Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA 97: 325-330

Louisiana State University, Baton Rouge, Louisiana, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2000; 97(1):325-330. DOI: 10.1073/pnas.97.1.325
Source: PubMed Central


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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Available from: David Goldstein, Oct 03, 2015
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    • "Some findings suggest that melancholic MDD is distinguished by a greater number of depressive episodes (Alvarez et al., 2011; Uher et al., 2011), greater physiological dysfunction (e.g., a central hypernoradrenergic state (Wong et al., 2000) or hypothalamic-pituitaryadrenal axis hyperactivity (Lamers et al., 2013)), less dysfunction of personality—namely exhibiting higher perfectionism, cooperativeness and effectiveness (with some resemblance to characteristics of conscientiousness and openness) (Rubino et al., 2009)—and less neuroticism (Kendler, 1997). "
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    ABSTRACT: Background: This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress. Methods: Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress. Results: Patients with melancholic features (n1⁄4339; 33.7%) were distinguished clinically from non- melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/ coping outcome measure of capacity for social skills remained significantly lower for melancholic participants. Limitations: Due to the cross-sectional nature of this study, causal pathways cannot be concluded. Conclusions: Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one's emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment.
    Journal of Affective Disorders 03/2015; 174:493-502. DOI:10.1016/j.jad.2014.10.046 · 3.38 Impact Factor
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    • "As a result, central administration of NPY decreases NE overflow by acting on Y 1 receptors (Hastings et al., 2004). Because evidence of elevated LC activity has been linked to depression and PTSD (Wong et al., 2000; Geracioti et al., 2001) this NPY-induced brake on LC over activation may therefore promote stress resilience. The anti-stress effect of NPY is not unique to the LC; decreased levels of NPY were observed in the amygdala, hippocampus and periaqueductal gray of rats that were vulnerable to predator-scent stress versus the resilient phenotype (Cohen et al., 2012). "
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    ABSTRACT: Exposure to stress or traumatic events can lead to the development of depression and anxiety disorders. In addition to the debilitating consequences on mental health, patients with psychiatric disorders also suffer from autonomic imbalance, making them susceptible to a variety of medical disorders. Emerging evidence utilizing spectral analysis of heart rate variability (HRV), a reliable non-invasive measure of cardiovascular autonomic regulation, indicates that patients with depression and various anxiety disorders (i.e., panic, social, generalized anxiety disorders, and post traumatic stress disorder) are characterized by decreased HRV. Social stressors in rodents are ethologically relevant experimental stressors that recapitulate many of the dysfunctional behavioral and physiological changes that occur in psychological disorders. In this review, evidence from clinical studies and preclinical stress models identify putative biomarkers capable of precipitating the comorbidity between disorders of the mind and autonomic dysfunction. Specifically, the role of corticotropin releasing factor, neuropeptide Y and inflammation are investigated. The impetus for this review is to highlight stress-related biomarkers that may prove critical in the development of autonomic imbalance in stress -related psychiatric disorders.
    Frontiers in Psychology 08/2014; 5:950. DOI:10.3389/fpsyg.2014.00950 · 2.80 Impact Factor
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    • "Hypercortisolism and altered feedback inhibition are HPA abnormalities of depression, T2D, and MetS (Figure 1).7–9,18 Depressed patients, given their hypercortisolism and compared to control subjects, have inappropriately “normal” plasma ACTH and cerebrospinal fluid CRH;19 that is, their levels should be lower in the presence of high cortisol, which triggers a negative feedback at the level of the hypothalamus and pituitary gland, thereby reducing CRH and ACTH. Thus CRHR, ACTH receptor, and glucocorticoid receptor dysfunctions are possible. "
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    ABSTRACT: Depression, type 2 diabetes (T2D), and metabolic syndrome (MetS) are often comorbid. Depression per se increases the risk for T2D by 60%. This risk is not accounted for by the use of antidepressant therapy. Stress causes hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, by triggering the hypothalamic corticotropin-releasing hormone (CRH) secretion, which stimulates the anterior pituitary to release the adrenocorticotropin hormone (ACTH), which causes the adrenal secretion of cortisol. Depression is associated with an increased level of cortisol, and CRH and ACTH at inappropriately "normal" levels, that is too high compared to their expected lower levels due to cortisol negative feedback. T2D and MetS are also associated with hypercortisolism. High levels of cortisol can impair mood as well as cause hyperglycemia and insulin resistance and other traits typical of T2D and MetS. We hypothesize that HPA axis hyperactivation may be due to variants in the genes of the CRH receptors (CRHR1, CRHR2), corticotropin receptors (or melanocortin receptors, MC1R-MC5R), glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), and of the FK506 binding protein 51 (FKBP5), and that these variants may be partially responsible for the clinical association of depression, T2D and MetS. In this review, we will focus on the correlation of stress, HPA axis hyperactivation, and the possible genetic role of the CRHR1, CRHR2, MCR1-5, NR3C1, and NR3C2 receptors and FKBP5 in the susceptibility to the comorbidity of depression, T2D, and MetS. New studies are needed to confirm the hypothesized role of these genes in the clinical association of depression, T2D, and MetS.
    The Application of Clinical Genetics 04/2014; 7:43-53. DOI:10.2147/TACG.S39993
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