Therapeutic mechanisms of psilocybin: Changes in... — Research Summary & Context

Therapeutic mechanisms of psilocybin: Changes in... — Research Summary & Context | Blossom

Abstract

Background

Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy.

Aims

Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin.

Methods

Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week.

Results

Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing.

Conclusion

These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.

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Research Summary of 'Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression'

Introduction

Serotonergic psychedelics such as psilocybin have shown therapeutic promise for conditions including depression, yet the neural mechanisms that underlie their clinical efficacy remain poorly understood. Previous work in this cohort of patients with treatment-resistant depression (TRD) identified increased right amygdala responsiveness to emotional faces one day after a high-dose psilocybin session, and this amygdala change correlated with clinical improvement. At the same time, other post-acute studies of psychedelics have reported alterations in resting-state connectivity and regional perfusion, suggesting that neural changes beyond the acute drug state may contribute to sustained symptom benefit. Mertens and colleagues set out to probe task-related functional connectivity (FC) changes that might accompany the earlier amygdala activation findings. Specifically, they tested whether psilocybin treatment leads to altered amygdala FC during an emotional face perception task, with a primary hypothesis of decreased amygdala–ventromedial prefrontal cortex (vmPFC) connectivity after treatment. The investigators also examined whether any FC changes related to clinical outcomes at one week, focusing on depressive symptoms and rumination as primary and secondary endpoints respectively.

Methods

This was an open-label feasibility study of psilocybin-assisted therapy in patients with TRD. Nineteen patients (six female; mean age 44.7 years) completed pre- and post-treatment fMRI scans and form the analysed sample. Participants received two psilocybin-assisted therapy sessions one week apart: an initial 10 mg oral test dose followed by a 25 mg oral therapeutic dose. Psychological support comprised a 4-hour preparation session, in-session and peri‑acute support during dosing, and a single integration session the morning after the high dose. Patients were requested to discontinue antidepressant medication before study entry; most complied, but two participants did not fully adhere (one continued venlafaxine throughout; another discontinued tramadol only one week before the high dose). Key inclusion criteria were moderate-to-severe major depression (HAM-D score ≥16) and treatment resistance defined as failure to respond to at least two pharmacologically distinct antidepressant trials. Functional MRI data were acquired on a 3T Siemens Tim Trio. The task was a blocked emotional face paradigm presenting fearful, neutral and happy faces (15 s blocks, faces shown for 3 s each) across an eight-minute run. Participants pressed a button on each face to ensure attention. Baseline scanning occurred before any intervention; the post-treatment scan was performed the morning after the high-dose psilocybin session. Preprocessing combined tools from FSL, AFNI, Freesurfer and ANTS and included motion correction, brain extraction, registration to standard space, scrubbing for framewise displacement >0.90 mm, spatial smoothing (6 mm FWHM), high-pass filtering (0.01 Hz) and regression of motion and CSF/white matter nuisance signals. The principal analytic approach was seed-based psychophysiological interaction (PPI) analysis, which assesses task-related changes in FC between a seed region's time-series and other brain areas. Separate PPI models used bilateral amygdala and a predefined vmPFC seed. Two PPI variants were run: a simple model contrasting all faces versus rest (primary, more powered) and a complex model modelling each expression (happy, fearful, neutral) separately (secondary). Contrast images comparing post- versus pre-treatment were entered into mixed-effects higher-level analyses (FLAME-1) with whole-brain cluster correction (z>2.3, cluster p<0.05). For hypothesis-driven tests, complementary ROIs (vmPFC when amygdala was seed and vice versa) were used as pre-threshold masks. Clinical measures included the Beck Depression Inventory (BDI) as the primary outcome at one week, the Ruminative Response Scale (RRS) for rumination, and the State-Trait Anxiety Inventory (STAI) and in-scanner state ratings for anxiety. Relations between FC changes (beta estimates) and clinical outcomes were assessed with Pearson correlations and independent t-tests; multiple comparisons were handled using Bonferroni corrections applied per cluster and construct.

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INTRODUCTION

Serotonergic psychedelics (e.g. lysergic acid diethylamide (LSD) and psilocybin) have shown promising results in disorders such as obsessive-compulsive disorder, end-of-life psychological distress, addictionand depression, when administered under supportive conditions. Our open-label study of psilocybin with psychological support (including one preparation and integration session, as well as support immediately before, during and after the acute drug session) for treatment-resistant depression (TRD) showed reductions in depressive symptoms in all 19 patients from baseline to one week, which was sustained in the majority for at least 3-5 weeks and was predicted by the quality of the acute psychedelic experience. Long-term follow-ups at six months revealed that of the nine responders (at five weeks), only three had relapsed, suggesting stable antidepressant effects for some patients. Despite accumulating evidence on its efficacy, the therapeutic mechanisms of the psychedelic treatment model are not well-understood (although see Carhart-Harris, 2019) and demand further investigation. Acutely, serotonergic psychedelics interact with multiple receptor types (reviewed in, but have high affinity for the serotonin (5-HT) 2A receptor, which mediates their hallucinogenic effects via full or partial agonism. This receptor's role in increased excitability, plasticity and adaptability has recently been put forward byas potentially underlying their therapeutic effects. Psychedelic-induced plasticity and changes to network level functioning (e.g. increased cortical entropy, disintegration of networks and an enhanced communication between normally segregated brain regions) have been identified as underlying the acute psychedelic state. However, considering the sustained antidepressant effects and improvements in well-being observed after psychedelic experiences (e.g., it is crucial to investigate potential neural changes beyond the acute state. Previous work has identified some post-acute neurofunctional changes after psychedelics: A recent study in a group of healthy ayahuasca-experienced individuals showed increased resting-state functional connectivity (RSFC) between the posterior and anterior cingulate cortex, and between the anterior cingulate and the right medial temporal lobe, 24 h after one ayahuasca dose, a N,Ndimethyltryptamine (DMT)-containing plant brew. Similarly, RSFC analysis on data acquired at pre-treatment baseline and one day after a high dose treatment session with psilocybin for TRD revealed the following changes: (a) increased connectivity within the default mode network (DMN) and decreased parahippocampal-prefrontal RSFC; both predictive of treatment response at five weeks, and (b) decreased cerebral blood flow in the temporal cortex (including the amygdala) that correlated with reductions in depressed mood. In the same group of patients, which also constitutes the sample of the present study, a functional magnetic resonance imaging (fMRI) paradigm was used to assess amygdala responsiveness to emotional faces pre-and post-treatment with psilocybin. The results of this study revealed an increased response in the right amygdala to fearful and happy faces one-day post-psilocybin, and right amygdala increases to fearful versus neutral faces which was predictive of depressive symptoms at one week and treatment response at one-day, oneweek, and three-weeks. Additionally, whole-brain analyses revealed increased activity in visual areas across all face conditions (happy, fearful, neutral) post-psilocybin, suggesting not just changes in amygdala reactivity, but also responsiveness in other brain regions. Additionally,provided compelling evidence for decreased amygdala functional connectivity (FC) to the striatum and the frontal pole during angry and happy discrimination respectively under acute psilocybin as compared with placebo in healthy volunteers. However, post-acute FC alterations have yet to be explored. Moreover, there are reasons to believe that post-acute brain changes are quite different to the acute brain effects of psychedelicsand are obviously vital to study given their potential relevance to therapeutic mechanisms. The changes in post-acute amygdala reactivity in depressed patientsand acute amygdala reactivity under psilocybinare particularly striking, as amygdala involvement, and particularly its hypersensitivity to negative stimuli, has long been thought to be a component of clinical depression, and thus a target for antidepressant medications. Dysfunctions in amygdala-prefrontal cortex (PFC) circuits and decreased amygdala-PFC FC are hypothesised to underlie disorders with disturbed emotional processing, such as depression and posttraumatic stress disorder (PTSD;. Current neural models of depression and anxiety disorders emphasise abnormalities in both limbic responsiveness and metabolism and topdown emotional control mechanisms. Accordingly, from a traditional antidepressant perspective, our previous finding of increased amygdala responsiveness to negative faces (that was predictive of better clinical outcome) may seem somewhat counterintuitive. In order to further investigate the therapeutic mechanisms of psilocybin, in the present study we aimed to examine the neural mechanisms responsible for this change in amygdala responsiveness post psilocybin. We predicted changes in amygdala FC during the same emotional face paradigm performed at pre-treatment baseline and one day after psilocybin for TRD. More specifically we predicted decreased FC between the amygdala and the ventromedial PFC (vmPFC) during face processing after psilocybin. The vmPFC is an important component of the emotional processing circuitry, shown to have a top-down inhibitory effects on limbic regionsand is implicated in emotional control, inhibition and regulation. Changes in amygdala-PFC connectivity are also a common finding in depressed patients (e.g.. We hypothesised that the reduction of FC between the vmPFC and amygdala might account for the increased amygdala responsivity after psilocybin, as shown previously by. Lastly, we predicted that altered amygdala and vmPFC FC might relate to post-treatment changes in depression severity and rumination tendencies. Rumination is a pattern of recursive self-directed and self-reflective thinking focused on one's negative emotionsand defined as the compulsively focused attention on the symptoms of one's distress, and on its possible causes, consequences and implications, as opposed to its solutions. Alongside basic depression scores, rumination scores using the Ruminative Response Scale (RRS;served as a secondary clinical outcome of interest. Rumination was chosen as a symptom of interest as: (a) it is a strong vulnerability factor in the development and maintenance of depressive episodes, and (b) it has been found to have different neural underpinnings in depressed patients as compared with healthy controls.

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Study Details

Study Type
individual
Population
humans
Characteristics
brain measuresre analysis
Journal
Journal of Psychopharmacology
Compound
Psilocybin
Topics
Depressive Disorders Treatment-Resistant Depression (TRD)
Authors
Robin Carhart-Harris

Results

Task-related FC changes after psilocybin differed by seed and expression. Using the amygdala as the seed, the simple PPI model (faces>rest) revealed increased connectivity post-treatment between the amygdala and visual cortical regions, including intracalcarine and supracalcarine cortex, cuneus, precuneus and right lateral occipital cortex. In the complex model, stronger amygdala–visual cortex connectivity was observed for happy (zmax=3.96, p<0.001) and neutral (zmax=3.31, p<0.001) faces but not for fearful faces; contrasts of fearful versus neutral did not show significant differences. When the vmPFC served as the seed, the primary PPI likewise showed greater post-treatment FC with left occipital and parietal visual areas (supracalcarine/intracalcarine cortex, precuneus, lingual gyrus). Importantly for the a priori hypothesis, pre-thresholded analyses (masking by the bilateral amygdala) indicated that vmPFC–right amygdala FC was higher before than after psilocybin during face processing—that is, vmPFC→right amygdala connectivity decreased post-treatment. The complex model clarified that vmPFC connectivity increases after treatment were condition-dependent: vmPFC showed enhanced FC with the right angular gyrus and lateral occipital cortex during fearful faces (zmax=3.74, p=0.044), with occipito-parietal visual cortex during happy faces (zmax=3.32, p=0.040), and with left cerebellum during neutral faces (zmax=3.54, p<0.001). Masked analyses indicated reduced vmPFC–right amygdala FC post-treatment for fearful (zmax=3.01, p=0.032) and neutral (zmax=3.47, p=0.041) faces but not for happy faces. Correlations between PPI-derived FC and amygdala activation from the task analysis were limited. The vmPFC×fearful PPI contrast did not correlate with amygdala task responses after treatment, nor did change scores; however, a significant negative correlation was present pre-treatment (r=-0.48, p=0.040), indicating that higher vmPFC–right amygdala FC before treatment associated with lower amygdala reactivity to fearful faces at baseline. Clinically, depressive symptoms (BDI) fell substantially by one week (mean reduction 22.26, SD=11.37, p<0.001), with 63.2% of participants meeting response criteria and 57.9% achieving remission at that time-point. Rumination (RRS) decreased significantly from baseline to one week and remained lower than baseline at three months, showing a quadratic pattern (drop at one week, partial rise by three months). After Bonferroni correction, amygdala FC measures were not significantly correlated with clinical outcomes. Absolute vmPFC–right amygdala FC post-treatment correlated with rumination at one week (r=0.54, p=0.018), such that lower connectivity related to lower rumination; this association survived the corrected α of 0.025. FC between the vmPFC and an occipital-parietal cluster post-treatment correlated with BDI at one week (r=-0.46, p=0.048) and with its change score (r=0.50, p=0.029). Responders and remitters differed in vmPFC–occipital-parietal FC change, with the remitter contrast remaining significant after Bonferroni correction. A larger increase in vmPFC–occipital-parietal FC change also correlated with greater decreases in STAI (r=0.54, p=0.017), though this latter finding narrowly missed the stricter corrected α of 0.013. No significant relations were found with in-scanner anxiety ratings.

Discussion

Mertens and colleagues interpret the findings as partial support for their prediction that psilocybin alters amygdala–prefrontal circuitry during emotional processing. The principal observation was reduced vmPFC–right amygdala functional connectivity during face viewing after treatment; this effect was driven mainly by fearful and neutral faces. One plausible interpretation offered is that reduced top-down inhibitory input from vmPFC might disinhibit the amygdala, consistent with the previously reported post-treatment increase in amygdala reactivity. The investigators link this neural pattern to clinical improvements in rumination: lower vmPFC–amygdala connectivity after treatment associated with lower rumination scores at one week, and rumination itself showed a marked decline following psilocybin. The authors also highlight increased connectivity of both the amygdala and vmPFC with occipital–parietal visual regions post-treatment. They suggest these changes could reflect greater task engagement, enhanced emotional stimulus processing, or strengthened amygdala–visual cortex circuitry involved in detecting emotionally salient stimuli. Correlations between vmPFC–occipital-parietal connectivity and depressive and anxiety measures at one week further suggest behavioural relevance, although several of these associations did not survive conservative correction for multiple testing. The paper acknowledges several important limitations. The study was open-label without placebo or active control, the sample size was small and comprised a highly selected TRD population, and two participants did not complete recommended washout of medications. Psychophysiological interaction analyses have limited power and do not provide directional or causal inference about information flow, so the proposed reduction in top-down control remains speculative. Multiple comparisons across two PPI models and two ROIs further weaken inferential strength. The authors recommend that future work employ larger, placebo-controlled designs where feasible, incorporate methods capable of assessing causal connectivity (for example dynamic causal modelling or magnetoencephalography), consider eye-tracking or reaction-time regressors to control for attention, and attempt to disentangle drug effects from psychological-support effects.

PROCEDURE

The full study procedure is reported inand. For an overview of the trial schedule and study interventions, also see the Supplementary Material Figure. The present study focused on changes in brain FC after psilocybin in 19 patients with TRD who underwent two psilocybin-assisted therapy sessions a week apart, first 10 mg p.o. (test dose), then 25 mg, p.o. (therapeutic dose). Provided psychological support consisted of three components: one preparation session with the allocated trial psychiatrists (lasting 4 h) before the first dose, acute and peri-acute support (i.e. before, during and immediately after dosing) and one integration session with the same psychiatrists one day after the high dose. Seed-based FC analysis using psychophysiological interaction (PPI) methods was conducted on fMRI data collected during an emotional face paradigm pre-and post-psilocybin. Baseline fMRI scanning took place prior to any intervention, and the post treatment fMRI scan occurred the morning (10:00) after the high-dose psilocybin session and prior to any subsequent psychological integration. Clinical outcome measures were administered at baseline and at multiple time-points after the high-dose session (see the Method section 'Relationship with clinical outcomes' for details); the one week post-treatment time-point constitutes the primary clinical endpoint of the present analysis. Inclusion criteria were (a) a diagnosis of moderate to severe major depression, as defined by a score of 16+ on the 21-item Hamilton Depression Rating Scale (HAM-D;; and (b) treatment-resistance as defined by lack of improvement despite two adequate courses of pharmacologically distinct antidepressant medications over at least six weeks each, within the present depressive episode. Additionally, patients were asked to stop their antidepressant medication before study entry. Typically, washout occurred under close supervision and over a period of at least two weeks before study entry. The main exclusion criteria were a current or past diagnosis of a psychotic disorder or an immediate family member with a diagnosed psychotic disorder, a history of serious suicide attempts and/or mania, pregnancy and current drug or alcohol dependence. Written informed consent was obtained from all participants during the screening visit. Ethical approval for the clinical trial was sought and granted by the National Research Ethics Service (NRES) London-West London, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and Imperial College London's Joint Research and Complication Organisation (JRCO) -who also sponsored the trial. Psilocybin was obtained from THC-Pharm (Frankfurt, Germany) and formulated into the investigational medicinal product (5 mg psilocybin in size 0 capsules) by Guy's and St Thomas' Hospital's Pharmacy Manufacturing Unit (London, UK).

GENERAL LINEAR MODELS (GLMS).

The BOLD-weighted fMRI data were then analysed with a standard GLM approach using the FEAT module in FSL. Anatomical images were segmented into grey/white matter (WM) and cerebro-spinal fluid (CSF) masks using FMRIB's Automated Segmentation Tool (FAST). These CSF and WM masks (thresholded at 0.75) were used to derive time-series from the functional data, which were entered as nuisance regressors in all GLMs. In order to identify brain regions where psilocybin affected the FC of the amygdala and vmPFC, separate PPI analyses were conducted using seed regions of interest (ROIs) in the (a) amygdala and (b) vmPFC (Supplementary Material Figure). The amygdala ROI was defined using a bilateral amygdala mask from the Subcortical Harvard-Oxford Atlas included in FSL () while the vmPFC ROI was drawn on a standard brain and was the same as used in previous studies. Mean time-series were extracted from the pre-processed functional data-series for each subject, for both ROIs and entered as physiological regressors in our PPI analyses. Two different PPI analyses were conducted (Supplementary Material Figure1. A simple model including faces (irrespective of expression) compared to the rest-blocks and its interaction with the ROI time-series as the PPI regressor as the primary analysis. 2. A complex model including separate regressors for all facial expression conditions (happy, fearful, neutral) as compared to the rest-period, and their respective interactions with the ROI time-series (i.e. the PPI regressors) as a secondary analysis. Face regressors derived from the onset times of the stimulus conditions were convolved with a gamma function, in order to simulate a canonical haemodynamic response function. Reasons for conducting both the simple and the complex PPI model were: (a) existing literature showing similar activation patterns for negative, neutral and positive emotional faces (e.g.) and (b) power considerations due to the relatively small sample size. The simple model should provide more robust, though less specific, results, while the complex model enables a more comprehensive exploration of the data, and comparisons between different facial expressions. Contrasts were defined that compared activity related to each regressor, i.e. (a) for faces, the ROI and their interaction in comparison to rest in the simple model; (b) for the different facial expressions (happy, fearful, neutral), the ROI, and their interactions relative to rest, as well as between the interaction terms for fearful vs neutral faces (ROI×fearful>ROI×neutral) in the complex model. Based on the results byshowing post-treatment effects for fearful and happy faces (vs rest) and fearful>neutral faces (see above), we expected differences in ROI FC for emotional (fearful, happy) faces in comparison to rest and neutral faces. Hence, the ROI×fearful and, ROI×happy versus rest, and ROI×fearful>ROI×neutral contrasts were of particular interest in this secondary analysis. We decided to also look at the ROI×neutral (vs rest) contrast, for completeness of results, as previous work has found similar activation patterns for different facial expressionsand in order to disentangle which emotional expressions were driving the PPI effect. Higher-level analyses across sessions, comparing subjects before any intervention and after the high dose of psilocybin, were performed with mixed-effects GLM (FMRIB's Local Analysis of Mixed Effects [FLAME-1]) models. A statistical threshold of z>2.3 (cluster-corrected for multiple comparisons with p<0.05) was used for all whole-brain analyses. Additionally, for more direct testing of our hypothesis, we added the complementary ROIs as a pre-threshold mask (i.e. a bilateral amygdala mask for the vmPFC analyses, and a vmPFC mask for the analyses with amygdala as ROI). Significant clusters were interpreted and labelled based on the Harvard-Oxford cortical and subcortical structural atlases provided in FSL (). Relationship with amygdala BOLD response. Subsequently (post-hoc), response amplitudes (beta-weights) from the fearful PPI (vmPFC×fearful) contrast showing a significant decrease in vmPFC-amygdala FC (see Results) were correlated with results from the respective task analysis contrast (fearful vs rest), that had shown increased right amygdala reactivity post-treatment (see. This allowed for a more specific test of the hypothesised decreased prefrontal inhibitory input to the amygdala as being involved in its increased reactivity after treatment. In line with our primary hypothesis, we expected to find correlations between responses from the PPI contrast (representing the degree of FC between the ROI and identified cluster during fearful face processing) and basic amygdala BOLD responses to fearful faces (i.e. results from the task analysis) as well as their difference scores respectively.

DEPRESSION.

In order to reduce the number of tests and avoid excessive correction of alpha levels, we limited the primary analyses to one clinical outcome of interest: the self-rated Beck Depression Inventory (BDI;completed at baseline and one week after therapy. The QIDS-SR16was administered at more time-points (at baseline, one day, one week, two weeks, three weeks, five weeks, three months and six months after treatment). For better comparison with results by, relations between brain outcomes and the QIDS-SR16 were also investigated as supplementary analyses. An overview of correlations with BDI at three-month and all QIDS-SR16 time-points is provided in the Supplementary Material. The BDI is a reliable and valid 21-item self-rating questionnaire for the assessment of depressive symptoms. Participants rate their mood and behaviour (e.g. sadness, feelings of guilt, disappointment, crying) according to four severity ratings per item (0-3). The total score determines the severity of depression, differentiating between absent (0-9), mild (10-18), moderate (19-29) and severe (⩾30) depression. Remission is defined as a score ⩽9, and treatment response as a 50% drop in BDI score from baseline. The QIDS-SR16 is a 16-item self-report inventory assessing the severity of depressive symptoms in reference to the past seven days. Symptoms cover the nine Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV symptom domains of major depression, namely: sad mood, concentration, self-criticism, suicidal ideation, interest, energy/fatigue, sleep disturbances, decrease/increase in weight and/or appetite, and psychomotor agitation or retardation. The total score determines the severity of depression, differentiating between absent (0-5), mild (6-10), moderate (11-15), severe (16-20) and very severe (21-27) forms. In line with the BDI classification, treatment response was defined as a 50% drop in score from baseline. Rumination. As a secondary hypothesis, the relationship between brain outcomes and ruminative thinking and behaviour at one week was examined. During the trial, rumination was measured with the RRS at baseline, one week after and at three-months follow-up. The RRS is a 22-item self-report scale assessing ruminative tendencies on a scale from almost never (=1) to almost always (=4), by asking to report what responders 'generally do' (e.g. 'think about how alone you feel' or 'analyse your personality and try to understand why you are depressed'). The scale score is determined by summing all 22 items, with a higher score reflecting more ruminative thinking and behaviour. Relation to RRS was analysed at one week, although relation to RRS at three months was also examined for explorative purposes (see Supplementary Material).

STATISTICAL ANALYSIS

Changes in depression (BDI) and anxiety (STAI) levels posttreatment have already been analysed and reported by. Changes in rumination (RRS) from baseline, to one week and three months post-treatment were analysed with repeated measures analysis of variance (RM ANOVA). In order to analyse the relationship to the primary clinical outcome, BDI scores at one week and their change from baseline were correlated with the absolute average parameter estimates (beta-weights) of significant clusters and their difference scores (∆beta=after-before) respectively. The relationship to the secondary outcomes of interest (RRS at one week; STAI at one week; anxiety in-scanner rating) were investigated in the same way. Additionally, independent samples t-tests were conducted, analysing whether those patients who responded to treatment (50% reduction in BDI score) and/or met the criterion for remission (BDI⩽9) differed in terms of average beta-values post-treatment and their change scores (∆beta) per cluster. We opted to correct for multiple comparisons for each cluster and construct separately, in order to reduce the risk of type two errors due to an overly conservative correction and because our tested clinical constructs were highly related (raw score, change score, remission and response). Accordingly, for the BDI at one week, six comparisons were made per identified cluster, leading to a Bonferroni-corrected α of 0.05/6=0.008. For the secondary outcome, RRS at one week, two comparisons were made per cluster, leading to a Bonferroni-corrected α of 0.025. Anxiety levels (inscanner ratings and STAI at one-week) were tested at a Bonferronicorrected α of 0.05/4=0.013. For transparency, an overview of all conducted correlation analyses and t-tests is provided in the tables in the Results section on 'Relationship with clinical outcomes'. Prior to all statistical tests, the clinical data were investigated in regard to statistical assumptions. Besides some deviation from normality in BDI scores, at one week in particular, all clinical data met the assumptions for parametric testing.

PPI: VMPFC

Similar to the amygdala, whole-brain analysis of the primary (simple) PPI model (Table, Figure(b)), with the vmPFC time-series as physiological and faces as psychological regressor, showed significantly greater FC between the vmPFC and areas in the left occipital and parietal lobes (supracalcarine and intracalcarine cortex, precuneus and lingual gyrus) during face processing (vs rest) post-treatment versus pre-treatment (vmPFC×faces). When adding a bilateral amygdala mask for Figure. Results of the psychophysiological interaction (PPI) whole-brain and pre-thresholded analysis comparing ventromedial prefrontal cortex (vmPFC) functional connectivity when processing different facial expressions (a=fearful, b=neutral) with rest (complex model) before and after treatment with psilocybin. The contrast with happy faces (vmPFC×happy) did not reveal any significant results. This analysis was conducted as a secondary analysis to provide a more comprehensive exploration of the different conditions in the experiment. Regions with increased connectivity (after>before) are depicted in red, decreased connectivity (before>after) in blue (cluster-corrected, p<0.05, z>2.3). pre-threshold masking, the interaction term revealed significantly higher connectivity between the vmPFC and right amygdala during face processing before psilocybin treatment as compared to after; thus, supporting our primary hypothesis. As secondary analysis, when taking the different facial expressions into account (complex PPI model, Tableand), the vmPFC showed increased FC with the right angular gyrus and lateral occipital cortex during fearful faces (vmPFC×fearful; z max= 3.74, p=0.044), with occipito-parietal visual areas centred around the cuneal cortex during happy faces (vmPFC×happy; z max =3.32, p=0.040) and with the left cerebellum during neutral faces (vmPFC×neutral; z max =3.54, p<0.001) after psilocybin treatment as compared with before. Contrasting the interaction term for neutral with fearful faces (vmPFC×fearful>vmPFC×neutral) revealed significantly larger vmPFC FC with visual areas in the right hemisphere (lateral occipital cortex, occipital pole and occipital-fusiform gyrus) during processing of fearful faces (z max =3.32, p=0.023) after treatment with psilocybin. In line with results from the primary analysis of the simple PPI model, when the bilateral amygdala was added as a pre-threshold mask, significantly higher FC between the vmPFC and right amygdala before treatment with psilocybin during processing of fearful (vmPFC×fearful; z max =3.01, p=0.032) and neutral (vmPFC×neutral; z max =3.47, p=0.041), but not happy (vmPFC×happy) faces was found.

RELATIONSHIP WITH CLINICAL OUTCOMES

The primary clinical outcome of interest was the relationship between post-treatment FC changes and changes in BDI scores at the one-week endpoint. Important secondary outcomes of interest were the relation to rumination and anxiety scores at one week, plus in-scanner anxiety scores. The relevant results are shown in Tablesand. Clinical outcomes. As already reported previously (Carhart- Harris et al., 2018a; 2016a), BDI scores were significantly reduced at one week (mean reduction=22.26, SD=11.37, p<0.001); 63.2% of patients showed a treatment response (50% drop in BDI score) at this time-point, with 57.9% meeting criteria for remission (BDI⩽9). As evident from the RM ANOVA, rumination levels (RRS) differed significantly between time-points, F(2,36)=17.98, p<0.001, ηp 2 =0.50. Pairwise comparisons revealed a significant mean difference between baseline and one week (mean reduc-tion=21.58, p<0.001, 95% confidence interval (CI) 14.3-28.83) as well as three months post-treatment (mean reduction=15.90, p<0.001, 95% CI 8.66-23.13), while there was no significant difference between the drop in scores at one week and three months. Within-subjects contrasts further suggested a quadratic trend, F(1,18)=15.51, p=0.001, ηp 2 =0.463, indicating that rumination levels decreased from baseline to one week and then rose at three months, despite remaining significantly lower than at baseline. Amygdala FC. With Bonferroni correction, none of the clinical outcome measures (BDI, RRS, STAI, in-scanner anxiety levels) was significantly correlated with amygdala FC after treatment or its change (∆beta) from baseline (Tablesand). vmPFC FC. Right amygdala-vmPFC FC post-treatment was not significantly related to depression levels at one week (r=0.28, p=0.253), and neither did the change in right amygdala-vmPFC FC relate to change inor rumination from baseline (r=0.12, p=0.613). Absolute FC between the vmPFC and right amygdala after treatment did, however, significantly correlate with rumination scores one-week post-treatment (r=0.54, p=0.018), with lower connectivity being linked to lower rumination levels (see Figure). This result remained significant with a Bonferroni corrected α of 0.025. FC between the vmPFC and the occipital-parietal cluster after treatment was significantly correlated with BDI scores at one week (r=-0.46, p=0.048; Figure), and so were the respective change scores (r=0.50, p=0.029 ; Figure). In line with this, responders (t(17)=-2.48, p=0.024) and remitters (t(17)=-3.45, p=0.003) at one week differed significantly in terms of vmPFCoccipital-parietal FC change, and the result for remitters remained significant after Bonferroni correction. Additionally, the vmPFCoccipital-parietal FC change was significantly correlated with change in STAI at one week (r=0.54, p=0.017), indicating that a larger increase in connectivity was associated with a greater decrease in anxiety from baseline. However, this result did not quite hold under a Bonferroni corrected α of 0.013. No significant correlations to anxiety levels rated during post-treatment scanning or its change from baseline were found.

VMPFC-RIGHT AMYGDALA FC

Our findings provide some support for the key hypothesis of altered amygdala-PFC FC after treatment with psilocybin. Consistent with the prior hypothesis, we observed a reduction in vmPFC FC to the right amygdala during face processing after treatment with psilocybin. Further analysis showed that this effect was driven by the viewing of fearful and neutral faces in particular. One plausible, although somewhat speculative, physiological mechanism which would be consistent with this effect is decreased inhibitory input from the vmPFC to the right amygdala during emotional face-viewing post-treatment with psilocybin resulting in a disinhibitory influence on amygdala responsiveness during the same paradigm. We previously found that increased amygdala responsiveness to fearful (versus neutral) faces was related to improved clinical outcomes at one day, one week, and three weeks post-treatment), but the reduction in vmPFC-right amygdala FC during face processing observed in the present analysis was not significantly associated with depression severity at one week. However, vmPFC-right amygdala FC post-treatment was significantly related to levels of rumination at one week, with lower connectivity being associated with less rumination. Additionally, rumination levels were significantly decreased at one week and three months post-treatment with psilocybin. Despite the non-significant relation to BDI scores, considering that rumination is a strong risk factor for the development and maintenance of depressive episodes, decreased amygdala-prefrontal connectivity after psilocybin may still be an important underlying mechanism for the observed symptom improvement. This is consistent with work bywho found that greater RSFC within the DMN, including the vmPFC, correlated with rumination scores in major depression. Failure to disengage DMN regions may be an important component of the mechanics of depression. At the same time -and in contrast to research on the aetiology of anxiety, fear conditioning and PTSDdecreased prefrontal-amygdala FC was not associated with levels of anxiety during scanning or one week after treatment. Similarly,found no association between amygdala response and levels of anxiety. Taken together, while certainly preliminary, these results challenge the general view of amygdala responsivity/hyperactivity and decreased amygdala-prefrontal connectivity as being indicative of psychopathology per se. While quite consistently described as a biomarker and risk factor in the literature on states of emotional dysregulation, such as depression, the current results, together with those of, suggest a more nuanced interpretation. One potential explanation is that conventional antidepressants and psilocybin have fundamentally different actions on emotional processing, with conventional antidepressants down-regulating emotional responsivenessand psychedelics allowing patients to more fully engage with emotions. One might connect these findings to patient reports of increased emotional acceptance and decreased emotional avoidance after psilocybin therapy, which contrasts with the emotionally-muting effects patients described with their past antidepressant use. Increased amygdala responsiveness, accompanied by decreased engagement of prefrontal control regions, as suggested by the current findings, might be an important underlying mechanism involved in the emotional reconnection reported with successful psychedelic therapy. Caution is needed not to draw firm conclusions here, however. While, as predicted, we did observe decreased vmPFC-right amygdala FC during the processing of fearful and neutral faces, the degree of this connectivity change did not significantly correlate with the degree of increased amygdala responsiveness after treatment identified in the task analysis and neither do we have information about the direction of information flow from the present analyses.

LIMITATIONS

Focusing on design limitations, the given study was an openlabel feasibility study; therefore, there was no blinding or placebo condition, and the sample size was relatively small. Small sample sizes generate low statistical power and increase the chances of inferential errors. PPI models generally suffer from lack of power due to multicollinearity between regressors (O'Reilly et al., 2012:). This makes the use of larger samples particularly important. In this regard, it is also crucial to keep in mind that some of the analyses on relation to clinical outcome did not survive the applied Bonferroni correction for multiple testing, which weakens the respective results. In this respect, it must also be considered that in fact two separate PPI analyses -a primary (simple) model and a secondary (complex) model -were conducted with two ROIs, the amygdala and the vmPFC, adding to the problem of multiple comparisons. Reasons for analysing both PPI models are given above, but the number of comparisons have to be kept in mind as an important limitation. A potential solution and option for future studies to partly resolve this, would be the use of non-parametric testing. Additionally, the sample comprised a very specific patient group: TRD. This limits the generalisability of the results and introduces bias in favour of alternative antidepressant treatments (e.g. psychedelic drugs), since multiple standard treatments had been unsuccessful in the patient sample. In order to rule out that these results are sample and/or TRD-specific, future studies should explore psilocybin as a treatment for non-treatment-resistant major depression in a larger sample, using a placebo-controlled design. However, it must be acknowledged that the inclusion of an effective placebo condition is very difficult when studying psychedelic drugs. This is due to the fact that the subjective effects of a high-dose psychedelic experience are so noticeable that they break the blinding. Alternative strategies include the use of a low dose of the psychedelic as a control condition or to compare the psychedelic against an active pharmacological control, such as stimulants (e.g. amphetamines or methylphenidate), a sedative (e.g. a benzodiazepine) or a selective serotonin reuptake inhibitor (SSRI). Furthermore, based on results from the present study, it is not possible to disentangle the drug-specific effects from those of the psychological support provided during the treatment. Adding a psilocybin without psychological support condition would resolve this issue, although it is questionable whether it is ethical to administer a high dose of psilocybin to a vulnerable population without psychological support, as it would imply risks for the patients and could certainly hinder clinical improvement, if not worsen outcomes. In this respect, it is important to consider that the provided psychological support and in-session 'check-ins' in the present study were kept to a minimum (i.e. only one preparation and one integration session, plus acute and periacute support, but no specific psychotherapeutic interventions), in order to minimise their potential effect. Additionally, while patients were requested to down-titrate their antidepressant medication over a minimum wash-out period of two weeks, it must be acknowledged that (a) patient 2 continued taking venlafaxine (a 5-HT-norepinephrine reuptake inhibitor) throughout both dosing and scanning sessions and was not excluded from the present analyses, and (b) in general a wash-out period of two weeks might be insufficient and could potentially bias the clinical and neurobiological results. Both factors constitute a limitation and should be ruled out in future studies. FC analyses provide information on the temporal correlation between activity in spatially separate regions of the brain; however, they do not provide information on directionality and causal interactions between brain regions. Given our prior hypothesis, that reduced top-down control from the vmPFC to the amygdala might explain the increased responsiveness of the amygdala to emotional faces seen previously, the next logical step would be to explore this question using a metric capable of providing information about causal information flow. Future work is now required to test this hypothesis more directly, not just by improving our imaging analyses, e.g. incorporating dynamic causal modelling (DCM;and perhaps using other complementary imaging modalities (e.g. magnetoencephalography (MEG)) and supplementary emotional processing paradigms, but also by improving our indices of emotional re-engagement and acceptance/avoidance (although see. Using the Dynamic Emotional Recognition Task,provided evidence for improved emotional processing to levels of healthy controls in TRD patients after treatment with psilocybin. Modulating techniques, such as repetitive transcranial magnetic stimulation (rTMS) to temporarily disrupt vmPFC function could also be applied. With the present paradigm, regressing out missed trials and/or including reaction times as a proxy of attention as a regressor in the GLM could be used to ensure that measured effects are not solely due to attentional changes or confounded by differences in engagement with, and more specifically, looking at, the relevant task stimuli. Alternatively, for the same purpose, eye-tracking could be employed in future studies.

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Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression

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Imperial College London Open-Label Psilocybin Pilot for Treatment-Resistant Depression (Carhart-Harris / Lyons 2016–2018)

References (26)

Abstract

Research Summary of 'Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression'

Introduction

Methods

INTRODUCTION

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Study Details

Cited By (31)

Results

Discussion

Conclusion

PROCEDURE

PATIENT CHARACTERISTICS

FMRI DESIGN

FMRI ANALYSIS

GENERAL LINEAR MODELS (GLMS).

RELATIONSHIP WITH CLINICAL OUTCOMES

DEPRESSION.

ANXIETY.

STATISTICAL ANALYSIS

PPI: AMYGDALA

PPI: VMPFC

RELATION WITH AMYGDALA RESPONSE TO FEARFUL FACES (TASK-ANALYSIS)

RELATIONSHIP WITH CLINICAL OUTCOMES

DISCUSSION

VMPFC-RIGHT AMYGDALA FC

FURTHER CHANGES IN FC

LIMITATIONS

CONCLUSION