Consequences of Hypercortisolemia
Corticosteroids are central to many metabolic and inflammatory processes, and in recent years, their role as modulators of neurotransmission has been established. Animal studies have highlighted the importance of corticosteroids in influencing neurotransmitter receptor expression and function, long-term potentiation, and even cell survival. Manipulation of corticosteroids is likely, therefore, to influence the behavioral indices of neurotransmitter function, such as mood and cognition.
It is now established that in conditions in which there are raised endogenous or exogenous corticosteroids (including Cushing's disease and severe mood disorders), there is also a significant degree of cognitive impairment (Wolkowitz et al., 1990). Studies in experimental animals have shown deficits in learning and memory following chronic administration of glucocorticoids (Lupien and McEwen, 1997), as well as marked atrophy of neurons in the hippocampal formation. It has been postulated that a similar neurodegenerative effect of cortisol may underlie some of the cognitive deficits observed in humans suffering from severe mood disorders (Sapolsky et al., 1986).
While there is substantial evidence to indicate that the hippocampus is particularly sensitive to elevation of glucocorticoids, the effects on other areas of the brain are less clear. Recent clinical data have reported that cortisol treatment induces cognitive deficits in healthy humans, and these deficits appear to be mediated in part via the frontal lobe, suggesting that this brain area may also be sensitive to the neurodegenerative effects of cortisol (Young et al., 1999). The deficits in healthy volunteer study participants are reversible, but this may not be the case with the cognitive deficits induced by hypercortisolemia associated with mood disorders (Ferrier et al., 1999; Young et al., 1999). A more recent study indicated that the frontal lobes are adversely affected by cortisol, which may illustrate a similar pattern of degeneration to that which occurs in the hippocampus (Young et al., in press). Moreover, the traditional assumption that patients with severe mood disorders make a full inter-episode recovery has recently been challenged. Although cognitive deficits do show some improvement on remission of affective symptoms (paralleling the return of normal HPA function), this improvement is not sustained. Studies have identified a specific deficit in executive control in a cohort of patients prospectively verified as euthymic (Thompson et al., 2001), replicating an earlier finding by our group (Ferrier et al., 1999). Executive function is a component of Baddeley's influential model of working memory (Figure 3). In that model, working memory is a tripartite system consisting of a central executive (the attentional controller) and two slave systems: the phonological loop and the visuo-spatial scratch pad. It has been suggested that the main role of the central executive is attentional control, which coordinates a variety of processes such as set-shifting and updating and monitoring of working memory. Executive function deficits may be manifested by impaired attentional set-shifting, planning, verbal fluency and response inhibition. Clearly such deficits may have important adverse consequences with regard to the individual's social and occupational functioning, as well as insight and compliance with prescribed medication. These cognitive deficits may represent permanent and possibly irreversible hypercortisolemia-induced damage to crucial neuronal circuits. An early re-establishment of normal HPA activity in mood disorders before permanent deficits in cognitive function occur may therefore be an important therapeutic goal.
It might appear contradictory that in mood disorders decreased GR function underlies excessive cortisol secretion and that a high cortisol level, in turn, induces deleterious effects on mood and cognition via an action on glucocorticoid receptors. However, there are three possible explanations for the deleterious effects of high cortisol levels in the face of reduced GR function. First, elevated levels of cortisol may be sufficient to overcome the reduction in GR function and so produce an overall increase in effect. Second, it is possible that, while GRs in the hippocampus and hypothalamus associated with autoregulation of the HPA axis are reduced in function, those in other brain regions are normal. Thus, increased cortisol levels combined with normosensitive GRs might result in an increase in the (deleterious) effects of cortisol in some regions. Third, the deleterious effects of high cortisol may, in part at least, be mediated via MRs (or a change in the balance of activation of MRs and GRs) or via non-receptor-mediated events.
There is increasing evidence to suggest that the consequences of HPA dysfunction described above are central to the pathogenesis of mood disorders and cognitive deficits. Modulation of the effects of hypercortisolemia may provide potential treatments for mood disorders, and such strategies are the focus of considerable research interest.
Dehydroepiandrosterone. The adrenal steroid dehydroepiandrosterone (DHEA) has been used with some success in the treatment of depression (Wolkowitz et al., 1999b). The physiological function of DHEA and its sulphated metabolite (DHEA-S) is unclear, but these circulating corticosteroids have been shown to possess antiglucocorticoid properties, and high cortisol/DHEA ratios are reported to be associated with persistent depression. Apart from their antiglucocorticoid properties, which may account for the therapeutic effects of DHEA, an alternative explanation is that DHEA is partially metabolized to testosterone and estrogen, both of which have effects on mood.
Steroid synthesis inhibitors. Lowering circulating cortisol levels by inhibiting steroid synthesis is one pharmacological intervention that has been utilized in the treatment of unipolar depression. Ketoconazole(Drug information on ketoconazole) (Nizoral) administered daily was shown to reduce both cortisol levels and depressive symptoms within 72 hours in a case of treatment-resistant depression (Ravaris et al., 1988). Subsequent studies have investigated the use of ketoconazole as well as metyrapone (Metopirone) and aminoglutethimide (Cytadren) as antidepressant therapies, but the results have been inconsistent (Murphy, 1997). In separate double-blind research studies, Wolkowitz et al. (1999a) reported a marked reduction in depressive symptoms following ketoconazole treatment in patients suffering from major depression, but Malison and colleagues (1999) found no such benefit in a similar patient group.
CRH antagonists. Over-secretion of CRH, resulting in hypercortisolemia, may be normalized by blockade of CRH receptors. Preclinical studies have suggested that CRH antagonists will have clinical utility in conditions related to HPA hyperactivity, particularly anxiety disorders. Clinical investigations into the use of CRH antagonists in a number of psychiatric disorders are currently underway, and we await their results.
Type II glucocorticoid receptor agonists. Activation of the GR-mediated negative feedback mechanism that regulates cortisol levels is another strategy for reducing circulating cortisol levels. The synthetic glucocorticoid dexamethasone(Drug information on dexamethasone) given at doses of 4 mg/day for four days has been shown to have antidepressant effects (Arana et al., 1995). At this dose, dexamethasone does not enter the central nervous system and, consequently, central GRs are not activated. Glucocorticoid receptors at the level of the pituitary are activated, leading to a lowering of endogenous circulating cortisol. The brief course of dexamethasone administration in these studies avoided the side effects associated with longer-term treatment.
GR antagonists. 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(Drug information on 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.
We have recently sought to establish proof of efficacy for the use of GR antagonists in the treatment of BD in a double-blind, placebo-controlled crossover design in which mifepristone was administered as adjunctive therapy (Young et al., in press). We hypothesized that antiglucocorticoid treatments, particularly corticosteroid receptor antagonists, would improve neurocognitive functioning and attenuate depressive symptoms in this disorder.
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.
On the basis of previous research, it was predicted that the principal cognitive domains that would be most sensitive to changes in HPA axis function were working memory and verbal declarative memory. Test batteries were therefore administered to explore these cognitive domains.
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.
These data suggest that the GR-antagonist mifepristone selectively improves neurocognitive function and may be an antidepressant in BD. Interestingly, mifepristone was the only GR antagonist examined in a recent study to increase both MR and GR binding in the frontal cortex (Bachmann et al., 2003). This may underpin the selective pattern of improvement in neurocognitive function seen in our study, which was restricted to tests that have been shown to be sensitive to frontal lobe dysfunction. The results of this small, preliminary trial require confirmation in studies of larger numbers of patients.
There is robust evidence demonstrating abnormalities of the HPA axis in mood disorders. Hypercortisolemia may be central to the pathogenesis of depressive symptoms and cognitive deficits, which in turn may result from the neurocytotoxic effects of raised cortisol levels. Identification and effective treatment of mood and cognitive symptoms are important clinical goals, but currently available treatments may fall short of this ideal. Manipulation of the HPA axis has been shown to have therapeutic effects in both preclinical and clinical studies, and recent data suggest that direct antagonism of GRs may be a future therapeutic strategy in the treatment of mood disorders.
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