Article

Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: Relation to hypercortisolism and corticotropin-releasing hormone

Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 01/2000; 97(1):325-330. DOI: 10.1073/pnas.97.1.325
Source: PubMed Central

ABSTRACT Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking,
and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone
(CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for
30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and
cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels
that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable
and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients
had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately
high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma
cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters.
These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress
of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state
and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate
that α-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or
in combination, in the treatment of major depression with melancholic features.

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