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Background <p>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.</p> Methods <p>We conducted a comprehensive investigation of the NSFR in a large adolescent sample (<i>N</i> = 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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • Mengyao Feng,
  • Jinxin He,
  • Qi Wen,
  • Jie Yao,
  • Yuting Zeng,
  • Yupan Tan,
  • Hongjie Li,
  • Yigang Wang,
  • Guanghai Wang,
  • Li Dong,
  • Xia Sun,
  • Yuanyuan Zhang,
  • Shuxian Yin,
  • Huan Peng,
  • Maolin Hu,
  • Xiaofen Zong

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.