Posted by Elroy on June 21, 2005, at 18:46:08
In reply to Re: HPA Axis Anti-Cortisol Therapy - MORE INFO 4 » Elroy, posted by Elroy on June 21, 2005, at 18:28:03
A really great explanation page, with more specific data about cortisol amd hypercortisolism as relates to psychiatric disorders...
http://www.psychiatrictimes.com/p040592.html
Despite considerable advances in the treatment of mood disorders during previous decades, there remains an urgent need to identify compounds that will successfully treat mood episodes (including the associated neurocognitive impairments) and prevent their recurrence. This article reviews some of these recent developments, with an emphasis on the role of cortisol in relation to depression...
Glucocorticoids are the end product of the hypothalamic-pituitary-adrenal (HPA) axis and are central to the stress response. There is overwhelming evidence that during periods of acute stress, glucocorticoids promote survival by mobilizing energy reserves. In addition to these short-term adaptive changes, glucocorticoids are also involved in other longer-term, stress-related adaptive changes such as shaping and regulating a number of physiological processes, including immune responsiveness and activation of the sympathetic nervous system. Although glucocorticoid production is essential for survival, overproduction is associated with a significant disruption of cellular functioning, which, in turn, leads to widespread physiological dysfunction...
Cortisol, a glucocorticoid released from the adrenal cortex, is the end product of the HPA axis. The HPA axis comprises the tissues of the hypothalamus, pituitary and adrenal cortices; regulatory neuronal inputs; and a variety of releasing factors and hormones... A variety of stressors, both physical and psychological, cause the neurosecretory cells within the paraventricular nucleus of the hypothalamus to secrete corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the microportal circulatory system of the pituitary stalk. These secretions cause the release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary. Cortisol is released from the adrenal cortex in response to ACTH. Cortisol has a panoply of central and peripheral effects that are mediated via at least two intracellular specialized glucocorticoid receptor subtypes: the high-affinity type I receptor (or MR) and the low-affinity type II receptor (or GR). ... activity of the HPA axis is highly regulated. Secretory cells within the paraventricular nucleus receive neuronal inputs from a number of brain regions including the amygdala, hippocampus and nuclei within the midbrain (Figure 2). The HPA axis also has an autoregulatory mechanism mediated by cortisol. Endogenous cortisol binds to glucocorticoid receptors in the HPA axis tissues and hippocampus and acts as a potent negative regulator of HPA activity. The relative contribution of the two receptor subtypes (GR and MR) in the regulation of HPA activity is as yet unclear. The MRs have a high affinity for endogenous glucocorticoids such as cortisol, as well as for the salt-regulating hormone aldosterone. However, the GRs have a relatively low affinity for cortisol, but bind avidly to synthetic steroids such as dexamethasone. These differences in affinity suggest that MRs play a primary role in regulating basal cortisol levels when hormone levels are low. When cortisol levels rise, as from stress or circadian fluctuations, the MRs become saturated, and GRs become the main transducers of glucocorticoid activity and therefore the primary mediators of HPA feedback. These regulatory mechanisms are important in determining basal levels and circadian fluctuations in cortisol levels. Changes in GR number or function may be important in altering the homeostatic function of the HPA axis observed in healthy individuals....
first observations of abnormalities of cortisol levels in patients with depression were made in the late 1950s by Board and colleagues (Michael and Gibbons, 1963), and these observations have been consistently replicated. Subsequent studies have shown that HPA hyperactivity--as manifested by hypersecretion of CRH; increased cortisol levels in plasma, urine and cerebrospinal fluid; exaggerated cortisol responses to ACTH; and enlarged pituitary and adrenal glands--occurs in individuals suffering from severe mood disorders... It is interesting, however, that neither citalopram (Celexa) (Seckl and Fink, 1992) nor fluoxetine (Prozac) (Rossby et al., 1995) alters GR mRNA or GR binding capacity, which suggests that the selective serotonin reuptake inhibitor class of antidepressants may lack the ability to modulate GR expression and/or function. This evidence suggests that if indeed GR regulation is involved in the therapeutic mechanism(s) of action of antidepressant drugs and mood stabilizers, it is not a unitary mechanism. Antidepressant drugs that have the ability to regulate GR expression and binding may, however, have greater therapeutic efficacy in patients who have hypercortisolemia...
Paradoxically, glucocorticoid receptor antagonists have also been advocated as agents with potential therapeutic properties for mood disorders. This is based on the ability of the GR antagonist to block any detrimental effect of hypercortisolemia and on the ability of an antagonist to upregulate its receptor. Administration of a GR antagonist results in an acute antiglucocorticoid effect, while presumably causing a compensatory upregulation of GR numbers, leading to enhanced negative feedback of the HPA axis. Initial clinical studies using the GR antagonist mifepristone (Mifeprex, RU-486) have been encouraging, but some clinical efficacy may have been masked by the prolonged administration of the drug (Murphy et al., 1993). Animal studies suggest that GR numbers are increased rapidly (within hours) after the administration of mifepristone, which may restore normal feedback, thus "resetting" the HPA axis (Lupien and McEwen, 1997). Such data suggest that a brief period of treatment with the GR antagonist may be adequate for restoring normal HPA axis function. This might reduce problems of noncompliance and side effects associated with longer-term administration.... Twenty patients, ages 18 to 65, with a diagnosis of BD (confirmed using the Structured Clinical Interview for DSM-IV [SCID]) and residual depressive symptoms were recruited. Patients' medication had been unchanged for six weeks prior to participation and remained so throughout the study period. Seventeen patients were taking at least one mood stabilizer, with 13 taking at least one antidepressant and 11 taking an antipsychotic agent. Following an initial baseline assessment of neurocognitive function and mood and basal neuroendocrine profiling, patients were randomly assigned to receive either 600 mg/day mifepristone or placebo for seven days. Administration was in a double-blind design. Mood ratings were taken after the week's treatment and then at weekly intervals. At day 21, the groups crossed over and received the alternative treatment (placebo or mifepristone) for seven days, again with ratings taken following the week's treatment and at weekly intervals. Neurocognitive function was assessed on three occasions over the study period: at baseline and 21 days after both treatments.... At 14 days following treatment with mifepristone, depression rating scores had significantly improved from baseline levels, without any significant change being observed at any time point following placebo. The Brief Psychiatric Rating Scale (BPRS) scores were also significantly lower in the mifepristone group at day 14 compared with baseline, with a similar lack of change in the placebo-treated group. With regard to neurocognitive performance, the mifepristone-treated group showed a significant reduction in the error rate of the spatial working memory task (Figure 4) compared with baseline. No such changes were observed in the placebo-treated patients. Furthermore, baseline cortisol output correlated positively with the percentage improvement in spatial working memory error rate following mifepristone administration. Verbal fluency and spatial recognition memory also improved in those patients treated with mifepristone...
poster:Elroy
thread:515432
URL: http://www.dr-bob.org/babble/20050617/msgs/516766.html