Association of baseline inflammatory markers and the development of negative symptoms in individuals at clinical high risk for psychosis

Brain Behav Immun. 2019 Feb;76:268-274. doi: 10.1016/j.bbi.2018.11.315. Epub 2018 Nov 26.


Negative symptoms are common in individuals at clinical high-risk (CHR) for psychosis and are associated with worse functional outcomes. Inflammation may be one mechanism underlying negative symptoms. Inflammatory markers are altered in individuals at CHR and are associated with negative symptoms in patients with schizophrenia. We thus hypothesized that baseline inflammatory markers would predict the development of negative symptoms in individuals at CHR for psychosis. Thirty seven individuals from the North American Prodromal Longitudinal Study who met CHR criteria were included in the study. Inflammatory cytokines, including interferon (IFN)-λ, Interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF) were measured at baseline. Negative symptoms as measured by the Scale of Prodromal Symptoms, were measured at baseline and six and twelve months. Associations between inflammatory markers and the trajectory of negative symptoms (slope) over the first year of follow-up, were assessed using linear regression models controlling for age, sex, race and depressive symptom severity (as assessed by the Calgary Depression Scale for Schizophrenia). Baseline TNF (beta = 0.361, p = 0.007) and IL-6 (beta = -0.306, p = 0.026) predicted negative symptoms slopes, along with depressive symptom severity at baseline (beta = -0.596, p = 0.000). These findings demonstrate that inflammatory cytokines may underlie the development of negative symptoms in some individuals at CHR for psychosis. TNF predicted the development of negative symptoms independent of baseline depression. Given the heterogeneity of the CHR population, the comorbidity of negative symptoms and depression in this population, and the particular challenges in treating negative symptoms, immune markers could represent potential biomarkers that underlie the development of negative symptoms, representing a potential treatment target.

Keywords: Clinical high risk; Cytokines; Inflammation; Negative symptoms; Psychosis; Schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Affect / physiology
  • Biomarkers / blood
  • Comorbidity
  • Cytokines / analysis
  • Cytokines / blood
  • Depression / diagnosis
  • Disease Progression
  • Female
  • Humans
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism
  • Longitudinal Studies
  • Lymphotoxin-alpha / metabolism
  • Male
  • Prodromal Symptoms
  • Psychiatric Status Rating Scales
  • Psychotic Disorders / epidemiology*
  • Psychotic Disorders / immunology*
  • Risk Factors
  • Schizophrenia / diagnosis
  • Schizophrenia / immunology
  • Schizophrenia / physiopathology
  • Young Adult


  • Biomarkers
  • Cytokines
  • Interleukin-6
  • Lymphotoxin-alpha