Background: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been hypothesized as an underlying neurobiological mechanism of severe psychopathology in adolescents, yet studies specifically characterizing salivary cortisol circadian patterns in hospitalized populations remain limited. This study aimed to comprehensively characterize salivary cortisol circadian rhythms in hospitalized adolescents with severe psychiatric and neurodevelopmental disorders and compare these patterns with a cohort of maltreated adolescents. Methods: 26 hospitalized adolescents (n=21 with cortisol data) provided salivary samples at six daily timepoints. Cortisol concentrations at every time-point and awakening response (CAR), area under the curve with respect to increase (AUCi) and ground (AUCg), and diurnal and maximum post-peak decline (slope and slope max) were measured. Psychopathological correlates were assessed via standardized questionnaires (CDI, YSR, DERS, MASC, YVACS). Comparison with maltreated kids’ cohort (n=106 adolescents with documented maltreatment/abuse history) was conducted to distinguish dysregulation patterns associated with primary psychiatric illness versus abuse/neglect exposure. Results: The hospitalized psychiatric sample demonstrated global HPA hypoactivation (AUCg reduced 34% below controls), flattened diurnal decline (62% less steep than normative trajectories), and markedly elevated prevalence of blunted awakening responses (38.5% negative CAR vs. <5% in healthy samples). The "cortisol-depression triad" (elevated CAR, steep slope, elevated AUCi) demonstrated remarkable convergence (r=0.60-0.75, p<0.01), suggesting circadian dysregulation as depression's core neurobiological substrate. Very strong inverse correlations emerged between baseline/integrated cortisol and suicidal ideation intensity (C2 r=-0.724, AUCg r=-0.715, p<0.01), supporting the cortisol insufficiency model of suicidality. By contrast, the maltreated sample demonstrated extreme heterogeneity in morning responses (CAR ranging +1340% to -93%) and a broad distribution from hyper- to hypoarousal, whereas the psychiatric sample showed relative homogeneity in consistently suppressed morning values (low standard deviations, prevalent blunted/negative CAR). Notably, the afternoon-evening convergence in cortisol suppression across both cohorts suggests the psychiatric sample may represent an evolutionary trajectory from the maltreated cohort. Conclusions: HPA axis dysregulation represents a transdiagnostic biological marker of severe adolescent psychopathology with clinical potential for biomarker-based risk stratification, treatment personalization, and targeted prevention efforts. The distinction between "constrained dysregulation" (preserved evening suppression and homogeneous blunted morning response in psychiatric illness) versus "complex dysregulation" (extreme heterogeneity including both morning hyper- and hypoactivation in maltreated youth) suggests cortisol phenotyping may objectively discriminate etiological contributions and inform personalized interventions. The observed afternoon-evening similarity supports the hypothesis that the psychiatrically hospitalized cohort partially evolves from maltreated individuals, progressively developing constrained HPA dysregulation over time.
Background: La disregolazione dell'asse ipotalamo-ipofisi-surrene (HPA) è stata ipotizzata come meccanismo neurobiologico sottostante grave psicopatologia anche nei pazienti pediatrici, ma gli studi che caratterizzano specificamente i pattern circadiani del cortisolo salivare in popolazioni ospedalizzate e pediatriche sono limitati. Obiettivo dello studio era caratterizzare il ritmo circadiano del cortisolo salivare in adolescenti ospedalizzati con disturbi psichiatrici e disturbi del neurosviluppo severi, e confrontare questi pattern con una coorte di adolescenti esposti a maltrattamento. Metodi: 26 adolescenti ospedalizzati (età media 14.7 anni, 76.9% femmine; n=21 con dati sul cortisolo) hanno fornito campioni salivari in sei timepoint giornalieri. Sono state misurate le concentrazioni di cortisolo a tutti i timepoint, oltre alla risposta di risveglio (CAR), area sottesa alla curva rispetto all'incremento (AUCi) e rispetto alla somma complessiva (AUCg), e declino diurno e massimo (slope e slope max). I correlati psicopatologici sono stati valutati attraverso questionari standardizzati (CDI, YSR, DERS, MASC, YVACS). Una comparazione con coorte di bambini maltrattati è stata condotta per distinguere i pattern di disregolazione legati a psicopatologia psichiatrica versus esposizione a abuso/neglect. Risultati: Il campione ospedalizzato ha mostrato ipoattivazione HPA globale, declino diurno appiattito (62% meno ripido delle traiettorie normative), e prevalenza marcatamente elevata di risposte di risveglio CAR attenuate (38.5% CAR negativa vs <5% in campioni sani). La "triade cortisolo-depressione" (CAR elevato, slope ripido, AUCi elevato) ha dimostrato convergenza notevole (r=0.60-0.75, p<0.01), suggerendo una disregolazione circadiana come substrato neurobiologico centrale della depressione. Correlazioni inverse molto robuste sono emerse tra cortisolo e ideazione suicidaria (C2 r=-0.724, AUCg r=-0.715, p<0.01), supportando il modello dell'insufficienza cortisolica della suicidalità. Al contrario, il campione maltrattato ha mostrato un'estrema eterogeneità nelle risposte mattutine (CAR compreso tra +1340% e -93%) e un'ampia distribuzione dall'iper- all'ipo-arousal, mentre il campione psichiatrico ha mostrato una relativa omogeneità nei valori mattutini costantemente soppressi (deviazioni standard basse, CAR prevalentemente attenuato/negativo). In particolare, la convergenza pomeridiana-serale nella soppressione del cortisolo in entrambi i gruppi suggerisce che il campione psichiatrico possa rappresentare una traiettoria evolutiva rispetto al gruppo maltrattato. Conclusioni: La disregolazione dell'asse HPA rappresenta un marker biologico transdiagnostico della psicopatologia severa negli adolescenti, con potenziale clinico per stratificazione del rischio biologico, personalizzazione del trattamento e prevenzione mirata. La distinzione tra "disregolazione limitata" (soppressione serale preservata e risposta mattutina omogenea attenuata nelle malattie psichiatriche) e "disregolazione complessa" (eterogeneità estrema che include sia iperattivazione che ipoattivazione mattutina nei giovani maltrattati) suggerisce che la fenotipizzazione del cortisolo possa discriminare oggettivamente i contributi eziologici. La somiglianza nei livelli di cortisolo osservata tra il pomeriggio e la sera nei due campioni supporta l'ipotesi che la coorte ospedalizzata psichiatricamente si evolva in parte da individui maltrattati, sviluppando progressivamente nel tempo una disregolazione HPA limitata.
The role of the hypothalamic-pituitary-adrenal (HPA) axis in developmental-age patients with psychiatric and neurodevelopmental disorders: a study investigating circadian rhythm of salivary cortisol in patients hospitalized at the Children and Adolescent Neuropsychiatry Unit of Padua.
FERRARESE, MARTINA
2023/2024
Abstract
Background: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been hypothesized as an underlying neurobiological mechanism of severe psychopathology in adolescents, yet studies specifically characterizing salivary cortisol circadian patterns in hospitalized populations remain limited. This study aimed to comprehensively characterize salivary cortisol circadian rhythms in hospitalized adolescents with severe psychiatric and neurodevelopmental disorders and compare these patterns with a cohort of maltreated adolescents. Methods: 26 hospitalized adolescents (n=21 with cortisol data) provided salivary samples at six daily timepoints. Cortisol concentrations at every time-point and awakening response (CAR), area under the curve with respect to increase (AUCi) and ground (AUCg), and diurnal and maximum post-peak decline (slope and slope max) were measured. Psychopathological correlates were assessed via standardized questionnaires (CDI, YSR, DERS, MASC, YVACS). Comparison with maltreated kids’ cohort (n=106 adolescents with documented maltreatment/abuse history) was conducted to distinguish dysregulation patterns associated with primary psychiatric illness versus abuse/neglect exposure. Results: The hospitalized psychiatric sample demonstrated global HPA hypoactivation (AUCg reduced 34% below controls), flattened diurnal decline (62% less steep than normative trajectories), and markedly elevated prevalence of blunted awakening responses (38.5% negative CAR vs. <5% in healthy samples). The "cortisol-depression triad" (elevated CAR, steep slope, elevated AUCi) demonstrated remarkable convergence (r=0.60-0.75, p<0.01), suggesting circadian dysregulation as depression's core neurobiological substrate. Very strong inverse correlations emerged between baseline/integrated cortisol and suicidal ideation intensity (C2 r=-0.724, AUCg r=-0.715, p<0.01), supporting the cortisol insufficiency model of suicidality. By contrast, the maltreated sample demonstrated extreme heterogeneity in morning responses (CAR ranging +1340% to -93%) and a broad distribution from hyper- to hypoarousal, whereas the psychiatric sample showed relative homogeneity in consistently suppressed morning values (low standard deviations, prevalent blunted/negative CAR). Notably, the afternoon-evening convergence in cortisol suppression across both cohorts suggests the psychiatric sample may represent an evolutionary trajectory from the maltreated cohort. Conclusions: HPA axis dysregulation represents a transdiagnostic biological marker of severe adolescent psychopathology with clinical potential for biomarker-based risk stratification, treatment personalization, and targeted prevention efforts. The distinction between "constrained dysregulation" (preserved evening suppression and homogeneous blunted morning response in psychiatric illness) versus "complex dysregulation" (extreme heterogeneity including both morning hyper- and hypoactivation in maltreated youth) suggests cortisol phenotyping may objectively discriminate etiological contributions and inform personalized interventions. The observed afternoon-evening similarity supports the hypothesis that the psychiatrically hospitalized cohort partially evolves from maltreated individuals, progressively developing constrained HPA dysregulation over time.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/97972