Depressive symptoms are highly prevalent in long COVID (LC) and may shape its symptom burden. As hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) alterations have been implicated in both LC and depressive disorders, this overlap raises the question of whether both conditions share psychobiological activity patterns or show distinct profiles. The present study compared these systems between youth with LC and depressive disorders during a developmental period of heightened mental health vulnerability. Thirty-four participants were included (n = 17 per subgroup; LC: M age = 16.3 years; depressive disorders: M age = 18.8 years). Cumulative HPA axis activity was indexed via hair cortisol concentration (HCC). Basal ANS activity was assessed via 5-min resting-state heart rate variability. Fatigue, perceived stress, and psychological distress were self-reported. Group differences were analysed using Mann-Whitney U tests, with correlational analyses. Participants with depressive disorders exhibited higher HCC than those with LC (p = .004, r = .69). In contrast, participants with LC showed reduced parasympathetic activity (lower HFnu; p = .018, r = .57) and diminished autonomic adaptability (higher DFA-α1, p = .013, r = -.60). Within LC, fatigue and psychological distress were associated with attenuated parasympathetic indices, while fatigue was also linked to lower HCC. Despite overlapping symptom profiles, LC and depressive disorders showed distinct psychobiological signatures, alongside divergent autonomic and endocrine correlates of subjective symptom burden. Longitudinal mechanistic studies are needed to clarify the development and specificity of these alterations following SARS-CoV-2 infection.
