Brain-derived extracellular vesicle (BDEV) abundance and BDEV protein associations with clinical phenotypes and treatment response in untreated first-episode psychosis.

Reliable biomarkers that capture central nervous system (CNS) processes during the earliest stages of psychosis are critically needed to improve early treatment and response monitoring. Brain-derived extracellular vesicles (BDEVs) that traverse the blood-brain barrier (BBB) can be isolated from peripheral blood, thereby offering a novel and minimally invasive approach to quantify CNS molecular biomarkers. We hypothesized that BDEV abundance and BDEV neuroinflammatory and neurotrophic protein cargo would differ between individuals with first-episode psychosis (FEP) and healthy controls (HCs), reflecting altered neuroinflammatory signalling and extracellular biology associated with psychosis and clinical outcomes. In a cohort of untreated individuals with FEP (n = 57) and HCs (n = 28), BDEVs were isolated from serum. Luminex assays quantified concentrations of brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B), and C-reactive protein (CRP) in BDEVs and serum. A subset of FEP participants (n = 34) subsequently completed four weeks of antipsychotic treatment. Group differences in BDEV characteristics and protein measures, as well as their associations with case-control status, baseline symptom severtity, and four-week symptom change, were examined. FEP participants showed a trend toward higher BDEV concentration than HCs (median 14.0 × 108 versus 10.2 × 108 particles/mL, p = 0.052), and higher baseline BDEV concentrations were significantly associated with more severe pretreatment symptoms (β = 4.09 × 10-10, p = 0.003) and greater symptom improvement after four-week antipsychotic treatment (β = 3.29 × 10-10, p = 0.029). Within BDEVs, BDNF (β = -1.05; p = 0.0018) and CRP (β = -0.84; p = 0.002) were significantly reduced in FEP vs HC, with a trend toward lower S100B level (β = -0.57; p = 0.061). In contrast, serum protein levels showed no case-control differences and did not correlate with corresponding BDEV protein levels. Lower baseline BDEV BDNF, S100B, and CRP were associated with greater therapeutic response among males. BDEVs offer a minimally invasive window into CNS-enriched biology in early psychosis. BDEV abundance and neuroinflammatory and neurotrophic cargo concentrations show associations with illness severity and sex-specific treatment response not detectable in serum, supporting their potential as biomarkers for early pathophysiology and treatment response in FEP.