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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    • "Although the original " Monoamine Hypothesis of Depression " posited that depression was caused by a deficit in NE (and/or serotonin) levels, a more modern hypothesis based on both clinical and preclinical evidence is that LC hyperactivity causes depression-like behaviors. For example, biochemical findings point to markedly elevated NE in the brains of depressed patients (Ehnvall et al., 2003;Wong et al., 2000), and postmortem studies revealed reduced α2 inhibitory autoreceptor function in the LC (Ordway et al., 1994Ordway et al., , 2003), indicating diminished negative feedback that would lead directly to elevated LC activity. A convergence of studies, mostly by Dr. Jay Weiss and colleagues, spanning many years and multiple approaches has established LC hyperactivity as a root cause of depression-like behavior in rodents. "
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    ABSTRACT: Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer's disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively.
    No preview · Article · Nov 2015 · Brain research
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    • "Notably, in the absence of stress, high tonic LC activity would not be adaptive and would translate to hyperarousal and an inability to concentrate or to maintain performance on tasks that require focused attention. These are characteristic symptoms of stress-related psychiatric disorders such as PTSD and major depression, both of which also show evidence of LC-NE hyperactivity (Southwick et al., 1999; Wong et al., 2000). 3. Corticotropin-releasing factor, the locus coeruleus and stress Substantial evidence now implicates the stress-related neuropeptide , CRF as a primary mediator of stress-induced LC activation. "
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    ABSTRACT: The stress response is characterized by the coordinated engagement of central and peripheral neural systems in response to life-threatening challenges. It has been conserved through evolution and is essential for survival. However, the frequent or continual elicitation of the stress response by repeated or chronic stress, respectively, results in the dysfunction of stress response circuits, ultimately leading to stress-related pathology. In an effort to best respond to stressors, yet at the same time maintain homeostasis and avoid dysfunction, stress response systems are finely balanced and co-regulated by neuromodulators that exert opposing effects. These opposing systems serve to restrain certain stress response systems and promote recovery. However, the engagement of opposing systems comes with the cost of alternate dysfunctions. This review describes, as an example of this dynamic, how endogenous opioids function to oppose the effects of the major stress neuromediator, corticotropin-releasing hormone, and promote recovery from a stress response and how these actions can both protect and be hazardous to health.
    Full-text · Article · May 2015 · F1000 Prime Reports
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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.
    Full-text · Article · Mar 2015 · Journal of Affective Disorders
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