Plasma complement and coagulation proteins as prognostic factors of negative symptoms: An analysis of the NAPLS 2 and 3 studies

Jonah F Byrne; Colm Healy; Melanie Föcking; Meike Heurich; Subash Raj Susai; David Mongan; Kieran Wynne; Eleftheria Kodosaki; Scott W Woods; Barbara A Cornblatt; William S Stone; Daniel H Mathalon; Carrie E Bearden; Kristin S Cadenhead; Jean Addington; Elaine F Walker; Tyrone D Cannon; Mary Cannon; Clark Jeffries; Diana Perkins; David R Cotter

doi:10.1016/j.bbi.2024.03.049

Plasma complement and coagulation proteins as prognostic factors of negative symptoms: An analysis of the NAPLS 2 and 3 studies

Brain Behav Immun. 2024 Mar 29:119:188-196. doi: 10.1016/j.bbi.2024.03.049. Online ahead of print.

Authors

Jonah F Byrne¹, Colm Healy², Melanie Föcking³, Meike Heurich⁴, Subash Raj Susai³, David Mongan⁵, Kieran Wynne⁶, Eleftheria Kodosaki⁴, Scott W Woods⁷, Barbara A Cornblatt⁸, William S Stone⁹, Daniel H Mathalon¹⁰, Carrie E Bearden¹¹, Kristin S Cadenhead¹², Jean Addington¹³, Elaine F Walker¹⁴, Tyrone D Cannon¹⁵, Mary Cannon¹⁶, Clark Jeffries¹⁷, Diana Perkins¹⁸, David R Cotter¹⁶

Affiliations

¹ Department of Psychiatry, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland; SFI FutureNeuro Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland. Electronic address: jonahbyrne21@rcsi.ie.
² Department of Psychiatry, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland; Department of Psychology, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.
³ Department of Psychiatry, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.
⁴ School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, United Kingdom.
⁵ Department of Psychiatry, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland; Centre for Public Health, Queen's University Belfast, United Kingdom.
⁶ School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
⁷ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁸ Department of Psychiatry, Zucker Hillside Hospital, Long Island, NY, USA.
⁹ Department of Psychiatry, Harvard Medical School at Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA; Mental Health Service 116d, Veterans Affairs San Francisco Health Care System, San Francisco, CA, USA.
¹¹ Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California, Los Angeles, CA, USA.
¹² Department of Psychiatry, University of California, San Diego, CA, USA.
¹³ Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
¹⁴ Departments of Psychology and Psychiatry, Emory University, Atlanta, GA, USA.
¹⁵ Departments of Psychology and Psychiatry, Yale University, New Haven, CT, USA.
¹⁶ Department of Psychiatry, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland; SFI FutureNeuro Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland; Department of Psychiatry, Beaumont Hospital, Dublin 9, Ireland.
¹⁷ Renaissance Computing Institute, University of North Carolina, Chapel Hill, NC, USA.
¹⁸ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.

PMID: 38555993
DOI: 10.1016/j.bbi.2024.03.049

Abstract

Introduction: Negative symptoms impact the quality of life of individuals with psychosis and current treatment options for negative symptoms have limited effectiveness. Previous studies have demonstrated that complement and coagulation pathway protein levels are related to later psychotic experiences, psychotic disorder, and functioning. However, the prognostic relationship between complement and coagulation proteins and negative symptoms is poorly characterised.

Methods: In the North American Prodrome Longitudinal Studies 2 and 3, negative symptoms in 431 individuals at clinical high-risk for psychosis (mean age: 18.2, SD 3.6; 42.5 % female) were measured at multiple visits over 2 years using the Scale of Psychosis-Risk Symptoms. Plasma proteins were quantified at baseline using mass spectrometry. Four factors were derived to represent levels of proteins involved in the activation or regulation of the complement or coagulation systems. The relationships between standardised protein group factors and serial measurements of negative symptoms over time were modelled using generalised least squares regression. Analyses were adjusted for baseline candidate prognostic factors: negative symptoms, positive symptoms, functioning, depressive symptoms, suicidal ideation, cannabis use, tobacco use, antipsychotic use, antidepressant use, age, and sex.

Results: Clinical and demographic prognostic factors of follow-up negative symptoms included negative, positive, and depressive symptoms, functioning, and age. Adjusting for all candidate prognostic factors, the complement regulators group and the coagulation regulators group were identified as prognostic factors of follow-up negative symptoms (β: 0.501, 95 % CI: 0.160, 0.842; β: 0.430, 95 % CI: 0.080, 0.780 respectively. The relationship between complement regulator levels and negative symptoms was also observed in NAPLS2 alone (β: 0.501, 95 % CI: -0.037, 1.039) and NAPLS3 alone, additionally adjusting for BMI (β: 0.442, 95 % CI: 0.127, 0.757).

Conclusion: The results indicate that plasma complement and coagulation regulator levels are prognostic factors of negative symptoms, independent of clinical and demographic prognostic factors. These results suggest complement and coagulation regulator levels could have potential utility in informing treatment decisions for negative symptoms in individuals at risk.

Keywords: Clinical high-risk; Coagulation; Complement; Early intervention; NAPLS; Negative symptoms; Positive symptoms; Prognostic factor; Proteins; Psychosis; Schizophrenia.