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Peer-reviewedCC BY-NCBrain, behavior, and immunity

Senescence-associated-secretory phenotype proteins and inflammatory pathways are involved in psychosis: A transdiagnostic study using the Human Connectome Project for Early Psychosis (HCP-EP) data

  • Johanna Seitz-Holland1
  • Moritz Haaf1,2
  • Ana Paula Mendes-Silva3
  • Nora Penzel1,4
  • Cornelius Berberich1,5
  • Sylvain Bouix1,6
  • Michael J. Coleman1
  • Elana Kotler1
  • Nicholas Kim1
  • Katherine E. Burdick1
  • Roman Kotov7
  • Peter Falkai4,8
13 more authors
  • Mark Vangel9
  • Gregor Leicht2
  • Christoph Mulert10
  • Tilo Kircher11
  • Kathryn E. Lewandowski12
  • Daphne Holt1
  • Matcheri S. Keshavan13
  • Dost Öngür12
  • Alan Breier14
  • Martha E. Shenton1,15
  • Steven E. Arnold16
  • Breno S. Diniz17,18
  • Marek Kubicki1,15
18 affiliations
  1. 1Department of Psychiatry, Mass General Brigham, Harvard Medical School, Boston, MA, USA
  2. 2Department of Psychiatry and Psychotherapy, Psychiatry Neuroimaging Branch, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
  3. 3Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada
  4. 4Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany
  5. 5Department of Diagnostic and Interventional Neuroradiology, School of Medicine, Technical University of Munich, Munich, Germany
  6. 6Département de génie logiciel et des TI, Ecole de Technologie Superieure, Montreal, QC, Canada
  7. 7Department of Psychiatry & Behavioral Health, Stony Brook University, Stony Brook, NY, USA
  8. 8Max-Planck-Institute of Psychiatry, Munich, Germany
  9. 9Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  10. 10Centre for Psychiatry and Psychotherapy, Justus-Liebig University Giessen, Giessen, Germany
  11. 11Department of Psychiatry and Psychotherapy, University of Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), University of Marburg, Germany
  12. 12Psychotic Disorders Division, McLean Hospital and Department of Psychiatry, Harvard Medical School, Boston, MA, USA
  13. 13Department of Psychiatry, Beth Israel Deaconess Medical Center and Massachusetts Mental Health Center, Harvard Medical School, Boston, MA, USA
  14. 14Indiana University School of Medicine, Indianapolis, IN, USA
  15. 15Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, MA, Boston, USA
  16. 16Department of Neurology, Massachusetts General Hospital Wang Ambulatory Care Center, Harvard Medical School, Boston, MA, USA
  17. 17UConn Center on Aging, University of Connecticut, Farmington, CT, USA
  18. 18Department of Psychiatry, UConn School of Medicine, Farmington, CT, USA
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Abstract

Biofluid proteins are promising transdiagnostic markers for delineating disease heterogeneity in psychosis. This study examined proteomic profiles in a transdiagnostic early psychosis sample to test the hypothesis that psychosis is associated with proteomic signatures of premature aging. We analyzed proteomic data from 85 individuals with early psychosis and 35 healthy controls from the Human Connectome Project for Early Psychosis (HCP-EP), using the Olink platform across four validated panels (Cardiometabolic, Inflammation, Cardiovascular II, and III). Our dual analytic strategy included: (1) calculating an index based on senescence-associated secretory phenotype (SASP) proteins to assess cellular aging, and (2) analyzing 341 proteins using Gene Set Enrichment Analysis to identify whether predefined biological pathways are collectively enriched. We compared the SASP index and enriched pathways between groups and examined associations with sociodemographic, physical health, cognitive, psychological well-being, psychosocial functioning, symptom, and medication data. The SASP index was significantly elevated in the psychosis group. Pathway analyses revealed enrichment of two inflammation-related pathways in psychosis after multiple comparison correction: Cellular Response to Tumor Necrosis Factor and Monocyte Chemotaxis. The higher SASP index and the enriched inflammatory pathways were associated with increased body mass index (BMI) and reduced psychological well-being. Our findings are consistent with prior research linking psychosis to premature aging and an increased inflammation response. They also underscore the value of examining multiple biomarkers and biological pathways simultaneously and highlight the importance of conceptualizing psychosis as a whole-body condition. However, given the sample size, results should be considered preliminary. Larger, longitudinal studies are needed to track proteomic changes over time and assess the predictive value of these biomarkers for identifying vulnerable individuals and clinical outcomes.

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Cite

BibTeXRIS
BibTeX
@article{seitzholland2026senescenceassociatedsecretory,
  title = {{Senescence-associated-secretory phenotype proteins and inflammatory pathways are involved in psychosis: A transdiagnostic study using the Human Connectome Project for Early Psychosis (HCP-EP) data}},
  author = {Johanna Seitz-Holland and Moritz Haaf and Ana Paula Mendes-Silva and Nora Penzel and Cornelius Berberich and Sylvain Bouix and Michael J. Coleman and Elana Kotler and Nicholas Kim and Katherine E. Burdick and Roman Kotov and Peter Falkai and Mark Vangel and Gregor Leicht and Christoph Mulert and Tilo Kircher and Kathryn E. Lewandowski and Daphne Holt and Matcheri S. Keshavan and Dost Öngür and Alan Breier and Martha E. Shenton and Steven E. Arnold and Breno S. Diniz and Marek Kubicki},
  journal = {Brain, behavior, and immunity},
  year = {2026},
  month = sep,
  doi = {10.1016/j.bbi.2026.107023},
  url = {https://doi.org/10.1016/j.bbi.2026.107023},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Senescence-associated-secretory phenotype proteins and inflammatory pathways are involved in psychosis: A transdiagnostic study using the Human Connectome Project for Early Psychosis (HCP-EP) data
AU  - Johanna Seitz-Holland
AU  - Moritz Haaf
AU  - Ana Paula Mendes-Silva
AU  - Nora Penzel
AU  - Cornelius Berberich
AU  - Sylvain Bouix
AU  - Michael J. Coleman
AU  - Elana Kotler
AU  - Nicholas Kim
AU  - Katherine E. Burdick
AU  - Roman Kotov
AU  - Peter Falkai
AU  - Mark Vangel
AU  - Gregor Leicht
AU  - Christoph Mulert
AU  - Tilo Kircher
AU  - Kathryn E. Lewandowski
AU  - Daphne Holt
AU  - Matcheri S. Keshavan
AU  - Dost Öngür
AU  - Alan Breier
AU  - Martha E. Shenton
AU  - Steven E. Arnold
AU  - Breno S. Diniz
AU  - Marek Kubicki
PY  - 2026
DA  - 2026/09/20
JO  - Brain, behavior, and immunity
DO  - 10.1016/j.bbi.2026.107023
UR  - https://doi.org/10.1016/j.bbi.2026.107023
AB  - Biofluid proteins are promising transdiagnostic markers for delineating disease heterogeneity in psychosis. This study examined proteomic profiles in a transdiagnostic early psychosis sample to test the hypothesis that psychosis is associated with proteomic signatures of premature aging. We analyzed proteomic data from 85 individuals with early psychosis and 35 healthy controls from the Human Connectome Project for Early Psychosis (HCP-EP), using the Olink platform across four validated panels (Cardiometabolic, Inflammation, Cardiovascular II, and III). Our dual analytic strategy included: (1) calculating an index based on senescence-associated secretory phenotype (SASP) proteins to assess cellular aging, and (2) analyzing 341 proteins using Gene Set Enrichment Analysis to identify whether predefined biological pathways are collectively enriched. We compared the SASP index and enriched pathways between groups and examined associations with sociodemographic, physical health, cognitive, psychological well-being, psychosocial functioning, symptom, and medication data. The SASP index was significantly elevated in the psychosis group. Pathway analyses revealed enrichment of two inflammation-related pathways in psychosis after multiple comparison correction: Cellular Response to Tumor Necrosis Factor and Monocyte Chemotaxis. The higher SASP index and the enriched inflammatory pathways were associated with increased body mass index (BMI) and reduced psychological well-being. Our findings are consistent with prior research linking psychosis to premature aging and an increased inflammation response. They also underscore the value of examining multiple biomarkers and biological pathways simultaneously and highlight the importance of conceptualizing psychosis as a whole-body condition. However, given the sample size, results should be considered preliminary. Larger, longitudinal studies are needed to track proteomic changes over time and assess the predictive value of these biomarkers for identifying vulnerable individuals and clinical outcomes.
SN  - 0889-1591
SN  - 1090-2139
ER  -