Dysregulation of the orexin-leptin-ghrelin axis and its associations with chronotype and sleep disturbances in drug-naïve children with ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder defined by inattention and behavioral dysregulation. Sleep disturbances are frequently reported in ADHD and strongly associated with circadian rhythms and sleep-wake regulation. Given the pivotal involvement of orexin, leptin and ghrelin systems in the modulation of cognitive, metabolic and circadian functions, this study aimed to investigate whether serum orexin-A, orexin-B, leptin and ghrelin levels are associated with chronotype and sleep disturbances in children with ADHD. Forty-five drug-naïve ADHD patients and 45 age and sex-matched healthy controls were assessed using validated measures of chronotype and sleep habits, and serum hormone levels were analyzed via two-site sandwich ELISA. Children with ADHD exhibited substantially higher eveningness chronotype, as well as markedly elevated bedtime resistance, sleep onset delay, night wakings and daytime sleepiness (all p < 0.001). Importantly, serum orexin-A (p < 0.001), orexin-B (p = 0.039) and leptin (p = 0.012) levels were significantly reduced in the ADHD group, whereas serum ghrelin levels were significantly increased (p < 0.001). Ghrelin levels showed strong positive associations with attention deficit scores, chronotype scores and total sleep disturbance scores (all p < 0.01), whereas orexin-A/B and leptin levels were negatively correlated with these parameters (all p < 0.05). Notably, children with an evening chronotype showed the highest ghrelin and lowest orexin/leptin levels. To our knowledge, these findings provide preliminary evidence of an association between disturbances in the orexin-leptin-ghrelin axis and chronotype-related circadian misalignment and sleep difficulties in childhood ADHD, suggesting that neurohormonal mechanisms may be relevant to the underlying pathophysiology.