Hypercortisolemia following pharmacological “Clamp” reveals women's vulnerability to major depressive disorder

Abstract

Background<br />Stress-evoked hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis—typically measured via cortisol activity—is a major risk factor in the pathogenesis of major depressive disorder (MDD). However, the standard laboratory assessment of stress reactivity—the Trier Social Stress Test (TSST)—reveals no sex differences, despite the finding that women experience MDD at about twice the rate of men. One possibility is that HPA axis responses to the TSST are at or the near physiologic ceiling. If true, then down-regulation of the HPA axis prior to TSST administration might reveal the expected sex difference in HPA axis response. Here, we hypothesized that suppression of HPA axis response using dexamethasone and propranolol would reveal the sex difference in TSST-evoked cortisol production, thus supporting the role of hypercortisolemia in the pathophysiology of MDD.<br /><br />Methods<br />In total, 92 healthy, never-depressed participants (50% female) were randomized to receive either two placebo pills, or 2 mg dexamethasone and 80 mg propranolol prior to completing an acute laboratory stressor (i.e., Trier Social Stress Task, or TSST). Cardiovascular (heart rate) and HPA axis (cortisol) responses were assessed before, during, and after TSST administration.<br /><br />Results<br />Replicating previous work, no sex differences in cortisol reactivity appeared in the placebo condition. However, as hypothesized, women showed greater TSST-evoked cortisol production in the drug condition, relative to men. This sex difference was not explained by sex differences in depression, anxiety, anxiety sensitivity, or history of adverse childhood experiences.<br /><br />Conclusions<br />By describing conditions under which sex differences in HPA axis response will emerge, the current study lends support to the role of stress-evoked hypercortisolemia in the pathophysiology of MDD. The results from the present study point to an important area of further research in both the prevention and treatment of MDD.