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Cited by 587Psychedelics and Drug StudiesTreatment of Major DepressionTranscranial Magnetic Stimulation Studies

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Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Open access
Carhart-Harris, Robin L, Roseman, Leor, Bolstridge, Mark, Demetriou, Lysia, Pannekoek, J Nienke, Wall, Matthew B, Tanner, Mark, Kaelen, Mendel, McGonigle, John, Murphy, Kevin, Leech, Robert, Curran, H Valerie, Nutt, David J·2017·Scientific Reports
DOI 10.1038/s41598-017-13282-7PMC PMC5640601
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Abstract

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.

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Figure 1 Whole-brain cerebral blood flow maps for baseline versus one-day post-treatment, plus the difference map (cluster-corrected, p < 0.05, n = 16). Correlation chart shows post-Treatment changes in bilateral amygdala CBF versus changes in depressive symptoms (r = 0.59, p = 0.01). One patient failed to completed the scan 2 QIDS-SR16 rating, reducing the sample size to n = 15 for the correlation analysis. In all of the images, the left of the brain is shown on the left.
Figure 1 Whole-brain cerebral blood flow maps for baseline versus one-day post-treatment, plus the difference map (cluster-corrected, p < 0.05, n = 16). Correlation chart shows post-Treatment changes in bilateral amygdala CBF versus changes in depressive symptoms (r = 0.59, p = 0.01). One patient failed to completed the scan 2 QIDS-SR16 rating, reducing the sample size to n = 15 for the correlation analysis. In all of the images, the left of the brain is shown on the left.CC BY · PubMed Central
Figure 2 Top two rows = sgACC (purple) RSFC before and after psilocybin treatment (hot colours = regions of significantly positive coupling). Bottom row reveals regions where there was a significant increase in sgACC RSFC post-treatment (hot colours). All maps are cluster-corrected, p < 0.05, Z > 2.3.
Figure 2 Top two rows = sgACC (purple) RSFC before and after psilocybin treatment (hot colours = regions of significantly positive coupling). Bottom row reveals regions where there was a significant increase in sgACC RSFC post-treatment (hot colours). All maps are cluster-corrected, p < 0.05, Z > 2.3.CC BY · PubMed Central
Figure 3 Top two rows = vmPFC (purple) RSFC before and after psilocybin treatment (hot colours = regions of significantly positive coupling). Bottom row reveals regions where there was a significant increase in vmPFC RSFC post-treatment (hot colours). All maps are cluster-corrected, p < 0.05, Z > 2.3. Increased coupling between the vmPFC and the displayed regions (bottom row) was predictive of clinical response at 5-weeks post-treatment. Chart shows mean values and positive standard errors.
Figure 3 Top two rows = vmPFC (purple) RSFC before and after psilocybin treatment (hot colours = regions of significantly positive coupling). Bottom row reveals regions where there was a significant increase in vmPFC RSFC post-treatment (hot colours). All maps are cluster-corrected, p < 0.05, Z > 2.3. Increased coupling between the vmPFC and the displayed regions (bottom row) was predictive of clinical response at 5-weeks post-treatment. Chart shows mean values and positive standard errors.CC BY · PubMed Central
Figure 4 Top two rows = Bilateral PH (purple) RSFC before and after psilocybin treatment (hot colours = regions of significantly positive coupling). Bottom row reveals regions where there was a significant decrease in PH RSFC post-treatment (cold colours). All maps are cluster-corrected, p < 0.05, Z > 2.3. Decreased coupling between the PH and the displayed regions (bottom row) was predictive of clinical response at 5-weeks post-treatment (t = −1.9, p = 0.04). Chart shows mean values and negative standard errors.
Figure 4 Top two rows = Bilateral PH (purple) RSFC before and after psilocybin treatment (hot colours = regions of significantly positive coupling). Bottom row reveals regions where there was a significant decrease in PH RSFC post-treatment (cold colours). All maps are cluster-corrected, p < 0.05, Z > 2.3. Decreased coupling between the PH and the displayed regions (bottom row) was predictive of clinical response at 5-weeks post-treatment (t = −1.9, p = 0.04). Chart shows mean values and negative standard errors.CC BY · PubMed Central
Figure 5 Differences in between-RSN RSFC or RSN ‘segregation’ before and after therapy. Each square in the matrix represents the strength of functional connectivity (positive = red, negative = blue) between a pair of different RSNs (beta values). The matrix on the far right displays the between-condition differences in covariance (t values). The RSNs are: 1) medial visual network, 2) lateral visual network, 3) occipital pole network, 4) auditory network, 5) sensorimotor network, 6) DMN, 7) parietal cortex network, 8) the dorsal attention network, 9) the salience network, 10) posterior opercular network, 11) left frontoparietal network, 12) right frontoparietal network. White asterisks represent significant differences (P < 0.05, non-corrected). Both of the significant differences did not survive FDR correction for multiple comparisons.
Figure 5 Differences in between-RSN RSFC or RSN ‘segregation’ before and after therapy. Each square in the matrix represents the strength of functional connectivity (positive = red, negative = blue) between a pair of different RSNs (beta values). The matrix on the far right displays the between-condition differences in covariance (t values). The RSNs are: 1) medial visual network, 2) lateral visual network, 3) occipital pole network, 4) auditory network, 5) sensorimotor network, 6) DMN, 7) parietal cortex network, 8) the dorsal attention network, 9) the salience network, 10) posterior opercular network, 11) left frontoparietal network, 12) right frontoparietal network. White asterisks represent significant differences (P < 0.05, non-corrected). Both of the significant differences did not survive FDR correction for multiple comparisons.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Avants, B. B., Tustison, N. & Song, G. Advanced normalization tools (ANTS). Insight J 2, 1–35 (2009).
  2. Carhart-Harris, R. L. et al. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences 113, 4853–4858 (2016). · DOI · Paper page
  3. Roseman, L., Leech, R., Nutt, D. J., Feilding, A. & Carhart-Harris, R. L. The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Frontiers in Human Neuroscience 8, https://doi.org/10.3389/fnhum.2014.00204 (2014). · DOI

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Metadata

Authors
Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., Tanner, M., Kaelen, M., McGonigle, J., Murphy, K., Leech, R., Curran, H. V., & Nutt, D. J.
Affiliations
  • Imperial College London (GB)
  • Hammersmith Hospital (GB)
  • University of Cape Town (ZA)
  • Cardiff University (GB)
  • University College London (GB)
Corresponding author
Carhart-Harris, Robin L
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-10-13
Volume
7
Issue
1
Pages
13187-13187
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-13282-7
PMC
PMC5640601
OpenAlex
W2762746674
Cited by
587
References
64
Citations by year
2026: 48 · 2025: 79 · 2024: 80 · 2023: 68 · 2022: 90 · 2021: 74 · 2020: 53 · 2019: 34 · 2018: 52 · 2017: 7
FWCI
49.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Research Bank (Australian Catholic University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (200804/Z/16/Z)
  • Alexander Mosley Charitable Trust
  • Medical Research Council
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
psilocybin, treatment-resistant depression, cerebral blood flow, resting-state functional connectivity, amygdala, default mode network, ventromedial prefrontal cortex, parahippocampal cortex, treatment response prediction, serotonin receptor agonists, psychedelics
MeSH terms
Adult, Brain, Depression, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Psilocybin

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