Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder

Area of Science:

• Neuroscience
• Psychiatry
• Molecular Biology

Background:

• Bipolar disorder (BD) is associated with impaired stress resilience and hypothalamic-pituitary-adrenal (HPA) axis dysfunction.
• The precise molecular mechanisms underlying HPA axis dysfunction in BD remain unclear.

Purpose of the Study:

• To investigate HPA axis activity and related molecular mechanisms in BD patients and their unaffected siblings.
• To explore the role of the glucocorticoid receptor (GR) and its associated proteins in BD pathophysiology.

Main Methods:

• Recruited 24 euthymic BD patients, 18 BD siblings, and 26 healthy controls.
• Administered a dexamethasone suppression test to assess HPA axis function.
• Analyzed peripheral blood mononuclear cells for GR responsiveness, FKBP51 protein levels, and FKBP5 gene methylation.

Main Results:

• BD patients showed increased salivary cortisol post-dexamethasone and reduced ex vivo GR responsiveness.
• Elevated FKBP51 protein and increased FKBP5 gene methylation were observed in BD patients.
• BD siblings had lower FKBP51 levels than BD patients, suggesting shared biological factors.

Conclusions:

• Epigenetic modification of the FKBP5 gene and increased FKBP51 are linked to GR hyporesponsiveness in BD.
• These findings suggest shared biological underpinnings for BD in first-degree relatives.
• HPA axis alterations are more pronounced in later stages of bipolar disorder.