Blunted niacin skin flushing response with subtype-specific clinical associations in adolescent bipolar disorder

Abstract Background Bipolar disorder (BD) typically emerges during adolescence and is associated with substantial functional impairment, but objective physiological markers are scarce. The niacin skin flushing response (NSFR) has been proposed as a potential biomarker in adults with BD. However, its characteristics in adolescents and its multivariate associations with behavioral phenotypes, particularly across BD subtypes, remain poorly characterized. Methods We recruited 402 adolescents (184 with BD [63 BD-I, 121 BD-II]; 218 healthy controls) and conducted quantitative niacin testing. Participants underwent comprehensive assessments of clinical symptoms and cognitive function. Generalized estimating equations and multiple linear regression analyses were performed to assess group differences. Machine learning models were applied for exploratory assessment of classification performance, and sparse canonical correlation analysis (SCCA) was used to identify multivariate associations between NSFR and behavioral dimensions. Results Adolescents with BD exhibited a significantly attenuated and delayed NSFR compared to HCs, showing an impairment gradient: BD-II showed the most severe deficits, followed by BD-I. Machine learning models demonstrated moderate performance in distinguishing BD from HCs (cvAUC = 0.740–0.741), with limited discrimination between BD-I and BD-II (cvAUC = 0.576–0.603). SCCA revealed distinct subtype-specific patterns: in BD-I, blunted NSFR was associated with activation, mania, anxiety-depression and processing speed impairments; in BD-II, blunted NSFR was linked to anergia, insomnia, somatic anxiety, depression, activation, anhedonia, and impairments in processing speed and social cognition. Conclusion NSFR may serve as a potential screening biomarker for the early detection of adolescent BD. While it may not be suitable for stratifying BD subtypes, NSFR may reflect the physiological basis of the psychopathology underlying these subtypes.