Metyrapone Improves Endothelial Dysfunction in Patients With Treated Depression

Metyrapone Improves Endothelial Dysfunction in Patients With Treated Depression Andrew J. M. Broadley, Ania Korszun, Eltigani Abdelaal, Valentina Moskvina, John Deanfield, Christopher J. H. Jones, Michael P. Frenneaux Endothelial dysfunction is a feature of depression and may explain patients’ increased risk of coronary heart disease. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction with increased cortisol production is also a feature. Cortisol produces endothelial dysfunction in normal subjects, which suggests that it may contribute to endothelial dysfunction (and increased vascular risk) in depression. In patients with depression, endothelial dysfunction improved after suppression of cortisol production by metyrapone, supporting this hypothesis. The HPA axis/cortisol are thus potential targets for future treatment of depression aimed at reducing vascular risk as well as relieving symptoms. This study sought to examine the effect of metyrapone on endothelial dysfunction in patients with treated recurrent major depression. Depression is an independent risk factor for the development of coronary heart disease, and patients with depression have endothelial dysfunction, an atherogenic abnormality. This abnormality may be attributable to abnormal hypothalamic-pituitary-adrenal (HPA) axis function, a feature of depression, resulting in increased exposure to cortisol. Cortisol administration produces endothelial dysfunction in healthy subjects. We measured endothelial function using flow-mediated dilation (FMD) of the brachial artery in 30 patients with depression and in 36 matched control subjects. Patients were randomized (double blind) to metyrapone (an inhibitor of cortisol synthesis) or placebo, and FMD was remeasured 6 h later. At baseline, FMD was impaired in patients versus control subjects (mean [standard error]), −1.27% [0.91%] vs. 4.37% [0.59%] (p < 0.001). The FMD was similar in the placebo and the metyrapone patient groups at baseline (0.17% [1.04%] vs. −2.72% [1.30%], p = 0.11). Metyrapone significantly reduced plasma cortisol levels. There was a significant improvement in FMD in the metyrapone group from −2.72% [1.30%] to 3.82% [0.99%] (p < 0.001), whereas the change in the placebo group, from 0.17% [1.04%] to 1.15% [1.14%], was not significant. Analysis of covariation showed that the effect of metyrapone was significant (p = 0.034). Inhibition of cortisol production by metyrapone ameliorates the endothelial dysfunction seen in depression, su