Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback

Abstract

Objective: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production.

Method: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects.

Results: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients.

Conclusion: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

Figure 1

Median plots in control subjects and high-cortisol depressed patients, showing comparable ACTH A and cortisol levels B at 0200h–0230h when both groups exceeded their Day 1 mean ACTH concentrations under metyrapone.

Figure 1

Median plots in control subjects and high-cortisol depressed patients, showing comparable ACTH A and cortisol levels B at 0200h–0230h when both groups exceeded their Day 1 mean ACTH concentrations under metyrapone.

Figure 2

Detail showing early increase of median ACTH concentrations under metyrapone in control subjects A and high-cortisol depressed patients B.

Figure 2

Detail showing early increase of median ACTH concentrations under metyrapone in control subjects A and high-cortisol depressed patients B.

Figure 3

Bar graphs representing paired (within-subject) comparisons of ACTH secretory changes during metyrapone (M) compared with placebo (P) exposure in the subjects presented in Figure 1. MPP denotes mass per pulse.

Figure 4

Estimates of basal (top) and pulsatile (bottom) ACTH secretion in healthy subjects (N =11), high-cortisol depressed (N=7) and low-cortisol depressed (N=5) patients. Data are the mean ± SEM. The overall ANCOVA model yielded P<0.001. Group, treatment and interaction effects are stated in the box. Bars with different (unshared) alphabetic superscripts differ significantly (P<0.05) by Tukey’s honestly significantly different post hoc multiple-comparison test. Thus, A differs from BC but not from AB.

Figure 5

Cross-ApEn of paired cortisol-ACTH (feedback asynchrony) concentration profiles. ANCOVA yielded overall P<0.001 for combined effects of treatment and group. Subanalysis showed a drug treatment effect of P=0.053 (see Figure 4 format). ACTH-cortisol (feedforward) cross-ApEn data are given in Table 3.