Gold Pw

Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states

Stress precipitates depression and alters its natural history. Major depression and the stress response share similar phenomena, mediators and circuitries. Thus, many of the features of major depression potentially reflect dysregulations of the stress response. The stress response itself consists of alterations in levels of anxiety, a loss of cognitive and affective flexibility, activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, and inhibition of vegetative processes that are likely to impede survival during a life-threatening situation (eg sleep, sexual activity, and endocrine programs for growth and reproduction). Because depression is a heterogeneous illness, we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia, the stress response seems hyperactive, and patients are anxious, dread the future, lose responsiveness to the environment, have insomnia, lose their appetite, and a diurnal variation with depression at its worst in the morning. They also have an activated CRH system and may have diminished activities of the growth hormone and reproductive axes. Patients with atypical depression present with a syndrome that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic, hypersomnic, reactive to the environment, and show diurnal variation of depression that is at its best in the morning. In contrast to melancholia, we have advanced several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis and CRH deficiency in atypical depression, and our data show us that these are of central origin. Given the diversity of effects exerted by CRH and cortisol, the differences in melancholic and atypical depression suggest that studies of depression should examine each subtype separately. In the present paper, we shall first review the mediators and circuitries of the stress system to lay the groundwork for placing in context physiologic and structural alterations in depression that may occur as part of stress system dysfunction.

Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications.

Primary depression can be associated with substantial hypercortisolism, thus prompting some researchers to suggest that depression shares pathophysiologic features with Cushings disease. Clinically, depression can be difficult or impossible to distinguish from mild or early Cushings disease that is associated with depressive features. The purpose of this study was to evaluate whether the pituitary-adrenal responses to ovine corticotropin-releasing hormone could help to clarify the mechanism of hypercortisolism in depression and in Cushings disease and to assist in the differential diagnosis of these disorders. As compared with controls (n = 34), depressed patients (n = 30) had basal hypercortisolism (P less than 0.001) that was associated with attenuated plasma ACTH responses to ovine corticotropin-releasing hormone (P less than 0.001). This indicates that in patients with depression, the corticotroph cell in the pituitary responds appropriately to the negative feedback of high cortisol levels. In contrast, patients with Cushings disease (n = 29) had plasma ACTH hyperresponsiveness to ovine corticotropin-releasing hormone (P less than 0.001), despite basal hypercortisolism (P less than 0.001), which indicates a gross impairment of the mechanism by which cortisol exerts negative feedback on the pituitary. Less than 25 percent of the patients with depression or Cushings disease had peak ACTH responses that overlapped. We conclude that the pathophysiologic features of hypercortisolism in depression and Cushings disease are distinct in each of the disorders and that the ovine corticotropin-releasing hormone stimulation test can be helpful in their differential diagnosis.

Clinical and Biochemical Manifestations of Depression: Relation to the Neurobiology of Stress

Major depressive disorder (MDD) is a chronic, recurrent, and severe psychiatric disorder with high mortality and medical comorbidities. Stress-related pathways have been directly involved in the pathophysiology and treatment of MDD. The present paper provides an overview on the stress system as a model to understand key pathophysiological paradigms in MDD. These mechanisms involve behavioral, cognitive, and systemic manifestations and are also associated with the mechanisms of action of effective antidepressants. Aspects such as depression subtypes, inflammation, insulin resistance, oxidative stress, and prothrombotic states in critical brain circuits and periphery are critically appraised. Finally, new strategies for approaching treatment-resistant major depression and potential adverse effects associated with this complex and intricate network are highlighted. The authors used PubMed as the database for this review. Each author extracted relevant data and assessed the methodological quality of each study.

Corticosterone effects on corticotropin-releasing hormone mRNA in the central nucleus of the amygdala and the parvocellular region of the paraventricular nucleus of the hypothalamus

Using in situ hybridization histochemistry, we report differential expression of corticotropin-releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA) and the parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) following systemic treatment with corticosterone (CORT) in adrenally-intact rats. Both injection of low (1 mg/kg/day) and high (5 mg/day) CORT reduced CRH mRNA expression in the PVN in a dose-dependent manner, although it returned to normal at the low dose by 14 days. By contrast, the high dose of CORT increased CRH mRNA transiently in the CEA at 4 days, although the low dose of CORT decreased it at 14 days. In a second experiment, we implanted a slowly-releasing CORT pellet for 2 weeks (200 mg, 60 day release) subcutaneously. This treatment produced an elevation of CRH mRNA in the CEA both at 1 and 2 weeks, whereas CRH mRNA in the PVN was decreased to a large extent as seen in the high CORT group of the first experiment. These results suggest that glucocorticoids can facilitate CRH mRNA expression in the CEA, a site implicated in anxiety and fear, while restraining the hypothalamic-pituitary-adrenal axis as indicated by the reduction in CRH mRNA in the PVN.

The corticotropin-releasing factor stimulation test: an aid in the evaluation of patients with Cushing's syndrome

We investigated the effect of exogenous corticotropin-releasing factor on plasma levels of ACTH and cortisol in 13 patients with ACTH-secreting pituitary adenomas (Cushings disease) and in 9 patients with other forms of Cushings syndrome. In all patients with Cushings disease, ovine corticotropin-releasing factor, given intravenously as a bolus injection (1 microgram per kilogram of body weight), caused a further increase in the already elevated levels of ACTH and cortisol. Successful transphenoidal adenomectomy was followed as early as one week after surgery by normalization or near-normalization of the ACTH and cortisol responses to corticotropin-releasing factor. On the other hand, patients with the ectopic ACTH syndrome, who also had high basal plasma concentrations of ACTH and cortisol, had no ACTH or cortisol responses to corticotropin-releasing factor. This difference in responsiveness between these two patient groups cannot be explained on the basis of different metabolic clearance rates of exogenous corticotropin-releasing factor, as shown by similar disappearance curves of immunoreactive corticotropin-releasing factor from plasma. Patients with Cushings syndrome of adrenal origin who were hypercortisolemic during testing had undetectable plasma levels of ACTH and no ACTH or cortisol responses to corticotropin-releasing factor. We conclude that stimulation of the pituitary-adrenal axis with corticotropin-releasing factor may be useful in differentiating pituitary from ectopic causes of Cushings syndrome.

Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus

We previously reported that corticosterone (CORT) increased corticotropin-releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA), while reducing it in the paraventricular nucleus (PVN) of the hypothalamus by using in situ hybridization histochemistry. The bed nucleus of the stria terminalis (BNST) is closely related to the amygdala, and it is also a source of extrahypothalamic CRH; therefore, we examined CRH mRNA changes in the BNST following systemic treatment with CORT in adrenally-intact rats. Effects of adrenalectomy on CRH mRNA in the BNST, PVN and CEA were also examined. In addition, CRH content in these nuclei and in the median eminence (ME) were determined by micropunch dissection technique combined with CRH radioimmunoassay in CORT pellet implanted rats. Subcutaneous injections of high CORT (5 mg/day, over 14 days) increased CRH mRNA in the dorsal part of the lateral BNST (BSTLD) at 2, 4 and 8 days, although the low dose of CORT (1 mg/kg/day) had no significant effects. By contrast, in the ventral part of the BNST (BSTV) neither the high nor low dose of CORT altered CRH mRNA levels. In a second experiment, a slowly-releasing CORT pellet (200 mg, 60-day release) produced an elevation of CRH mRNA at both 1 and 2 weeks or at 1 week in the BSTLD or in the BSTV, respectively. These results show that glucocorticoids can facilitate CRH mRNA expression in the BSTLD in the same manner as seen in the CEA, and that CRH mRNA in the BSTLD can respond to CORT more than in the BSTV. In a third experiment, bilateral adrenalectomy, however, did not affect CRH mRNA in the BNST although there was a modest decrease in the CEA and a robust increase in the PVN. Finally, in CORT pellet (200 mg, for 2 weeks) implanted rats, CRH content in the ME significantly decreased and modestly increased in the CEA compared with control rats, whereas it did not change in the PVN and BNST. Taken together, these results suggest that (1) CRH in the BNST and the CEA may share some common functions in neuroendocrine and behavioral changes, but that (2) mechanisms of CRH synthesis or its releasing sites may be different in the BNST and CEA.

Multiple feedback regulatory loops upon rat hypothalamic corticotropin-releasing hormone secretion. Potential clinical implications.

To examine whether the hypothalamic corticotropin-releasing hormone (CRH) neuron is regulated by CRH, by products of the proopiomelanocortin (POMC) gene, and/or by glucocorticoids, we used a rat hypothalamic organ culture system in which rat CRH secretion from single explanted hypothalami was evaluated by an RIA (iCRH) specific for rat CRH. The effects of graded concentrations of ovine CRH (oCRH), adrenocorticotropin hormone (ACTH), beta-endorphin (beta-EP), alpha-melanocyte-stimulating hormone (alpha-MSH), corticotropin-like intermediate lobe peptide (CLIP), ovine beta-lipotropin (ovine beta-LPH), and dexamethasone (DEX) upon unstimulated and serotonin- (5HT), acetylcholine- (ACh), and norepinephrine-(NE) stimulated CRH secretion were determined. oCRH and DEX inhibited unstimulated iCRH secretion with ID50 at the 10(-8) M range. ACTH had no detectable suppressive effect at 10(-8) M. oCRH, ACTH, and DEX inhibited 5HT-, ACh-, and NE-stimulated iCRH secretion in a dose-dependent fashion. beta-EP, alpha-MSH, and CLIP also inhibited 5HT-induced iCRH secretion. Of the latter peptides, the strongest inhibitor was beta-EP and the weakest was CLIP. Ovine beta-LPH had only a weak inhibitory effect on 5HT-induced iCRH secretion. Generally, the concentrations required for 50% suppression of neurotransmitter-stimulated iCRH secretion were significantly lower than those required for a similar suppression of unstimulated iCRH secretion. In conclusion, these data suggest the presence of multiple negative feedback loops involved in the regulation of the hypothalamic CRH neuron: an ultrashort CRH-mediated loop, a short, hypothalamic POMC-derived peptide loop, and a long, glucocorticoid-mediated negative feedback loop. The potency of these negative feedback loops may be determined by the state of activation of the CRH neuron.

Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis.

Two studies examined sex differences in responsiveness of the hypothalamic-pituitary-adrenal cortical axis, a major component of the stress response. The first measured pituitary-adrenal responses to ovine corticotropin-releasing hormone (oCRH) in 24 health men and 19 healthy women. Plasma adrenocorticotropin hormone (ACTH) response to oCRH were significantly greater among women than among men. In contrast, cortisol concentrations were similar in both groups, though elevations were more prolonged in women. Differences in corticotropin-releasing activity between men and women may help account for these findings; such differences in central components of the stress response might play a role in the known epidemiological differences in diseases of stress system dysregulation between men and women.

Clinical Applications of Corticotropin-Releasing Factor

Abstract Ovine and human corticotropin-releasing factors (CRF) have similar potencies in causing adrenocorticotropic hormone (ACTH) and cortisol secretion in normal humans. Using long-acting ovine ...

Peptides in the cerebrospinal fluid of neuropsychiatric patients: an approach to central nervous system peptide function.

This review highlights that essentially all of the recently discovered putative central nervous system (CNS) peptides and other peptide substances are measurable in human cerebrospinal fluid (CSF). Preliminary evidence also suggests that peptides in CSF may have an active regulatory role in relation to CNS function and behavior. Even if this is not the case, CSF peptides may prove to be a useful indirect marker of CNS peptide function and metabolism. Alterations in peptides have been reported in neurological and psychiatric illness, pain symptoms and their treatment, symptoms such as anxiety, and following treatment with CNS active drugs such as carbamazepine. CSF methodologies provide a strategy for the study of the interaction of classical neurotransmitters and peptide substances and their relationship to neural function and behavior in man. Assessment of peptides in CSF may supplement post mortem studies of peptide levels and receptor distribution and help lead to new diagnostic and treatment approaches in neuropsychiatric disorders.