Schizophrenia (SCZ) and major depressive disorder (MDD) share overlapping clinical features. We examined plasma neutrophil gelatinase-associated lipocalin (NGAL) in drug-naïve patients to investigate differences between diagnostic groups and their associations with clinical symptoms and cognitive performance. We recruited 510 participants (246 with SCZ, 158 with MDD, and 106 healthy controls HC) from 2017 to 2025. Plasma NGAL was measured using ELISA. Cognition was assessed with MCCB (SCZ) and RBANS (MDD). We employed partial correlations and multiple linear regression (FDR-corrected) to examine NGAL-clinical and cognitive associations. Receiver operating characteristic (ROC) curves with five-fold cross-validation were used to evaluate diagnostic discrimination. Plasma NGAL levels differed significantly across groups ( P < 0.001): levels were highest in MDD, lowest in SCZ, with HC intermediate. Following Box-Cox transformation, partial Pearson correlation revealed that in SCZ, NGAL correlated consistently and negatively with core symptoms (Positive: r = -0.289, P < 0.001; Negative: r = -0.138, P = 0.005), while remaining positively associated with general psychopathology ( r = 0.185, P = 0.005) and cognitive domains. Ten-times repeated five-fold cross-validation demonstrated high discriminative utility for NGAL: the highest accuracy was achieved in distinguishing SCZ from MDD (AUC = 0.857), followed by SCZ versus others (AUC = 0.826) and MDD versus others (AUC = 0.805). Our findings demonstrate a distinctive bidirectional profile in plasma NGAL levels, where elevations in MDD and reductions in SCZ reflect divergent immune dysregulation signatures at the early stages of these disorders. Within the Immune Response System (IRS)–Compensatory Immune-regulatory System (CIRS) framework, these results suggest a failure of compensatory neuroprotective mechanisms in SCZ compared to persistent inflammatory activation in MDD. Collectively, NGAL serves as a promising biological adjunct to enhance the objective differentiation between SCZ and MDD, though longitudinal studies are warranted to validate its predictive value across illness trajectories.
Zhou et al. (Fri,) studied this question.