ABRAHAM «C al portance in mania, psychotic depression and substance misuse (Schatzberg, et al, 1985) NEUROCOGNITIVE IMPAIRMENT ENDOCRINE DISORDERS Cushing's disease in which ACTH and hence Cortisol are increased is associated with depression in 70% of patients. Memory disturbances, in particular, biasing toward negative contents, overlapping sleep abnor­ malities (marked reduction of stages 3 and 4), increased fatigue and loss of energy, attentional deficits and irritability, are just part of the common symptoms presented by patients with both Cushing's disorder and depression. All of these behavioural manifestations are known to be affected by adrenal steroid hormones (Dubrovsky, 1993). Whilst antidepressants offer some benefit, controlling Cortisol levels appears to be the most effective treatment. Addison's disease, in which Cortisol syn­ thesis is defective, is also associated with high rates of psychiatric disorder, which improve on successful steroid replacement. A number of chronic medical diseases such as multiple sclerosis are also associated with both elevated Cortisol levels and high rates of psychopathology. NEUROGENESIS Mood disorders are associated with a loss of brain cells, particularly glia and schizo­ phrenia is associated with neuronal atrophy. Throughout adult life new neurones con­ tinue to be made in brain areas including the hippocampus and olfactory bulb. Corticosteroids have an important role in mediating neurogenesis and survival of new cells. Although difficult to study in humans, it has been hypothesised that reduced neurogenesis is causative in depression and that the therapeutic effect of antidepres­ sants is mediated by an enhancement of new cell production and survival, perhaps via effects on the HPA axis. Evidence for this includes the demonstration that stress reduces neurogenesis and causes learned helplessness in rodents, effects that are prevented by chronic treatment with an antidepressant (Gould, rt al, 2000). Corticosteroids are essential for cognitive performance. MR appear to promote reac­ tivity in novel situations whereas GR are involved in consolidation of learned infor­ mation. It may therefore seem paradoxical mat disorders (including Cushing's disease and severe mood disorders) and experimen­ tal conditions in which endogenous or exogenous corticosteroids are elevated ei­ ther acutely or chronically are associated with a significant degree of cognitive im­ pairment. It appears that the effects of corticosteroids on cognition can become maladaptive when the activity of the two types of receptor becomes either persist- endy unbalanced or out of context with the situation (De Kloet, et al, 1998). Sapolsky has suggested a causal link between chronic hypercortisolaemia, hip- pocampal atrophy and neurocognitive im­ pairment (Sapolsky, et al, 1986). Evidence for this is growing and includes studies in experimental animals which has shown that chronic administration of corticosteroids results in deficits in learning and memory (Lupien, et al, 1997; White-Gbadebo, et al, 1993) and atrophy of neurones in the hippocampal formation. Chronic adminis­ tration of corticosteroids in healthy humans is also associated with cognitive impairment (Young, et al, 1999). Furthermore, the cognitive tests which are most affected are dependent on intact function of frontal- hippocampal activity. Studies comparing mood disorder patients with normal con­ trols suggest that the cognitive deficits in patients are irreversible and suggest long term hypercortisolaemia-induced damage to crucial neuronal circuits (Ferrier, et al, 1999). The findings that Cortisol levels after pre- treatment with dexamethasone correlate with neurocognitive impairment and tests of executive function in recovered bipolar patients suggest that the causal link may be driven by GR dysfunction rather than sim­ ple hypercortisolaemia (Watson, et al, 2002). An early re-establishment of normal HPA activity in mood disorders before perma­ nent deficits in cognitive function occur may therefore be an important therapeutic goal. What are the treatment implications? (10) CURRENTLY AVAILABLE TREATMENTS Currendy available psychotropic drugs may act via the HPA axis. Thus, (Heuser, et al, 1996) and colleagues have shown that successful treatment of unipolar depression with amitryptiline is associated with a re­ duction in the Cortisol response to the dex/ CRH test. This may be mediated by nor­ malisation of dysfunctional corticosteroid receptors (McQuade, et al, 2000). It is of interest that whilst some drugs such as lithium which appear to act on GR, stabilise mood in bipolar disorder, others such as the tricyclics increase cycle frequency rate and can induce mania (McQuade, et al, 2000; Wehr, et al, 1987). IMPLICATIONS FOR NOVEL TREATMENTS ANTIGLUCOCORTICOID TREATMENT Antiglucocorticoid treatment, which is aimed at lowering Cortisol levels, has been investigated using ketoconazole, ammoglutethirnide or metyrapone in several studies in MDD and one in bipolar disorder. The majority of the trials have been open studies but there have also been two randomised-controlled trials. Side-effects are common but the data suggests that in the patients who are able to tolerate the treat­ ment there is an association with improve­ ment in mood, particularly in those patients with previously demonstrated hypercortisolaemia (Brown, et al, 2001). The equivocal results may be explained by the mechanism of action of antiglucocorticoids, which exert effects on the steroid biosyn­ thesis pathway. They therefore reduce the synthesis of Cortisol but also exert profound effects on the synthesis of other adrenal steroids. Cortisol synthesis inhibitors are unlikely to become routine drugs in the treatment of bipolar disorder, largely be­ cause of side effects and drug interactions. However, their efficacy in some patients supports the use of other pharmacological interventions that target specific sites in the HPA axis.