotonergic pharmacological interventions on functional brain hierarchy in major depressive disorder in a two-arm double-blind phase II randomized controlled trial comparing psilocybin therapy (22 patients) with escitalopram (20 patients). Patients with major depressive disorder received either 2 × 25 mg of oral psilocybin, three weeks apart, plus six weeks of daily placebo (‘psilocybin arm’) or 2 × 1 mg of oral psilocybin, three weeks apart, plus six weeks of daily escitalopram (10–20 mg; ‘escitalopram arm’). Resting-state functional magnetic resonance imaging scans were acquired at baseline and three weeks after the second psilocybin dose ( NCT03429075 ). The brain mechanisms were captured by generative effective connectivity, estimated from whole-brain modeling of resting state for each session and patient. Hierarchy was determined for each of these sessions using measures of directedness and trophic levels on the effective connectivity, which captures cycle structure, stability and percolation. The results showed that the two pharmacological interventions created significantly different hierarchical reconfigurations of whole-brain dynamics with differential, opposite statistical effect responses. Furthermore, the use of machine learning revealed significant differential reorganization of brain hierarchy before and after the two treatments. Machine learning was also able to predict treatment response with an accuracy of 0.85 ± 0.04. Overall, the results demonstrate that psilocybin and escitalopram work in different ways for rebalancing brain dynamics in depression. This suggests the hypothesis that neuropsychiatric disorders could be closely linked to the breakdown in regions orchestrating brain dynamics from the top of the hierarchy.

The Influence of Psilocybin on Subconscious and Conscious Emotional Learning

Article

Full-text available

May 2024

Serotonergic psychedelics hold promise as a treatment modality for various psychiatric disorders and are currently applied in psychedelic-assisted psychotherapy. We investigated the learning effects of the serotonin receptor agonist psilocybin in a probabilistic cue-reward task with emotional cues in the form of neutral or fearful faces, presented either consciously or subconsciously. This study represents the first investigation into reinforcement learning with psilocybin. Across different dosages, psilocybin preserved learning effects and was statistically noninferior compared to placebo, while suggesting a higher exploratory behavior. Notably, the 20 mg group exhibited significantly better learning rates against the placebo group. Psilocybin induced inferior results with subconscious cues compared to placebo, and better results with conscious neutral cues in some conditions. These findings suggest that modulating serotonin signaling in the brain with psilocybin sufficiently preservers reinforcement learning.

Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study

Article

Full-text available

Jan 2023

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of ‘cold’ cognition (including inhibition, cognitive flexibility, memory) and ‘hot cognition’ including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on ‘cold’ or ‘hot’ cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the ‘blunting’ effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339.

The Watts Connectedness Scale: a new scale for measuring a sense of connectedness to self, others, and world

Article

Full-text available

Aug 2022
PSYCHOPHARMACOLOGY

Rationale A general feeling of disconnection has been associated with mental and emotional suffering. Improvements to a sense of connectedness to self, others and the wider world have been reported by participants in clinical trials of psychedelic therapy. Such accounts have led us to a definition of the psychological construct of ‘connectedness’ as ‘a state of feeling connected to self, others and the wider world’. Existing tools for measuring connectedness have focused on particular aspects of connectedness, such as ‘social connectedness’ or ‘nature connectedness’, which we hypothesise to be different expressions of a common factor of connectedness. Here, we sought to develop a new scale to measure connectedness as a construct with these multiple domains. We hypothesised that (1) our scale would measure three separable subscale factors pertaining to a felt connection to ‘self’, ‘others’ and ‘world’ and (2) improvements in total and subscale WCS scores would correlate with improved mental health outcomes post psychedelic use. Objectives To validate and test the ‘Watts Connectedness Scale’ (WCS). Methods Psychometric validation of the WCS was carried out using data from three independent studies. Firstly, we pooled data from two prospective observational online survey studies. The WCS was completed before and after a planned psychedelic experience. The total sample of completers from the online surveys was N = 1226. Exploratory and confirmatory factor analysis were performed, and construct and criterion validity were tested. A third dataset was derived from a double-blind randomised controlled trial (RCT) comparing psilocybin-assisted therapy (n = 27) with 6 weeks of daily escitalopram (n = 25) for major depressive disorder (MDD), where the WCS was completed at baseline and at a 6-week primary endpoint. Results As hypothesised, factor analysis of all WCS items revealed three main factors with good internal consistency. WCS showed good construct validity. Significant post-psychedelic increases were observed for total connectedness scores (η2 = 0.339, p < 0.0001), as well as on each of its subscales (p < 0.0001). Acute measures of ‘mystical experience’, ‘emotional breakthrough’, and ‘communitas’ correlated positively with post-psychedelic changes in connectedness (r = 0.42, r = 0.38, r = 0.42, respectively, p < 0.0001). In the RCT, psilocybin therapy was associated with greater increases in WCS scores compared with the escitalopram arm (ηp2 = 0.133, p = 0.009). Conclusions The WCS is a new 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. We believe that the operational definition of connectedness captured by the WCS may have broad relevance in mental health research.

Increased global integration in the brain after psilocybin therapy for depression

Article

Full-text available

Apr 2022
NAT MED

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. The antidepressant response to psilocybin in individuals with treatment-resistant depression is distinct from escitalopram and depends on a global increase in brain network integration.

Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder

Article

Full-text available

Nov 2021

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

Article

Full-text available

Jun 2021
J PSYCHOPHARMACOL

Background Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aim Evaluate changes in resting-state functional connectivity (RSFC) at 1 week and 3 months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. Methods Participants received 0.2–0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state functional magnetic resonance imaging (fMRI) scans at baseline, 1-week and 3-month post-administration and [11C]Cimbi-36 PET scans at baseline and 1 week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. Results Psilocybin was well tolerated and produced positive changes in well-being. At 1 week only, executive control network (ECN) RSFC was significantly decreased (Cohen’s d = −1.73, pFWE = 0.010). We observed no other significant changes in RSFC at 1 week or 3 months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at 1 week predicted increased mindfulness at 3 months ( r = −0.65). Conclusions These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic ‘afterglow’ period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at 3 months, when personality changes are observed, remain to be identified.

The use of the psychological flexibility model to support psychedelic assisted therapy

Article

Full-text available

Jan 2020

Psychedelic assisted therapy comprises three stages: Preparation, Psychedelic Session, and Integration. Preparation is key for maximising the potential of a beneficial psychedelic experience and integration is important for prolonging improvements. The psychological flexibility model (PFM) appears to be a promising one to guide psychedelic preparation and integration. This paper proposes a model that utilises the PFM as informed by a previously published qualitative study of patient accounts of change processes in psilocybin therapy that identified themes of acceptance and connection as associated with positive outcomes. This new model, the ACE (Accept, Connect, Embody) model presents the six psychological flexibility processes, renamed and rearranged in an acceptance triad (defusion, present moment focus, willingness) and a connection triad (self as context, values, committed action). This paper describes the ACE model and how it is being used in an ongoing trial of psilocybin treatment for major depression. It also describes qualitative evidence supportive of the idea that psychological flexibility may be key to characterizing the processes of change involved in psilocybin assisted therapy for depression. These and other results suggest that psilocybin may be specifically increasing psychological flexibility and point to the possibility that psychotherapy approaches incorporating the PFM may serve as a means to deepen and extend the benefits of psilocybin treatment, thus bridging the experiential gap between a potent inner experience and an outer life better lived.

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial

Article

Mar 2023

Background: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature. Methods: In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period. Results: Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin (d' = 1.02-2.27) than after placebo (d' = 0.65-0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects. Conclusions: The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.

Translational Challenges in Psychedelic Medicine

Article

Feb 2023
NEW ENGL J MED

Robin L Carhart-Harris

Canalization and plasticity in psychopathology

Article

Dec 2022
NEUROPHARMACOLOGY

This theoretical article revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. To achieve this, we have distinguished between two types of plasticity, an early one that we call 'TEMP' for 'Temperature or Entropy Mediated Plasticity', and another, we call 'canalization', which is close to Hebbian plasticity. These two forms of plasticity can be most easily distinguished by their relationship to 'precision' or inverse variance; TEMP relates to increased model variance or decreased precision, whereas the opposite is true for canalization. TEMP also subsumes increased learning rate, (Ising) temperature and entropy. Dictionary definitions of 'plasticity' describe it as the property of being easily shaped or molded; TEMP is the better match for this. Importantly, we propose that 'pathological' phenotypes develop via mechanisms of canalization or increased model precision, as a defensive response to adversity and associated distress or dysphoria. Our model states that canalization entrenches in psychopathology, narrowing the phenotypic state-space as the agent develops expertise in their pathology. We suggest that TEMP - combined with gently guiding psychological support - can counter canalization. We address questions of whether and when canalization is adaptive versus maladaptive, furnish our model with references to basic and human neuroscience, and offer concrete experiments and measures to test its main hypotheses and implications.

Trial of Psilocybin versus Escitalopram for Depression

Article

Apr 2021

Background Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. Methods In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. Results A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. Conclusions On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London’s Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.) VISUAL ABSTRACT Psilocybin versus Escitalopram for Depression

Reduced brain responsiveness to emotional stimuli with escitalopram but not psilocybin therapy for depression

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