RHYTHM The biochemical, cognitive or mood effects of the flattened Cortisol rhythm seen in bipolar disorder patients has not yet been examined in man, however it is possible to speculate that modulation of the Cortisol rhythm of mood disorder patients may have effects on mood and cognition and may represent a novel therapeutic approach. CRH-I RECEPTOR ANTAGONIST The CRH, receptor antagonist R121919 has been used in an open treatment trial of 24 patients with major depression and appears to be safe and well tolerated and is associated with a reduction in anxiety and depression (Zobel, et al, 2000). GR ANTAGONISTS The GR antagonist mifepristone has been shown to reduce depressive symptoms in open trials of patients with psychotic and non-psychotic depression (Belanoff, et al, 2001), to reduce depressive and psychotic symptoms in Cushing's syndrome (Nieman, et al, 1985; van der Lely, et al, 1991) and improve cognitive performance in Alzheim­ er's disease (Pomara, et al, 2002). It may exert acute therapeutic effect by blocking GR receptors thereby creating a "functional hypocortisolaemia". Additionally, it is hy­ pothesised that prolonged blockade may increase corticosteroid receptor function or number and reset the homeostatic set point thereby restoring the characteristic diurnal rhythm and potentially offering long-term benefit. Its use in bipolar disorder is being examined in a placebo controlled cross-over trial by our group and preliminary results presented at the society of biological psy­ chiatry annual meeting in Philadelphia sug­ gest an association with an improvement in executive function (Young, et al, 2002b). Org 34517 has been shown in vitro, in animals and humans to be a selective glucocorticoid receptor antagonist. A multicentre, randomised, double-blind, G L U C O C O R T I C O I D R E C E P T O R D Y S F U N C T I O N paroxetine controlled study of Org34517 in patients with major depressive has shown that it is well tolerated during the 4 weeks treatment period in the dose range of 150- 600 mg (Hoyberg, et al, 2002). Although it was not shown to be significantly more effective than 20-40 mg paroxetine in sub­ jects with moderate to severe MDD, when focusing on patients with detectable HPA disturbances, a clear indication was found for stronger efficacy of the low dose (150- 300mg) Org regimen as compared with paroxetine. This effect was more pronounced in DST-nonsuppressors and during the first two weeks of treatment. High dose Org34517 increased Cortisol, DHEA-s and testosterone levels, which is evidence for a detectable degree of GR-blockade. Subjects who seemed to benefit from treatment with low dose Org34517 did not show a detect­ able increase in Cortisol and other HPA driven hormones levels during the first weeks of treatment. AVPIB RECEPTOR ANTAGONISTS The AVP|b receptor antagonists, SSR149415 and d(CH2)Tyr(Et)VAVP (Griebel, et al, 2002; Liebsch, et al, 1996) have been shown to have anxiolytic prop­ erties in animal studies and represent an exciting potential pharmacological strategy for the treatment of mood disorders. DEHYDROEPIANDROSTERONE (DHEA) Improvements in cognition have been observed after administration of DHEA to middle-aged and elderly depressed patients (Wolkowitz, et al, 1997) and the antidepres­ sant actions of DHEA have recently been demonstrated in a small randomised con­ trolled trial in depression (Wolkowitz, et al, 1999). Case reports of mania induced by massive DHEA doses (Dean, 2000; Kline, et al, 1999; Markowitz, et al, 1999) suggest the need for caution, however DHEA administration represents an exciting poten­ tial novel therapeutic approach in bipolar disorder. ( I I ) CONCLUSIONS HPA axis dysfunction is prevalent in patients with mood disorder, particularly the psychotic disorders and bipolar affective disorder. It has implications in the patho­ physiology and cognitive impairment in mood disorders. It is more overt when patients are unwell, but still present in euthymia and present in a third of appar­ ently healthy patients with genetic loading. The HPA axis dysfunction may be second­ ary to genetic factors or early life adversities. Elevated Cortisol levels are not consistently shown but tests which incorporate exami­ nation of glucocorticoid receptor function reveal higher rates of abnormality. 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