A comprehensive examination of circadian rhythm and tryptophan pathway parameters: Assessing their role in predicting bipolar disorder in patients, siblings, and controls

The complex interplay between sleep, circadian rhythms, and tryptophan pathway metabolites in bipolar disorder (BD) remains poorly understood. This study examined these mechanisms in euthymic individuals with BD (n = 20), their unaffected siblings (n = 20), and healthy controls (n = 24). Subjective and objective sleep and circadian rhythm parameters were assessed using questionnaires and actigraphy, alongside plasma measurements of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid (QUIN). Compared to controls, both BD patients and siblings showed reduced sleep efficiency and increased wake after sleep onset. Patients had longer time in bed, whereas siblings had shorter total sleep time. Elevated KYN/TRP ratios were found in both groups. Higher 3-HAA levels predicted both BD and sibling status, while increased QUIN levels were specific to BD. Lasso regression identified 12 variables associated with BD and 6 with sibling status. These results suggest that altered tryptophan metabolism and circadian disruption may contribute to the pathophysiology of BD and familial risk, providing potential biomarkers for early identification and intervention.