THE GLUCOCORTICOID RECEPTOR (GR) HYPOTHESIS It has been hypothesised that dysfunc­ tion of GR is the core underlying patho­ physiological abnormality in mood disor­ ders. See fig. 4 (McQuade, et al, 2000; Pariante, et al, 2001). Two post-mortem studies have shown low levels of GR mRNA in the frontal cortex and hippoc­ ampus in mood disorder patients (Lopez, et al, 2003; Webster, et al, 2002) Glucocor­ ticoid mediated negative feedback can be examined using the dexamethasone sup­ pression test (DST) and the dex/CRH test. An abnormal response on the DST and the dex/CRH test ie. non-supression of Cortisol secretion, suggests dysregulation of GR mediated feedback. GR knockout mice have impaired feedback regulation within the HPA axis, with elevated levels of plasma ACTH and corticosterone (Cole, et al, 1995; Cole, et al, 2001). A number of studies have examined GR number in peripheral blood mononuclear cells in affective disorder patients with largely inconsistent results (Pariante, et al, 2001). The CRH neurones in many brain areas are inhibited by GR activation. Therefore, it is suggested that the CRH overdrive, which has previously been hypothesised to be central to the aetiopathophysiology of affective disorders, could be a result of the underlying GR dysfunction. Reduced function of GR may be expected to exert greater effect on Cortisol level during the afternoon trough when the influence of other factors such as CRH and AVP is relatively less. It has not been satisfactorily shown experimen­ tally, but one can speculate that reduced GR function may give rise to the characteristic flattened diurnal Cortisol rhythm of mood disorder patients DEHYDROEPIANDROSTERONE (DHEA) DHEA is an androgen secreted by the adrenal gland and to a lesser extend by the ovaries and testes. It can also be converted in to other steroid hormones such as oestrogen and testesterone and exists in both a free, and sulphated (DHEA-S) form. Animal studies show that DHEA counter­ acts the deleterious effects of corticosteroids on long-term potentiation, a neurophysi- ological correlate of learning and memory (Kaminska, et al, 2000). DHEA levels regu­ late glucocorticoid action in the brain. The ratio of Cortisol to DHEA therefore reflects the degree of 'functional' hypercortisolaemia and has recently been shown to be en­ hanced in a drug free population of patients with major depressive disorder (Young, et al, 2002a). 4) Is HPA axis dysfunction a cause or consequence of affective disorder? Two separate groups have demonstrated that bipolar patients when manic or de­ pressed show abnormalities on the dex/ CRH test (Rybakowski, etal, 1999; Schmider, et al, 1995). They both re-examined the patients on symptomatic recovery and showed that the Cortisol response, whilst partially normalising still remained signifi­ cantly different from the response of healthy controls (Rybakowski, et al, 1999; Schmider, et al, 1995). Similarly, bipolar patients with a stringent prospective diagnosis of euthymia have been shown to have an abnormally enhanced Cortisol response using the same test . This suggests that this measure of HPA axis dysfunction may be a trait abnor­ mality and as such may potentially represent a vulnerability factor for bipolar disorder. In a longitudinal follow up study, (Goodwin, 1984) found that individual's DST responses were consistent over time, regardless of their clinical state, providing further support for the hypothesis that the HPA axis dys­ function is a trait abnormality of bipolar disorder. This has been further addressed by the Munich vulnerability studv (Lauer, et al, 1998), in which 32% of healthy volun­ teers with a family history of mood disorder had an abnormal response to the dex/CRH test. Unfortunately, the high drop out in this study will make it difficult to determine if these relatives have an increased risk of developing bipolar disorder (Modell, et al, 1998). However, researchers in the UK have demonstrated that morning salivary Cortisol concentrations are a risk factor for subse­ quent development of unipolar major de­ pressive disorder (Harris, et al, 2000). (9) GLUCOCORTICOID RECEPTOR DYSFUNCTION CONSEQUENCES OF AXIS DYSFUNCTION HPA In recent years it has become clear that, in addition to effects on metabolic and inflammatory processes, corticosteroids also play an extensive modulatory role in neurotransmission. Studies in experimental animals have indicated that expression and function of neurotransmitter receptors and enzymes, long-term potentiation and even cell survival are all influenced by corticosteroids. Glucocorticoid therapy has been shown to be associated with a range of psychopathology including depression, euphoria, mood lability, cognitive impair­ ment and psychosis (Baker, et al, 1999). It is unsurprising, therefore, that behavioural indices of neurotransmitter function, such as mood and cognition, are also influenced by corticosteroid manipulations. MONOAMINE SYSTEMS Disorders of the serotonin system have been thought to be of aetiological and therapeutic importance in depression since the 1960's. A number of strands of evi­ dence converge to suggest a pathophysi­ ological role for reduced transmission through post synaptic 5-HT|A receptors in depression. Chronic elevation of corticosteroids reduces post synaptic 5- HT|A receptor number, an effect which may promote depression (McAllister-Williams, et al, 1998). In contrast, acutely elevated plasma Cortisol levels, induced by acute stress or administration of hydrocortisone reduces somatodendritic rather than post-synaptic 5- HT1A receptor function, thereby facilitating 5-HTM neurotransmission in an antidepres­ sant like way (Laaris, et al, 1999; Young, et al, 1994a; Young, et al, 1994b) and has been shown to exert a mood elevating effect (DeBattista, et al, 2000). Our group has shown that flattening the rhythm without increasing the 24 hour output results in reduced 5HT|A neurotransmission (Leitch, et al, 2003). Pre-clinical studies have also shown that corticosteroids increase dopamine neurotransmission. This mechanism has been hypothesised to be pathophysiological im-