Peripheral orexin system alterations in acute bipolar mania: Associations with clinical features and diagnostic...

The orexin system regulates arousal, sleep-wake cycles, and reward processing, yet its role in acute bipolar mania (BD-M) remains unclear. This study aimed to examine peripheral levels of orexin-A (OXA), orexin-B (OXB), soluble orexin-1 receptor (sOX1R), and orexin-2 receptor (sOX2R) in BD-M and to explore their associations with clinical features, discriminative patterns, and system-level interactions.

This cross-sectional case-control study included 30 treatment-naïve BD-M inpatients and 30 healthy controls. Fasting serum orexin parameters were measured using ELISA. Clinical severity was assessed with the Young Mania Rating Scale. Group comparisons, correlation analyses, receiver operating characteristic (ROC) analyses, and correlation-based network analyses were performed.

Serum OXA, OXB, sOX1R, and sOX2R levels were significantly lower in the BD-M group (all p < 0.001). OXA levels were negatively associated with duration since manic onset and positively associated with reduced sleep need, while increased sexual interest was associated with higher sOX2R levels. ROC findings were exploratory and indicated group discrimination (AUC > 0.90), with sOX1R showing the highest AUC (0.931). Network analysis revealed strong positive associations among orexin components in controls (r = 0.883-0.970), whereas correlations were uniformly attenuated in BD-M (r = 0.671-0.789). All connections were significantly weaker in the patient group after FDR correction, with lower global network strength.

Peripheral orexin system alterations in acute mania are characterized not only by reduced biomarker levels but also by disrupted inter-component connectivity. These findings suggest a potential role for orexinergic dysregulation in BD-M and highlight its relevance as a candidate system-level biomarker. Longitudinal studies are needed to clarify the state versus trait nature of these alterations.