Functional changes often referred to as dysregulations of the HPA system have been extensively documented in patients with depression (Akil & Ines Morano, 1995; Post & Weiss, 1995; Holsboer & Barden, 1996). These include increased episodes of ACTH and Cortisol secretion, elevated mean Cortisol levels in the blood and increased free urinary Cortisol levels. Various observations from both clinical and experimental animal studies support a causal link between dysregulation of the HPA system and psy-chopathology. Increased episodes of enhanced Cortisol levels will lead to overexposure of the brain to this glucocorticoid and will affect the functioning of limbic forebrain structures including the hippocampus that are involved in processing of cognitive stimuli and the regulation of mood, learning, and memory processes, as well as aminergic systems in the brain stem that play a role in arousal and appraisal of environmental stimuli (De Kloet & Joels, 1996; Joels, 1997). Glucorticoid induced alterations in the functioning of these brain structures as seen in chronic stress and depression in turn, are believed to facilitate activation of hypothalamic CRH neurons, and thereby sustain enhanced Cortisol exposure (McEwen & Sapolsky, 1995). There is an ongoing debate as to the initial changes that drive the hyperactivity of the HPA system in depressed patients. One of the hypotheses concerns an acquired or inherited glucocorticoid feedback resistance (De Kloet, Vreugdenhil, Oitzl, & Joels, 1997). In accordance with this hypothesis, deficient Cortisol responses to dexamethasone have been reported in up to 50% of patients with major depression. The finding that relatives of depressed patients that are at genetic risk for developing the disease, show excessive Cortisol responses in combined dexamethasone/CRH tests (Holsboer, Lauer, Schreiber, & Krieg, 1995) further supports the view that disturbances of glucocorticoid feedback (which is crucial for the normal functioning of the HPA system) represent a risk factor for the development of depression (Young, Haskett, Murphy-Weinburg, Watson, & Akil, 1991). In addition, increased AVP production and secretion by hypothalamic CRH neurons which is known to occur in depression (see below) may generate a less glucocorticoid suppressible signal for ACTH release (Aguilera 1994, Von Bardeleben, Holsboer, Stalla, & Muller, 1985).
CRH provocation studies in depressed patients revealed blunted ACTH but normal Cortisol responses relative to controls. It is reasoned that the defective ACTH response may be due to reduced CRH receptor efficacy. Alternatively, elevated Cortisol levels may account for the blunted ACTH response by their feedback action at the pituitary gland (Von Bardeleben, Stalla, Muller, & Holsboer, 1988).The dissociation of ACTH and Cortisol responses to a CRH challenge points to yet another level of dysregulation in the system. Together with enhanced Cortisol responses to ACTH, these findings indicate that adrenal glands of depressed patients are hyper-responsive to circulating ACTH. In support of this, computer tomography studies revealed adrenal enlargement in major depressed patients (Nemeroff, Krishnan, Reed, Leder, Beam, & Dunnick, 1992) which disappears after successful treatment (Rubin, Phillips, Sadow, & McCracken, 1995). What exactly controls the changes in adrenal volume and responsiveness is not known but non-ACTH mechanisms including intra-adrenal CRH production (Van Oers, Hinson, Binnekade, & Tilders, 1992) and increased sympathetic drive (Dijkstra, Binnekade, & Tilders, 1996) are potential candidates.
In major depression, dysregulation of the HPA system is associated with increased activity of hypothalamic CRH neurons. This is supported by increased CRH concentrations in the CSF of depressed patients (Nemeroff, Widerlov, Bissette, Walleus, Karls-son, Eklund, Kilts, Loosen, & Vale, 1984). Furthermore, CRH mRNA is markedly increased in the PVN of major depressives (Raadsheer, Van Heerikhuizen, Lucassen, Tilders, & Swaab, 1995) and the numbers of CRH immunoreactive neurons and the numbers and of CRH neurons that co-express AVP are strongly increased in depressed patients (Raadsheer, Hoogendijk, Stam, Tilders, & Swaab, 1994c; Swaab 1997). Several mechanisms may be involved in the hyper-activation of these neurons in depression including excessive stimulatory input from sensitized limbic or brainstem neurons, reduced input from inhibitory circuits, or intrinsic changes in CRH neurons such as reduced glucocorticoid receptor function in CRH neurons (De Kloet et al., 1997) or altered efficacy of efferent signal transfer to CRH neurons.
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