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CLINICAL RESEARCH: DEPRESSION

Metyrapone Improves Endothelial Dysfunction in Patients With Treated Depression

Andrew J.M. Broadley, MRCP^_*, Ania Korszun, MRCPsych, Eltigani Abdelaal, MRCP^_*, Valentina Moskvina, PhD, John Deanfield, FRCP, Christopher J.H. Jones, FRCP and Michael P. Frenneaux, FRCP, FACC^_*,_*

^_* Department of Cardiovascular Medicine, University of Birmingham, Birmingham, England
Department of Psychological Medicine, St. Bartholomew’s and Royal London Hospital School of Medicine, London, England
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, Wales
Department of Cardiology, Great Ormond Street Hospital for Children, London, England.

Manuscript received August 18, 2004; revised manuscript received November 11, 2005, accepted December 14, 2005.

^_* Reprint requests and correspondence: Dr. Michael P. Frenneaux, Department of Cardiovascular Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom. (Email: m.p.frenneaux{at}bham.ac.uk).

OBJECTIVES: This study sought to examine the effect of metyrapone on endothelial dysfunction in patients with treated recurrent major depression.

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: Inhibition of cortisol production by metyrapone ameliorates the endothelial dysfunction seen in depression, suggesting that the mechanism of the endothelial dysfunction may involve cortisol.

Abbreviations and Acronyms   ANCOVA = analysis of covariance   CHD = coronary heart disease   ECG = electrocardiogram   FMD = flow-mediated dilation   GTN = glyceryl trinitrate   GTNMD = glyceryl trinitrate-mediated dilation   HPA = hypothalamic-pituitary-adrenal   NO = nitric oxide

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