Blood-Brain Biomarker Signatures Differentiate Early Depression and Psychosis
Key Clinical Summary
- Multicenter PRONIA study (n=678) identified distinct multivariate inflammation–gray matter volume (GMV) signatures for recent-onset psychosis and recent-onset depression.
- Psychosis was linked to elevated interleukin (IL)-6 and tumor necrosis factor α (TNF-α) with corticothalamic gray matter shifts, while depression showed heightened IL-1β, IL-2, IL-4, S100 calcium-binding protein B (S100B), and brain-derived neurotrophic factor (BDNF) with limbic GMV reductions.
- Childhood trauma patterns predicted signature expression across disorders, while cognition predicted psychosis signatures only.
A new analysis from the multicenter PRONIA consortium reports that integrated peripheral inflammatory markers and whole-brain gray matter volumes can distinguish early-stage depression from psychosis. Published in JAMA Psychiatry, the study identifies biologically distinct blood–brain signatures relevant to early psychiatric stratification.
Study Findings
In this cross-sectional study of 678 participants (median age, 24 years), researchers evaluated individuals with recent-onset depression (ROD), recent-onset psychosis (ROP), clinical high-risk states for psychosis (CHR-P), and healthy controls. All symptomatic groups had minimal medication exposure, and participants underwent MRI, cytokine assays, clinical evaluations, and cognitive testing.
Sparse partial least squares analysis revealed 4 latent signatures. A psychosis-specific signature (ρ=0.27; P=.002) differentiated ROP from CHR-P. This signature featured elevated interleukin (IL)-6 and tumor necrosis factor α (TNF-α), reduced C-reactive protein, and gray matter volume (GMV) alterations within corticothalamic circuits. According to investigators, these coordinated immune–neuroanatomical shifts suggest early psychosis involves distinct patterns of neuroinflammation and structural remodeling.
A separate depression-specific signature (ρ=0.19; P=.02) distinguished ROD from healthy individuals. Key elements included increased IL-1β, IL-2, IL-4, S100 calcium-binding protein B (S100B), and brain-derived neurotrophic factor (BDNF), alongside GMV reductions in limbic regions. These findings point to a unique neurobiological profile for early depression, independent of psychosis.
Two additional signatures reflected age (ρ=0.67) and sex or MRI quality (ρ=0.53). Psychosocial factors were influential: childhood trauma patterns predicted the psychosis signature with balanced accuracy (BAC) of 67.2% and the depression signature with BAC of 78.0%. Cognitive measures predicted only the psychosis signature (BAC=65.1%).
Clinical Implications
The emerging ability to distinguish depression and psychosis at early stages using coordinated blood and brain biomarkers could reshape diagnostic pathways; the identified signatures provide objective, biologically grounded markers that may support earlier and more precise intervention strategies. Integrating inflammatory cytokines, neurotrophic factors, and GMV metrics may eventually help clinicians better classify at-risk individuals, differentiate high-risk psychosis from emerging psychotic disorders, and identify depression subtypes with distinct neuroimmune profiles.
The findings also underscore the influence of childhood trauma and cognition, suggesting that psychosocial and neurocognitive assessments may enhance biomarker-driven stratification. While additional validation is required, the results offer a potential framework for personalized psychiatric care.
Expert Commentary
“Overall, these findings challenge fully dimensional models of psychopathology by revealing distinct early-stage neurobiological profiles that separate psychosis and depression,” wrote David Popovic, MD, PhD, Max Planck Institute of Psychiatry, Munich, Germany, and study coauthors.
The researchers acknowledged that further longitudinal research is needed to determine how these biomarkers can guide targeted, stage-specific psychiatric treatment.
