HPA Axis in Depression and Anxiety Disorders Depression

Overactivity of the HPA axis as manifested by an increase in cortisol secretion is now a well-established phenomenon in depression (Carroll et al. 1976; Sachar et al. 1973). The first studies (Sachar et al. 1973) showed that up to 50% of depressed patients have higher mean plasma cortisol concentrations and an increased number and duration of cortisol secretory episodes, suggesting increased cortisol secretory activity. Numerous studies have subsequently validated these findings (Carroll et al. 1976; Halbreich et al. 1985; Krishnan et al. 1990a; Pfohl et al. 1985; Rubin et al. 1987). As many as two-thirds of endogenously depressed patients fail to suppress cortisol, or show an early escape of Cortisol, following overnight administration of 1 mg of dexamethasone (using a Cortisol cutoff of 5 L g/dL to define "escape") (Carroll et al. 1981). While nonsuppression of Cortisol in response to dexamethasone is strongly associated with endogenous depression, this finding is less robust in outpatients with depression. Although both hypercortisolemia and feedback abnormalities in response to dexamethasone are present in depressed patients, they do not necessarily occur in the same individuals (Carroll et al. 1981; Halbreich et al. 1985). Other abnormalities, such as reduced glucocorticoid fast feedback (Young et al. 1991) and a blunted ACTH response to exogenous CRH, have also been reported in depressed patients (Gold et al. 1986; Holsboer et al. 1984; Young et al. 1990).

The blunted response to CRH appears to be dependent on increased baseline cortisol, since blockade of cortisol production with metyrapone normalizes the ACTH response (Von Bardeleben et al. 1988; Young et al. 1995). It was expected that the increased cortisol would be accompanied by an increased level of ACTH in plasma, but this has been difficult to validate, although several studies (Linkowski et al. 1985; Pfohl et al. 1985; Young et al. 2001) have demonstrated small differences in mean 24-hour plasma ACTH levels between healthy control subjects and depressed subjects. The demonstration of enhanced sensitivity to ACTH 1-24 in depressed patients suggests that increased ACTH secretion is not necessarily the cause of increased cortisol secretion (Amsterdam et al. 1983). However, other studies using very low "threshold" doses of ACTH 1-24 have not been able to demonstrate increased sensitivity to ACTH in depressed patients (Krishnan et al. 1990b), which suggests that increased cortisol secretion is secondary to increased ACTH secretion. Our 24-hour studies of ACTH and cortisol secretion demonstrated that subjects with increased mean cortisol also demonstrated increased mean ACTH, supporting a central origin of the HPA axis overactivity (Young et al. 2001). Further studies with metyrapone in major depression also support the presence of increased central nervous system (CNS) drive, at least in the evening (Young et al. 1994, 1997). It appears likely that there is increased CRH/ACTH secretion, which is then probably amplified by the adrenal, leading to increased cortisol secretion.

These changes in cortisol secretion are commonly considered to be "state" changes that resolve when the depression resolves. However, almost all studies examining the HPA axis in major depression in euthymic subjects have examined patients on tricyclic antidepressants, which exert direct effects on the HPA axis. Three of our recent studies in epidemiological samples and a recent British study (Bhagwagar et al. 2003) found that salivary cortisol is increased in subjects with lifetime major depression, most of whom had no current mood symptoms (Bhagwagar et al. 2003; Young et al. 2000a). The overall picture suggests that depression generally shows both an increase in activity of circadian activational elements of the system and reduced feedback inhibition.

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