J Neural Transm (Vienna). 2026 Sep 8. doi: 10.1007/s00702-026-03279-w. Online ahead of print.
ABSTRACT
Adolescent depression shows marked heterogeneity in symptom severity, yet mechanisms linking early-life adversity to severe depressive presentations remain unclear. Childhood maltreatment may induce persistent alterations in immune and stress-regulatory systems, increasing vulnerability to severe depression. This study examined whether childhood adversity, circulating biomarkers, and recent stress contribute to differences between severe and non-severe adolescent depression. Seventy adolescents with depressive disorder were classified into severe (SD, n = 40, HAMD-17 ≥ 24) and non-severe (NSD, n = 30, HAMD-17 < 24) groups, along with 39 healthy controls (HC). Childhood maltreatment was assessed using the Maltreatment and Abuse Chronology of Exposure (MACE), and recent stress using the Adolescent Life Events Scale. Serum levels of Pentraxin-3 (PTX3), S100B, matrix metalloproteinases (MMP-8, MMP-9), FKBP5, oxytocin, epidermal growth factor, and APCDD1 were measured by enzyme-linked immunosorbent assays. Adolescents with SD reported significantly higher childhood maltreatment than those with NSD. PTX3 and FKBP5 levels were significantly elevated in the severe group compared with both non-severe patients and HC and were positively associated with symptom severity. Receiver operating characteristic analyses showed that childhood maltreatment had good discriminative ability for depressive severity, whereas PTX3 and FKBP5 showed moderate discriminative performance. Multivariable logistic regression identified childhood maltreatment and PTX3 as independent predictors of SD. Hierarchical regression showed that recent life stress explained additional variance in self-reported symptom severity and partly attenuated the associations of early adversity and inflammatory markers. These findings suggest that severe adolescent depression represents a clinically defined severity stratum associated with neuroimmune alterations in the context of childhood adversity and recent life stress, rather than a discrete biological subtype.
PMID:42709166 | DOI:10.1007/s00702-026-03279-w
