Chronobiological disruption in ADHD: Developmental mechanisms linking sleep, behavior, and comorbid conditions

Attention-Deficit/Hyperactivity Disorder (ADHD) is increasingly recognized as a neurodevelopmental condition involving both dopaminergic dysfunction and circadian misalignment. While these mechanisms have traditionally been studied independently, their combined impact on symptom expression and comorbidity-particularly with mood disorders, substance use disorders, and obesity-remains insufficiently understood. This review aims to integrate current evidence on the interaction between circadian and dopaminergic dysfunction in ADHD and to evaluate the therapeutic potential of chronobiological interventions.

We conducted an integrative review of studies across neurobiology, chronobiology, psychopharmacology, and genetics, including evidence from both human and animal models. The review focuses on molecular and clinical findings related to circadian regulation, dopaminergic signaling, and their interaction in ADHD pathophysiology and treatment response.

Evidence indicates that dopaminergic dysregulation contributes to impaired reward processing and motivational deficits, while circadian disruption is associated with sleep disturbances, emotional dysregulation, and metabolic dysfunction. These processes appear to interact bidirectionally, potentially amplifying symptom severity and comorbidity. Emerging findings implicate circadian genes-particularly CRY1-in the regulation of both neural and metabolic pathways. Chronotherapeutic interventions, including light therapy, melatonin supplementation, and sleep-focused behavioral strategies, show promise, particularly when aligned with individual circadian profiles.

Elucidating the interplay between circadian misalignment and dopaminergic dysfunction may inform more precise, biomarker-guided treatment strategies in ADHD. Stratified care models that incorporate circadian timing and individual variability have the potential to improve outcomes and address the high comorbidity burden. Large-scale, controlled clinical studies are needed to validate these approaches and facilitate their translation into personalized interventions.