Comparison of copeptin levels in manic episode and remission periods in patients with bipolar disorder and its relationship with sleep, circadian rhythm and functionality

Bipolar disorder (BD) involves complex neurobiological and metabolic dysregulation. Copeptin, a stable fragment of the vasopressin precursor, has been studied in stress and metabolic conditions but rarely in BD. This study investigated serum copeptin levels during manic and remission phases and their associations with sleep, circadian rhythm, and functionality, aiming to explore its potential clinical utility as a state- and prognosis-related biomarker in bipolar disorder.

Methods

Fifty BD patients in manic episodes, 41 of the same patients in remission, and 50 healthy controls were included. Clinical assessments comprised the Young Mania Rating Scale (YMRS), Clinical Global Impression(CGI), and Hamilton Depression Rating Scale (HDRS). During remission, participants completed the Bipolar Disorder Functioning Questionnaire (BDFQ), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale(ESS), Morningness-Eveningness Scale(MES), and Social Rhythm Metric (SRM-II). Serum copeptin and related biochemical parameters were analyzed. Receiver operating characteristic (ROC) analysis evaluated the diagnostic performance of copeptin.

Results

Copeptin levels were significantly lower in BD patients during both manic and remission phases compared with controls (p < 0.001). Although levels increased in remission (p = 0.005), they remained below control values (p < 0.001). ROC analysis indicated a copeptin cut-off of 4.01 ng/mL(AUC = 0.924; sensitivity = 90%, specificity = 84%) distinguishing mania from controls, highlighting copeptin’s potential role as a clinically applicable biomarker rather than a purely experimental parameter. To determine the discriminative power of copeptin levels in identifying disease stage, ROC analysis indicated a copeptin cut-off of 3.15 ng/mL (AUC = 0.783, sensitivity = 73.2%, specificity = 75.6%), indicating “moderate to good” diagnostic accuracy. After adjusting for multiple comparisons, only the bipolar remission group showed poorer sleep duration than health controls, and no significant association was observed between copeptin levels and clinical measurements.

Conclusion

Reduced copeptin levels suggest the complexity of vasopressin-system involvement in BD, with partial recovery during remission. Taken together, these results suggest that copeptin may function more robustly as a state-sensitive biomarker reflecting acute disease activity. Therefore, future studies may benefit from combining copeptin with additional biomarkers or clinical parameters to improve phase-specific discrimination.