Posted by temoigneur on June 16, 2005, at 1:32:41
Full article: http://bjp.rcpsych.org/cgi/content/full/177/5/390
excerpt on therapeutic approaches,FUTURE THERAPEUTIC TARGETS
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ABSTRACT
INTRODUCTION
HYPOTHALAMIC-PITUITARY-ADRENAL...
ANTIDEPRESSANTS, MOOD...
PRIMARY CONSEQUENCES OF...
FUTURE THERAPEUTIC TARGETS
Clinical Implications and...
REFERENCES
As discussed above, there is robust evidence of a dysfunction in HPA autoregulatory mechanisms in mood disorders, and it has been proposed that the consequent hypercortisolaemia is in some way integral to the pathogenesis of affective symptoms and cognitive deficits. It is therefore not surprising that research into potential treatments of mood disorders has focused on strategies designed to modulate the effects of hypercortisolaemia and/or the mechanisms underlying it.Dehydroepiandrosterone
One strategy for counteracting the effects of hypercortisolaemia, used with some success in the treatment of depression, makes use of the adrenal steroid dehydroepiandrosterone (DHEA; Bloch et al, 1999; Wolkowitz et al, 1999a). Although the physiological function of DHEA and its sulphated metabolite (DHEA-S) is unclear, these circulating corticosteroids have been shown to possess antiglucocorticoid properties, and high cortisol/DHEA ratios are reported to be associated with persistent depression (Goodyer et al, 1998). However, although DHEA does possess antiglucocorticoid activity, it is partially metabolised to testosterone and oestrogen, which have mood effects of their own and may contribute to DHEA's antidepressant effect (Wolkowitz et al, 1999a).Steroid synthesis inhibitors
Raised levels of cortisol can be lowered pharmacologically by inhibitors of steroid synthesis, and drugs of this class have been used with some success in the treatment of unipolar depression. Ravaris et al (1988) were the first to report that daily doses of ketoconazole reduced both cortisol levels and depressive symptoms within 72 hours in a case of treatment-resistant depression. Since then there have been a number of systematic studies and case reports investigating the use of not only ketoconazole but also metyrapone and aminoglutethimide as antidepressant therapies; as yet, however, the results of these studies are inconsistent (see Murphy, 1997, for review). This inconsistency is emphasised by two recent double-blind studies. Thus, while Wolkowitz et al (1999b) found a marked reduction in depressive symptoms following ketoconazole treatment in patients suffering from major depression, Malison et al (1999) found no therapeutic effect of the drug in a similar patient group. It is worth noting that in the former study, ketoconazole was effective in hypercortisolaemic but not normocortisolaemic patients with depression (Wolkowitz et al, 1999b). Unfortunately, one of the main factors which limits the use of steroid biosynthesis inhibitors as antidepressive therapy is the high incidence of side-effects resulting from generalised steroid biosynthesis inhibition.Corticotropin-releasing hormone antagonists
On the basis of the evidence for oversecretion of CRH in mood disorders, blockade of CRH receptors has been proposed as an approach to normalising hypercortisolaemia. Preclinical studies do indeed indicate that CRH antagonists will be of use in clinical conditions related to HPA hyperactivity, particularly anxiety disorders. Clinical investigations into the use of these compounds in many psychiatric conditions are presently underway and we await their results (see Holsboer, 1999, for review).Type II glucocorticoid receptor (GR) agonists
An alternative strategy for lowering circulating cortisol is activation of the GR-mediated negative-feedback mechanism that regulates cortisol levels. Sub-acute doses of dexamethasone (e.g. 3-4 mg daily for 4 days) have been reported to show antidepressant efficacy (Arana et al, 1995; Bodani et al, 1999). At this dose dexamethasone is thought not to enter the central nervous system and consequently central GRs are spared activation by this exogenous glucocorticoid. Activation of GRs at the level of the pituitary does occur, leading to a lowering of endogenous cortisol. If dexamethasone treatment does indeed act by lowering endogenous cortisol, then it would be interesting to correlate its therapeutic efficacy with the response of patients in the DST. Finally, it should be added that an advantage of the brief course of administration advocated by these studies is a reduction of the side-effects associated with longer-term dexamethasone treatment.Type II glucocorticoid receptor (GR) antagonists
Paradoxically, as well as GR agonists, GR antagonists have also been advocated as potentially of therapeutic benefit for mood disorders. This is based on the ability of the GR antagonist to block any detrimental effects of the raised levels of circulating cortisol and on the ability of an antagonist to up-regulate its receptor. Thus, administration of a GR antagonist might be predicted to have an acute antiglucocorticoid activity, while also causing a compensatory up-regulation of GR number, leading to enhanced negative feedback on the HPA axis. Preliminary clinical studies using the GR antagonist RU-486 (mifepristone) have been encouraging, even though some clinical efficacy may have been obscured by the prolonged administration of the drug (Murphy et al, 1993). However, animal work suggests that GR numbers can be increased rapidly (within hours) and it is possible that normal feedback is maintained after administration of the antagonist has ceased. This indicates that a brief (i.e. a few days) period of administration of antagonist may be adequate to increase number and normalise HPA function. This might reduce problems of non-compliance and side-effects associated with longer-term administration (Laue et al, 1990). A number of new, selective GR antagonists are currently being developed, although preliminary reports suggest that some of these drugs may lack ability to up-regulate the receptors (Bachmann et al, 1999).An evaluation and critique of case reports and clinical trials of some of the treatments outlined above has recently been reported (Wolkowitz & Reus, 1999). The cumulative evidence makes a strong case implicating GRs in the pathogenesis of affective disorders and suggests targeting these receptors in development of new therapies. We predict that drugs designed specifically to up-regulate GRs will be integral to future therapeutic strategies and may provide a long-awaited paradigm shift in the treatment of unipolar and bipolar mood disorders.
poster:temoigneur
thread:513549
URL: http://www.dr-bob.org/babble/20050611/msgs/513549.html