It has been known for some time that people who have very high levels of circulating glucocorticoids such as cortisol are prone to depression. This condition, called Cushing’s syndrome, may have several different causes, including hormone-secreting tumors or medical treatments with synthetic glucocorticoids. In more than 85% of patients with Cushing’s syndrome, depression appears quite early in the disorder, even before other typical signs, such as obesity or unusual growth and distribution of body hair (Krystal et al., 1990). These observations suggest that dysfunction of the hypothalamic-pituitary-adrenal axis (see Figure 1a) may be involved in depression, perhaps as part of a depression-inducing stress reaction (Heit et al., 1997).

Figure 1  The Hypothalamic-Pituitary-Adrenal Axis in Depression
(a) Evidence shows that the hypothalamic-pituitary-adrenal system is involved in depression. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone. (b) Circulating cortisol levels are usually higher in depressed subjects than in psychiatric or normal controls. In this plot, each dot represents an individual case. (c) The normal circadian rhythm in the secretion of cortisol (day 1) is abolished by treatment with the synthetic glucocorticoid dexamethasone (day 2). (d) The same dose of dexamethasone is far less effective in patients with depression, as if their brains are less responsive to the negative feedback effects (see part a) of steroids.

Suicide victims show very high levels of circulating cortisol (Roy, 1992), and hospitalized patients with depression show elevated cortisol levels as well (see Figure 1b). These findings suggest that adrenocorticotropic hormone (ACTH) is released in excessive amounts by the anterior pituitary. A standard method for assessing hypothalamic-pituitary-adrenal function—the dexamethasone suppression test—can reveal a tendency to release excess cortisol.

Dexamethasone is a potent synthetic glucocorticoid that ordinarily suppresses the early-morning rise in ACTH that is typical in normal people. When given late at night, dexamethasone seems to “fool” the hypothalamus into believing that there is a high level of circulating cortisol. In normal individuals, dexamethasone suppresses cortisol release the next day (see Figure 1c); but in many individuals suffering from depression, it fails to have this effect (see Figure 1d). As depression is relieved, dexamethasone again suppresses cortisol normally, no matter what caused the relief—passage of time, psychotherapy, pharmacotherapy, or electroconvulsive shock therapy.


Heit, S., Owens, M. J., Plotsky, P., and Nemeroff, C. B. (1997). Corticotropin-releasing factor, stress, and depression. Neuroscientist 3: 186–194.

Krystal, A., Krishnan, K. R., Raitiere, M., Poland, R., et al. (1990). Differential diagnosis and pathophysiology of Cushing’s syndrome and primary affective disorder. Journal of Neuropsychiatry and Clinical Neurosciences 2: 34–43.

Roy, A. (1992). Hypothalamic-pituitary-adrenal axis function and suicidal behavior in depression. Biological Psychiatry 32: 812–816.