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

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 ␣-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. M ajor depression is a complex disorder with an estimated lifetime prevalence of 15% in women and 8% in men (1). Depression is the main cause of suicide: Ϸ70% of all suicides are attributed to untreated depression. Studies in the United States suggest that, at any given time, Ϸ2-3% of the population is hospitalized or seriously impaired by affective illness. The World Health Organization has declared major depression as the single largest cause of morbidity for women and the leading cause of disability worldwide.The current standard diagnostic instrument for psychiatry, the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV) (2), lists two subtypes of major depression, melancholic and atypical. The features of melancholic depression include insomnia (most often early morning awakening), loss of appetite, weight loss, inappropriate guilt, and lack of pleasure (anhedonia). The second major subtype is major depression with atypical features, characterized in part by hypersomnia, hyperphagia, lethargy, and fatigue. The subclassification of depression provides direction for the appropriate choice of antidepressant medication. Studies in identical twins show a significantly higher concordance for ...

Flattening the Glucocorticoid Rhythm causes Changes in Hippocampal Expression of Messenger RNAs Coding Structural and Functional Proteins: Implications for Aging and Depression

“…In the present study, we used a manipulation that produces glucocorticoid levels that are clamped at the midpoint of the diurnal rhythm and hence are increased at the nadir but decreased at the zenith relative to the normal rhythm. The corticosterone profile generated is very similar to that seen in aged rats (Hauger et al, 1994) and similar to the profile of cortisol levels in aged human subjects (Deuschle et al, 1997a;Ferrari et al, 2001;Van Cauter et al, 1996;Wong et al, 2000). The elevated nadir and flattened rhythm is also consistent with the pattern observed in depressed patients, although in this group the peak of the diurnal rhythm is preserved, or even marginally elevated, resulting in an increase in 24 h cortisol exposure (Deuschle et al, 1997b;Wong et al, 2000).…”

“…The corticosterone profile generated is very similar to that seen in aged rats (Hauger et al, 1994) and similar to the profile of cortisol levels in aged human subjects (Deuschle et al, 1997a;Ferrari et al, 2001;Van Cauter et al, 1996;Wong et al, 2000). The elevated nadir and flattened rhythm is also consistent with the pattern observed in depressed patients, although in this group the peak of the diurnal rhythm is preserved, or even marginally elevated, resulting in an increase in 24 h cortisol exposure (Deuschle et al, 1997b;Wong et al, 2000). Aging and depressive illnesses are both accompanied by cognitive deficits, including impairments in aspects of memory function (Golomb et al, 1996;Mayeux et al, 2001;Austin et al, 2001;Quraishi and Frangou, 2002), which are believed to be hippocampally mediated (Silva et al, 1998).…”

Effects of cytokines and infections on brain neurochemistry

“…There is also substantial evidence for a hyperactivity of noradrenergic systems in depression. CSF concentrations of MHPG have often been found to be elevated [203], and more recently CSF concentrations of NE itself have also been shown to be increased [204].…”

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

“…[4][5][6] There is a long body of evidence indicating disruption of hypothalamicpituitary-adrenal (HPA) axis function in depression, including the following key observations: increased 24-h elevations in cortisol production, 7 lack of suppression of plasma cortisol levels by dexamethasone, 8 increased concentrations of CRH in cerebrospinal fluid, 9 dysregulation of HPA responses to exogenous CRH administration [10][11][12] and loss of the negative correlation between plasma cortisol and continuously collected CSF CRH. 13 Of particular relevance, it has been demonstrated that antidepressants of various classes suppress CRH gene expression [14][15][16] in rodents and HPA activity in depressed 17 and healthy humans. 18 It has therefore been proposed that suppression of CRH activity is a common, final effect of antidepressant treatment.…”