A transdiagnostic niacin flushing biomarker with disorder-specific multivariate relationships in adolescent unipolar and bipolar depression

Identifying objective biomarkers for adolescent unipolar depression (UD) and bipolar depression (BD) remains a critical challenge. The niacin skin flushing response (NSFR) is a promising peripheral biomarker that is blunted in adults with mood disorders; however, its profile in adolescent and its multivariate relationships with behavioral phenotypes remain unestablished. We conducted a comprehensive investigation of the NSFR in a large adolescent sample ( N = 315), including 114 with BD, 46 with UD, and 155 healthy controls (HCs). We quantified NSFR features using a multi-parametric approach, alongside comprehensive clinical and cognitive profiling. Analyses included machine learning classification and sparse canonical correlation analysis (SCCA) to decipher multivariate NSFR-behavior relationships. Both UD and BD groups exhibited significantly blunted NSFR compared to HCs, establishing it as a transdiagnostic feature. NSFR features differentiated patients from HCs (AUC-ROC up to 0.804) but not UD from BD. Critically, SCCA revealed disorder-specific relationship patterns: in UD, blunted NSFR was associated with anergia and anxiety-related symptoms, whereas in BD, it correlated with diurnal variation, anhedonia, non-suicidal self-injury, and cognitive changes in processing speed, continuous attention, and social cognition. This study establishes blunted NSFR as a shared biological vulnerability in adolescent UD and BD. More importantly, clinical heterogeneity arises not from the biomarker itself, but from disorder-specific architectures linking this shared abnormality to distinct clinical and cognitive domains. Our findings support a paradigm shift toward a relationship-based framework for understanding psychiatric heterogeneity.