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Evidence of altered monoamine oxidase B, an astroglia marker, in early psychosis and high-risk state

Molecular Psychiatry volume 30, pages 2049–2058 (2025)Cite this article

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Abstract

A novel radiotracer, [11C]SL25.1188, targets monoamine oxidase-B (MAO-B) enzyme, found primarily in astrocytes, which metabolizes monoamines (including dopamine), particularly in subcortical regions. Altered astrocyte function in schizophrenia is supported by convergent evidence from post-mortem, genetic, transcriptomic, peripheral and preclinical findings. We aimed to test whether levels of MAO-B, an index of astrocyte function are low in the living brains of early psychosis and their high-risk states. Thirty-eight participants including antipsychotic-free/minimally exposed clinical participants with first-episode psychosis (FEP), clinical high-risk (CHR) individuals and healthy volunteers (HVs) underwent a 90-min positron emission tomography (PET) scan with [11C]SL25.1188, to measure MAO-B VT, an index of MAO-B concentration. Participants were excluded if tested positive on urine drug screen (except for cannabis). This study of 14 FEP (mean[SD] age, 25.7[5.7] years; 6 F), 7 CHR (mean[SD] age, 20.9[3.7] years; 4 F) and 17 HV (mean[SD] age, 31.2[13.9] years; 9 F) demonstrated significant group differences in regional MAO-B VT (F(2,37.42) = 4.56, p = 0.02, Cohen’s f = 0.49), controlling for tobacco (F (1,37.42) = 5.37, p = 0.03) and cannabis use (F(1,37.42) = 5.11, p = 0.03) with significantly lower MAO-B VT in CHR compared to HV (Cohen’s d = 0.99). We report a significant cannabis effect on MAO-B VT (F(1,39.19) = 12.57, p = 0.001, Cohen’s f = 0.57), with a significant group-by-cannabis interaction (F(2,37.30) = 3.82, p = 0.03, Cohen’s f = 0.45), indicating lower MAO-B VT in cannabis-using clinical groups. Lower MAO-B VT levels were more robust in striatal than cortical regions, in both clinical groups (F(12,46.84) = 2.08, p = 0.04, Cohen’s f = 0.73) and in cannabis users (F(6,46.84) = 6.42, p < 0.001, Cohen’s f = 0.91). Lower MAO-B concentration supports astrocyte dysfunction in cannabis-using CHR and FEP clinical populations. Lower MAO-B is consistent with replicated striatal dopamine elevation in psychosis, as well as astrocyte dysfunction in schizophrenia.

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Fig. 1: Lower MAO-B Total Distribution Volume in Early Psychosis Spectrum (FEP and CHR vs. HV) across brain regions.
Fig. 2: Interaction plots.

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Data availability

Anonymized individual participant data are available in the Supplementary Appendix.

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Analysis codes are available in the Supplementary Appendix.

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Acknowledgements

This work was partially funded by Canadian Institutes of Health Research (CIHR) Grant (APP461645) and was done as part of the research undertaken thanks, in part, to funding from the Canada First Research Excellence Fund, awarded to the Healthy Brains for Healthy Lives initiative at McGill University to Dr. Mizrahi. The authors thank the staff of the FYPP clinic (Dr. Michael Kiang) for aiding in participant recruitment in Toronto and the PET Research Imaging Centre for the acquisition of data. We would also like to thank the participants and their families for their cooperation.

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Authors and Affiliations

  1. Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada

    Kankana Nisha Aji, Nittha Lalang & Jeffrey H. Meyer

  2. Clinical and Translational Sciences Lab, Douglas Research Centre, Montreal, QC, Canada

    Kankana Nisha Aji, Christian Ramos-Jiménez, Pablo M. Rusjan & Romina Mizrahi

  3. Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Kankana Nisha Aji, Isabelle Boileau & Jeffrey H. Meyer

  4. Vertex Pharmaceuticals, Boston, MA, USA

    Nittha Lalang

  5. Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada

    Christian Ramos-Jiménez, Naguib Mechawar & Gustavo Turecki

  6. Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada

    Reza Rahimian, Naguib Mechawar & Gustavo Turecki

  7. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Reza Rahimian, Naguib Mechawar, Gustavo Turecki, Pablo M. Rusjan & Romina Mizrahi

  8. Department of Anesthesia, McGill University, Montreal, QC, Canada

    Daniel Chartrand

  9. Department of Anesthesia, Montreal Neurological Institute, Montreal, QC, Canada

    Daniel Chartrand

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Contributions

Dr. Mizrahi and Dr. Nisha Aji had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Mizrahi. Acquisition, analysis, or interpretation of data: Lalang, Nisha Aji, Ramos-Jiménez, Rusjan, Mizrahi, Rahimian. Drafting of the manuscript: Nisha Aji, Mizrahi, Rahimian, Rusjan. Critical revision of the manuscript for important intellectual content: Nisha Aji, Mizrahi, Rusjan, Meyer, Boileau, Rahimian, Mechawar, Turecki, Chartrand. Statistical analysis: Nisha Aji, Mizrahi, Ramos-Jiménez. Obtained funding: Mizrahi. Administrative, technical, or material support: Rusjan, Chartrand. Supervision: Mizrahi, Rusjan.

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Correspondence to Pablo M. Rusjan or Romina Mizrahi.

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NL is an employee at the Vertex Pharmaceuticals and the authors collectively declare that they have no financial relationships with commercial interests that could have appeared to influence the work reported in this paper. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Nisha Aji, K., Lalang, N., Ramos-Jiménez, C. et al. Evidence of altered monoamine oxidase B, an astroglia marker, in early psychosis and high-risk state. Mol Psychiatry 30, 2049–2058 (2025). https://doi.org/10.1038/s41380-024-02816-x

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  • DOI: https://doi.org/10.1038/s41380-024-02816-x

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