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Selective KOR antagonist alters functional patch sizes in individualized brain system: results from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS)

Neuropsychopharmacology volume 50, pages 1430–1438 (2025) Cite this article

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Abstract

In our prior study involving a transdiagnostic sample of individuals with anhedonia, we showed that an 8-week administration of a selective κ-opioid receptor (KOR) antagonist enhanced fMRI ventral striatal activation during reward anticipation in the Monetary Incentive Delay task as compared to a placebo. However, individual differences in brain architecture may limit the translation of this finding to the context of precision medicine. Here, we adopted an individual-specific approach to elucidate the effects of selective KOR antagonism on cortical-subcortical reward circuits in individuals with anhedonia. Sixty-four participants with anhedonia (30 KOR Antagonist, 34 Placebo) who completed both pre- and post- treatment MRI scans in the FAST-MAS study were included in this analysis. Using an individualized-brain-systems-functional-brain-mapping approach, functional networks were mapped at the individual level, and individual-specific cortical patches and subcortical-cortical clusters were obtained. Statistical analyses were conducted to examine the pre- and post-treatment changes in patch and cluster sizes, as well as their relationships with clinical-cognitive measures. ROI analyses revealed a significant patch size decrease in the right medial posterior prefrontal cortex within the frontoparietal control network, and significant size increases in three right subcortical clusters – pallidum, amygdala, and thalamus – within the orbitofrontal-limbic network, following KOR antagonist treatment. In short, we applied recently developed computational neuroimaging approaches to examine changes in the individualized brain systems of FAST-MAS participants before and after eight weeks of KOR antagonist treatment for anhedonia. Our results revealed alterations in functional cortical patch and subcortical-cortical cluster sizes in anhedonia-related brain regions following KOR antagonist treatment.

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Fig. 1: Workflow of methodological pipeline.
The alternative text for this image may have been generated using AI.
Fig. 2: Significant cortical patch of interest: right medial posterior prefrontal cortex (PFCmp) patch within the frontoparietal control network and significant subcortical-cortical clusters of interest.
The alternative text for this image may have been generated using AI.
Fig. 3: Correlations between cluster sizes and cognitive functioning.
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Data availability

Study data are available through the NIH/NIMH data archive and are accessible by emailing NDAHelp@mail.nih.gov.

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Funding

This research is supported by the National Institute of Mental Health (Project Number R01MH125850) and Brain and Behavior Research Foundation (Grant Number 28972), Rappaport Foundation, The Ride for Mental Health, and Gatto Foundation.

Author information

Authors and Affiliations

  1. Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA

    Hoki Fung, Ruby M. Potash & Matthew D. Sacchet

  2. Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, 94143, USA

    Andrew Krystal

  3. Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA

    Diego A. Pizzagalli

  4. Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, MA, 02478, USA

    Diego A. Pizzagalli

  5. McLean Imaging Center, McLean Hospital, Belmont, MA, 02478, USA

    Diego A. Pizzagalli

Authors
  1. Hoki Fung
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Contributions

Hoki Fung: Conceptualization, Analysis, Visualization, Writing - original draft, Writing - review & editing. Andrew Krystal: Conceptualization, Writing - review & editing. Diego A. Pizzagalli: Conceptualization, Writing - review & editing. Ruby M. Potash: Writing - review & editing. Matthew D. Sacchet: Conceptualization, Writing - original draft, Writing – review.

Corresponding author

Correspondence to Matthew D. Sacchet.

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Competing interests

Over the past 3 years, DAP has received consulting fees from Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Karla Therapeutics, Neumora Therapeutics, Neurocrine Biosciences, Neuroscience Software, Otsuka, Sage Therapeutics, Sama Therapeutics, Sunovion Therapeutics, and Takeda; he has received honoraria from the American Psychological Association, Psychonomic Society and Springer (for editorial work) as well as Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Dana Foundation, Wellcome Leap, Millennium Pharmaceuticals, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors have no conflicts of interest or relevant disclosures.

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Fung, H., Potash, R.M., Krystal, A. et al. Selective KOR antagonist alters functional patch sizes in individualized brain system: results from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS). Neuropsychopharmacol. 50, 1430–1438 (2025). https://doi.org/10.1038/s41386-025-02125-z

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