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 ...

These findings reveal the presence of greater CNS noradrenergic activity under baseline conditions in patients with chronic PTSD than in healthy subjects and directly link this pathophysiologic observation with the severity of the clinical posttraumatic stress syndrome.

Rationale Abuse and neglect are highly prevalent in children and have enduring neurobiological effects. Stressful early life environments perturb the hypothalamic–pituitary–adrenal (HPA) axis, which in turn may predispose to psychiatric disorders in adulthood. However, studies of childhood maltreatment and adult HPA function have not yet rigorously investigated the differential effects of maltreatment subtypes, including physical abuse. Objective In this study, we sought to replicate our previous finding that childhood maltreatment was associated with attenuated cortisol responses to stress and determine whether the type of maltreatment was a determinant of the stress response. Methods Salivary cortisol response to the Trier Social Stress Test (TSST) was examined in a non-clinical sample of women (n=110). Subjects had no acute medical problems and were not seeking psychiatric treatment. Effects of five maltreatment types, as measured by the Childhood Trauma Questionnaire, on cortisol response to the TSST were investigated. To further examine the significant (p<0.005) effect of one maltreatment type, women with childhood physical abuse (PA) (n=20) were compared to those without past PA (n=90). Results Women reporting childhood PA displayed a significantly blunted cortisol response to the TSST compared with subjects without PA, after controlling for estrogen use, age, other forms of maltreatment, and other potential confounds. There were no differences between PA and control groups with regard to physiological arousal during the stress challenge. Conclusions In a non-clinical sample of women with minimal or no current psychopathology, physical abuse is associated with a blunted cortisol response to a psychosocial stress task.

The catecholamine norepinephrine is a critical effector of the mammalian stress response and has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD)-a syndrome intrinsically related to the experience of extraordinary stress. Symptom-linked hypernoradrenergic derangements have been observed in PTSD and several studies have examined the potential therapeutic effects of agents that dampen the centrally hyperactive noradrenergic state. These agents include compounds that decrease norepinephrine release (e.g. centrally acting alpha(2) agonists such as clonidine) and those which block post-synaptic norepinephrine receptors (e.g. centrally acting alpha(1) or beta receptor antagonists such as prazosin or propranolol). In this article, we review studies of central noreadrenergic hyperactivity under both basal and challenge conditions and explore the evidence for these derangements as potential psychopharmacologic targets in patients with PTSD. Given the significant involvement of CNS norepinephrine hyperactivity in PTSD, and its link to intrusive and hyperarousal symptoms, it is not surprising that interventions directed at this system have therapeutic potential in PTSD. The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.

Background: Interleukin-6 (IL-6) secretion is suppressed by glucocorticoids and stimulated by catecholamines. Patients with posttraumatic stress disorder (PTSD) have decreased cortisol and increased catecholamine secretion. The purpose of this study was to assess the relation of IL-6 levels and hypothalamic-pituitary-adrenal and noradrenergic activity in patients with well-characterized PTSD. Methods: Cerebrospinal fluid (CSF) was withdrawn via a lumbar subarachnoid catheter over 6 h from 11 combat veterans with PTSD and 8 age- and sex-matched healthy controls. Blood was withdrawn concurrently. We measured IL-6, CRH and norepinephrine concentrations in the CSF and IL-6, ACTH, cortisol and norepinephrine in plasma. Results: Mean and median CSF IL-6 concentrations were higher in PTSD than in controls (mean = 24.0 vs. 14.6, p = 0.05; median = 26.7 vs. 14.3, p < 0.03): plasma IL-6 concentrations, however, were not different between the two groups. Plasma IL-6 and norepinephrine were positively correlated in the PTSD group (r = +0.74, p < 0.04), but not in normals (r = –0.55, p = 0.20). Conclusions: PTSD patients have increased CSF concentrations of IL-6. Their plasma IL-6 is not elevated but is more tightly associated with noradrenergic output in these patients than in normals. Both findings might be explained by the low cortisol secretion previously reported in PTSD as a result of lowered glucocorticoid suppression of IL-6 secretion. High levels of CSF IL-6 may reflect neurodegeneration or compensatory neuroprotection.

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Background-Neuropeptide Y (NPY), a peptide neurotransmitter that regulates stress and anxiety, has been proposed to be a stress resilience factor in humans. Posttraumatic stress disorder (PTSD) is a stress-related anxiety disorder. We hypothesized that central nervous system NPY is dysregulated in PTSD and sought to redress the absence of central NPY data in the disorder.