ABRAHAM at al 3) What facets of HPA axis art abnormal? BASAL CORTISOL State dependent hypercortisolaemia asso­ ciated with depression were first demon­ strated by (Gibbons, 1964) and has since been repeatedly replicated although more recent studies suggest more moderate ab­ normalities than the original description (Dubrovsky, 1993); (Kirschbaum, et al, 1994; Rybakowski, et al, 1999; Schmider, et al, 1995; Swann, et al, 1992; Whalley, et al, 1989); (Vieta, et al, 1997; Watson, et al, 2001; Young, et al, 2001). A flattening of the diurnal Cortisol rhythm with an elevation in the afternoon trough appears to be a more robust finding fig. 3 (Cervantes, et al, 2001; Sachar, 1975). This abnormal rhythm can be expected to alter the activation of MR and GR. CRH HYPOTHESIS Professor Nemeroff's group has hypoth­ esised CRH overdrive (increased synthesis and release of CRH) to be central to the aetiopathophysiology of affective disorders (Nemeroff, 1988): Extra-hypothalamic CRH sites may play an important role in the mediation of behavioural response to stress and in the pathophysiology of anxiety and depression (Arborelius, et al, 1999). CRH immunoreactivity is present in the raphe nuclei and locus coeruleus (LQ which form the origin of the major serotonergic and noradrenergic projections to the forebrain (Valentino, et al, 1993). The amygdala, thought to mediate fear and anxiety (Davis, 1992) is also innervated by CRH nerve terminals. Moreover, central administration of CRH to laboratory animals produces stress like effects including an increase in locomotor activity, an increased responsive­ ness to acoustic stimuli and reduced ex­ ploratory behaviour. It also produces de­ pression like effects, including diminished food intake, decreased sexual activity and disturbed sleep (Dunn, et al, 1990). The number, of CRH secreting neurones is increased in limbic areas of the brain (Raadsheer, et al, 1994) and die CRH \ Increased CRH synthi Increased XVP Increased levels of ACTH GR Theory of Mood Disorders Reduced sensitivity in DEX Suppression Test Central effects of CRH / Down regulation of CRH R Up regulation of AVP l b receptors Possible changes in and 5-HT neurotransmission \ Increased levels of Cortisol Desensitization of 5HT1A receptor function concentration of CSF is increased (Nemeroff, et al, 1984). Gold and colleagues (Gold, et al, 1984) have shown that both depressed unipolar and bipolar patients have a blunted ACTH response to intravenously infused CRH, but a normal Cortisol response. The blunted ACTH response may be mediated by sub- sensitivity of pituitary receptors to CRH, secondary to downregulation via CRH hyper- drive or to homeostatic effects of elevated Cortisol levels. The anatomical correlate of this functional change is the reduced size of the pituitary gland that has been re­ corded in bipolar patients (Sassi, et al, 2001). The normal Cortisol response despite the reduced ACTH secretion is in keeping with rhe demonstration that depressed patients have an increased Cortisol response to ACTH (Amsterdam, et al, 1988; Amsterdam, et al, 1983; Jaeckle, et al, 1987). Interestingly in Gold's study, in contrast to depressed pa­ tients, euthymic and manic patients had a normal ACTH response to CRH challenge (Gold, et al, 1984). Vieta and colleagues similarly demonstrated that bipolar patients who had been well for 6 months did not have a blunted ACTH response to CRH. Those patients with a more blunted re­ sponse were more likely to have a depressive relapse within 12 months and those with an exagerated response were at increased (8) Neuropsychological / cognitive effects ^. Blunted HPA and prolactin responses to 5-HT stimulation risk of subsequent mania (Vieta, et al, 1997; Vieta, et al, 1999). It is the CRH, rather than the CRH2 receptor that appears to convey anxiety and possibly, depression related signalling (Liebsch, et al, 1999). CRH, receptor deficient mice display less anxiety related behaviour (Timpl, et al, 1998). ARGININE VASOPRESSIN Like CRH, AVP is a hypothalamic hor­ mone. It acts synergistically with CRH to facilitate ACTH and hence Cortisol release. Physiologically, it appears to allow an acute stress response in conditions of chronic stress. Post-mortem studies of unipolar and bipolar patients who died by suicide show that AVP is increased in the PVN and that there is an increase in the number of CRH neurones co-expressing AVP (Purba, et al, 1996; Raadsheer, et al, 1994). AVP release is suppressed by GR activation (Erkut, et al, 1998). This suggests that the increase in plasma and CSF AVP levels which have been shown in some but not all studies in depression (Scott, et al, 1998), suggesting that AVP changes in patients may be sec­ ondary to GR dysfunction. This hypothesis is supported by our unpublished data show­ ing that AVP levels are greater in bipolar patients than controls after pre-treatment with the glucocorticoid, dexamethasone.