Postmortem and Cerebrospinal Fluid Studies of Corticotropin‐releasing Factor in Humansa

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 04/1996; 780(1):96-105. DOI: 10.1111/j.1749-6632.1996.tb15114.x
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Available from: Charles B Nemeroff
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    • "Elements of the HPA axis have previously been implicated in the physiological and pathological regulation of stress reactivity (Heinrichs and Koob 2004) and elevated cerebrospinal fluid (CSF) concentrations of CRH have repeatedly been reported in patients with depression (see e.g., Hartline et al 1996; Nemeroff et al 1984), as well as in combat veterans with PTSD (Baker et al 1999; Bremner et al 1997). In addition, several studied have found data indicating that the transcription (Raadsheer et al 1995) as well as expression (Raadsheer et al 1994) of CRH may be increased in postmortem tissue in patients with depression. "
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    ABSTRACT: Exposure to stressful events during development has consistently been shown to produce long-lasting alterations in the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to disease, including posttraumatic stress disorder and other mood and anxiety disorders. Recently reported genetic association studies indicate that these effects may be mediated, in part, by genexenvironment interactions involving polymorphisms within two key genes, CRHR1 and FKBP5. Data suggest that these genes regulate HPA axis function in conjunction with exposure to child maltreatment or abuse. In addition, a large and growing body of preclinical research suggests that increased activity of the amygdala-HPA axis induced by experimental manipulation of the amygdala mimics several of the physiological and behavioral symptoms of stress-related psychiatric illness in humans. Notably, interactions between the developing amygdala and HPA axis underlie critical periods for emotional learning, which are modulated by developmental support and maternal care. These translational findings lead to an integrated hypothesis: high levels of early life trauma lead to disease through the developmental interaction of genetic variants with neural circuits that regulate emotion, together mediating risk and resilience in adults.
    Full-text · Article · Nov 2009 · Depression and Anxiety
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    • "Link between childhood trauma and depression: HPA axis studies in humans 697 responses (Arborelius et al., 1999). Elevated CSF CRF concentrations have been repeatedly reported in patients with major depression [Nemeroff et al., 1984; Bánki et al., 1987; Widerlöv et al., 1988; Hartline et al., 1996). Postmortem studies reported increased CRF content or mRNA expression was found in the hypothalamic PVN, locus coeruleus and prefrontal cortex (Raadsheer et al., 1994, 1995; Bissette et al., 2003; Merali et al., 2006) of patients with major depression. "
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    ABSTRACT: Childhood trauma is a potent risk factor for developing depression in adulthood, particularly in response to additional stress. We here summarize results from a series of clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor (CRF) activity, immune activation, and reduced hippocampal volume, closely paralleling several of the neuroendocrine features of depression. Neuroendocrine changes secondary to early-life stress likely reflect risk to develop depression in response to stress, potentially due to failure of a connected neural circuitry implicated in emotional, neuroendocrine and autonomic control to compensate in response to challenge. However, not all of depression is related to childhood trauma and our results suggest the existence of biologically distinguishable subtypes of depression as a function of childhood trauma that are also responsive to differential treatment. Other risk factors, such as female gender and genetic dispositions, interfere with components of the stress response and further increase vulnerability for depression. Similar associations apply to a spectrum of other psychiatric and medical disorders that frequently coincide with depression and are aggravated by stress. Taken together, this line of evidence demonstrates that psychoneuroendocrine research may ultimately promote optimized clinical care and help prevent the adverse outcomes of childhood trauma.
    Full-text · Article · Aug 2008 · Psychoneuroendocrinology
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    • "Dysregulation of the hypothalamic–pituitary–adrenal (HPA) system in patients with depression is reflected by an increased cortisol secretion at baseline (Halbreich et al., 1985), by an exaggerated ACTH and cortisol response in the combined dexamethasone/corticotropin releasing hormone (CRH) test (Heuser et al., 1994; Zobel et al., 2001), and by elevated levels of CRH in the cerebrospinal fluid corresponding to decreased CRH binding in the prefrontal cortex of depressed patients (Nemeroff et al., 1984; Hartline et al., 1996; Holsboer, 1999). "
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    ABSTRACT: A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been hypothesized to account for a myriad of cardinal symptoms of affective disorders. Specifically, increased CRH signalling via CRH type 1 receptors is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of drugs have been developed in order to target the postulated increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was recently tested in an open-label study conceptualized as a safety and tolerability study. As part of this study, a thorough endocrine evaluation and detailed clinical laboratory analysis were assessed several times during 30 days of treatment with two different dose regimens of R121919 (5-40 mg vs. 40-80 mg) in 24 patients with a major depressive episode. During treatment with the experimental drug no serious side effects were noted. In particular, there were no adverse effects or impairment of the hypothalamic-pituitary-gonadal system, the hypothalamic-pituitary-thyroid axis, the renin-angiotensin system, prolactin or vasopressin secretion. Furthermore, no changes in the serum corticotropin and cortisol concentrations and in the responsivity of corticotropin and cortisol following a CRH stimulation test were noted. No effects of R121919 on clinical laboratory parameters including liver enzymes, EEG and ECG were observed. These results encourage the development of other CRH-1-R antagonists as a novel class of antidepressive drugs.
    Full-text · Article · Nov 2003 · Journal of Psychiatric Research
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