test (Heuser, et al, 1994). These findings raise a number of questions discussed below. I) What is the cause of HPA axis dysfunction? EARLY LIFE ADVERSITY Rodent studies show that early life ad­ versity such as maternal separation is asso­ ciated with persistent changes in the HPA axis, including alteration of hypothalamic CRH mRNA, median eminence CRH con­ tent and stress induced release in adult rats (Ladd, et al, 1996; Plotsky, et al, 1993) Studies in grown monkeys who were exposed as infants to adverse early rearing conditions showed that in comparison to monkeys reared by mothers foraging under predictable conditions, infant monkeys ex­ posed to early stress of being raised by mothers foraging under unpredictable con­ ditions exhibited persistently elevated cer­ ebrospinal fluid (CSF) concentrations of CRF. (Coplan, et al, 1996) These studies suggested that the increased risk of devel­ oping mood and anxiety disorders in adult­ hood that is consequent on childhood abuse and neglect and parental loss may be mediated by persistent alterations in CRH systems (Baker, et al, 1999; Coplan, et al, 1996; Ladd, et al, 1996; Plotsky, et al, 1993). Non-depressed women with a history of childhood physical or sexual abuse have been shown to have an enhanced ACTH response to both the Trier social stress test (Heim, et al, 2000) and to CRH challenge (Heim, et al, 2001). The same group has shown that abused women without major depressive disorder exhibited greater than usual ACTH responses to CRH administra­ tion, whereas abused women with major depressive disorder and depressed women without early life stress demonstrated blunted ACTH responses. In the ACTH stimulation test, abused women without major depres­ sive disorder exhibited lower baseline and stimulated plasma Cortisol concentrations. Abused women with co-morbid depression more often suffered from posttraumatic stress disorder and reported more recent life stress than abused women without major depressive disorder. These findings suggest sensitisation of the anterior pituitary and GLUCOCORTICOID RECEPTOR DYSFUNCTION counter-regulative adaptation of the adrenal cortex in abused women without major depressive disorder. On subsequent stress exposure, women with a history of child­ hood abuse may hypersecrete CRF, resulting in down-regulation of adenohypophyseal CRH receptors and symptoms of depres­ sion and anxiety (Heim, et al, 2001). GENETICS The Swedish twin registry study has shown that mood disorders are highly heritable. The authors estimated a heritabil- ity of 64 to 83%. The same genetic and environmental factors appeared to influence liability to affective illness in men and women to the same degree, although women had a lower threshold of manifestation. The heritability of bipolar disorder has more recently been estimated at between 85 and 89% (McGuffin, et al, 2003) and may share common genetic risk factors with schizo­ phrenia (Cardno, et al, 2002). The complex inheritance of bipolar disorder and the failure of multiple genome wide scans to detect major gene effects suggests that bipolar susceptibility loci probably have small to moderate effects. The Munich vulnerability study suggests that the familial association may be mediated via the HPA axis (Lauer, et al, 1998), however the her­ itability of bipolar disorder has not yet been convincingly shown to be mediated by genes acting on the HPA axis. 2 1 y 1«- PLASMA CCHmSOL CONTROLS DEPRESSED 8 12- E 8 *- £ o - 10 12 1 4 16 18 2 0 22 ' 1 S T L W (7) 2) Are some patients with mood disorder more likely than others to have an abnormal HPA axis? The HPA axis has been less well studied in bipolar disorder than in MDD. However, the nature of HPA axis dysregulation de­ scribed in both manic and depressed bipolars appears to be similar to those described in MDD. Abnormal neuroendocrine function in mood disorders has been most convinc­ ingly demonstrated using the dexametha- sone/ corticotropin releasing hormone (dex/ CRH) test (Heuser, et al, 1994). Studies using this technique and the dexamethasone suppression test (DST) have shown that HPA axis dysfunction is more prevalent in bipolar than in unipolar disorder (Rush, et al, 1996; Rybakowski, et al, 1999). DST abnormalities in mixed mania (71%) and bipolar depression (25-60%) are more com­ mon than in major depressive disorder (37%-41%) (Rush, et al, 1996); (Nelson, 1987). During mania, there is large variation in the results of different studies, with the rate of non-suppression being the same as in normal controls (Carroll, et al, 1976; Greden, et al, 1982) or equivalent to that seen in bipolar depression (Arana, et al, 1983; Goodwin, 1984; Graham, et al, 1982). One explanation for this discrepancy in mania may be variation in the clinical state of patients sampled, e.g. the presence or absence of psychotic or depressive symp­ toms or the severity of the mania. C O N T R O L S D E P R E S S E D TME(h) 10 12 14 16 18 2ND DAY