Abstract

This research focuses on the role of the HPA axis (hypothalamic-pituitary-adrenal axis) in stress regulation and possible disruptions thereof in neuropsychiatric disorders such as depression and ADHD. The study specifically investigates the receptor translocation mechanisms that may lead to new therapeutic approaches.

Introduction

The hypothalamic-pituitary-adrenal axis (HPA axis) is a crucial endocrine system that regulates the stress response through the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol. Dysregulation of this system is associated with various psychiatric conditions, including depression, anxiety disorders and ADHD.

Recent research has shown that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) play an important role in the fine regulation of the HPA axis. These receptors show different affinities for cortisol and corticosterone, with the MR having a higher affinity for both hormones compared to the GR.

Methodology

For this study, 120 participants were recruited, divided into four groups: healthy controls (n=30), patients with depression (n=30), patients with ADHD (n=30) and patients with comorbid depression and ADHD (n=30). All participants underwent extensive neuropsychological testing and neuroimaging.

Blood samples were taken at various times throughout the day to determine the circadian rhythm of cortisol. In addition, the dexamethasone suppression test was performed to evaluate the feedback sensitivity of the HPA axis.

Results

The results showed significant differences in basal cortisol levels between the four groups (F(3,116) = 12.34, p < 0.001). Patients with depression showed elevated morning cortisol values compared to healthy controls (p < 0.01), while patients with ADHD showed decreased values (p < 0.05).

The dexamethasone suppression test revealed that 43% of depressive patients were non-suppressors, compared to only 10% in the control group. This suggests reduced feedback sensitivity of the HPA axis in depression. Interestingly, patients with comorbid depression and ADHD showed an intermediate pattern.

Neuroimaging data showed structural changes in the hippocampus and prefrontal cortex in all patient groups. The volume reduction in the hippocampus correlated significantly with the severity of symptoms (r = -0.58, p < 0.001).

Discussion

These findings support the hypothesis that dysregulation of the HPA axis plays a central role in the pathophysiology of both depression and ADHD. However, the opposite patterns in cortisol secretion suggest different underlying mechanisms.

The receptor translocation studies showed that in depressive patients, GR density in the hippocampus was significantly reduced, which may contribute to the reduced feedback sensitivity. In ADHD patients, on the other hand, an increased MR/GR ratio was found, possibly as a compensation mechanism for the chronically low cortisol levels.

These results have important implications for the development of new therapeutic interventions. Medication specifically aimed at restoring receptor balance could be more effective than current treatments.

Conclusion

This research confirms the complex role of the HPA axis in neuropsychiatric disorders and emphasizes the importance of receptor-specific approaches in future research and therapy development.