Reduced Corticotropin Releasing Factor Binding Sites in the Frontal Cortex of Suicide Victims

Nemeroff, Charles B.; Owens, Michael J.; Bissette, Garth; Andorn, Anne C.; Stanley, Michael

doi:10.1001/archpsyc.1988.01800300075009

Cited by 544 publications

(246 citation statements)

References 27 publications

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“…In the former case, CRF mRNA levels should also increase and, if release is sustained, should be associated with locally reduced numbers of postsynaptic CRF receptors. This receptor 'downregulation' was originally reported for CRF receptors in the frontal cortex of suicides (Nemeroff et al, 1988). However, decreased numbers of CRF receptors were not confirmed in the two later studies (Leake et al, 1990;Hucks et al, 1997), although in none of these studies was depressive symptoms documented at the time of death as in the present study.…”

Section: Discussioncontrasting

confidence: 49%

Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects

Bissette

Klimek

Pan

et al. 2003

Neuropsychopharmacol

132

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Research evidence that corticotropin-releasing factor (CRF) plays a role in the pathophysiology of major depressive disorder (MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors to challenge with synthetic CRF, and increased levels of serum cortisol in MDD subjects support the hypothesis that CRF is chronically hypersecreted in at least the endocrine circuits of the hypothalamic-pituitary-adrenal (HPA) axis and may also involve other CRF brain circuits mediating emotional responses and/or arousal. One such circuit includes the excitatory CRF input to the locus coeruleus (LC), the major source of norepinephrine in the brain. Furthermore, there are now reports of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief from chronic treatment with antidepressant drugs or electroconvulsive therapy. Whether this normalization reflects therapeutic effects on both endocrine-and limbic-associated CRF circuits has not yet been effectively addressed. In this brief report, we describe increased concentrations of CRF-like immunoreactivity in micropunches of post-mortem LC from subjects with MDD symptoms as established by retrospective psychiatric diagnosis compared to nondepressed subjects matched for age and sex.

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Section: Discussioncontrasting

confidence: 49%

Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects

Bissette

Klimek

Pan

et al. 2003

Neuropsychopharmacol

132

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“…In fact, the elevated levels of CRF in the CSF of depressed individuals was shown to be normalized following successful electroconvulsive therapy (Nemeroff et al, 1991). Furthermore, this evidence was strengthened by the findings in suicide victims where in post-mortem frontal cortical tissue, the CRF receptor-binding sites were significantly decreased, consistent with the mechanism of elevated levels of CRF in brain causing a homologous downregulation of CRF receptors (Merali et al, 2004;Nemeroff et al, 1988). Central administration of CRF as well as overexpression of CRF in transgenic mice resulted in behavioral changes including anxiety, disturbances of psychomotor activity, and sleep, anorexia, vegetative abnormalities, etc.…”

Section: Introductionmentioning

confidence: 90%

High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response

Ising

Zimmermann

Kuenzel

et al. 2007

Neuropsychopharmacol

134

101

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There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF 1 antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague-Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF 1 receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic-pituitaryadrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 mg of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.

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“…5 1996). This hypothesis was derived from the following clinical observations in depressives: 1) the number of ACTH and cortisol secretory pulses is increased which is also reflected in elevated urinary cortisol production rates (Rubin et al 1987); 2) levels of CRH in the CSF are elevated (Nemeroff et al 1984); 3) the number of CRH secreting neurons in limbic brain regions is increased (Raadsheer et al 1994); and 4) the number of CRH binding sites in the frontal cortex is reduced secondary to increased CRH concentration (Nemeroff et al 1988). These studies were complemented by many neuroendocrine function tests including the suppressibility of ACTH and corticosteroids by the synthetic glucocorticoid dexamethasone (dexamethasone suppression test, DST).…”

Section: Functional Impairment Of Central Corticosteroid Receptors CLmentioning

confidence: 99%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,994

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Reduced Corticotropin Releasing Factor Binding Sites in the Frontal Cortex of Suicide Victims

Cited by 544 publications

References 27 publications

Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects

Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects

High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response

The Corticosteroid Receptor Hypothesis of Depression

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