Metyrapone improves endothelial dysfunction in patients with treated depression.

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.

[1]  L. Grunhaus,et al.  The DST as a predictor of outcome in depression: a meta-analysis. , 1993, The American journal of psychiatry.

[2]  R. Kelly,et al.  Glucocorticoids Regulate Inducible Nitric Oxide Synthase by Inhibiting Tetrahydrobiopterin Synthesis and L-Arginine Transport* , 1996, The Journal of Biological Chemistry.

[3]  N. Taylor,et al.  Extra‐adrenal effects of metyrapone include inhibition of the 11‐oxoreductase activity of 11β‐hydroxysteroid dehydrogenase: a model for 11‐HSD I deficiency , 1995, Clinical endocrinology.

[4]  R. Hughson,et al.  Flow-mediated dilation in human brachial artery after different circulatory occlusion conditions. , 2004, American journal of physiology. Heart and circulatory physiology.

[5]  K. Yusoff,et al.  Soluble intercellular adhesion molecule-1 and interleukin-6 levels reflect endothelial dysfunction in patients with primary hypercholesterolaemia treated with atorvastatin. , 2003, Atherosclerosis.

[6]  G. Brabant,et al.  Oral L-arginine improves endothelial function in healthy individuals older than 70 years , 2003, Vascular medicine.

[7]  A. Steiger,et al.  Sleep EEG and nocturnal secretion of cortisol and growth hormone in male patients with endogenous depression before treatment and after recovery. , 1989, Journal of affective disorders.

[8]  H. Akil,et al.  Normal pituitary response to metyrapone in the morning in depressed patients: Implications for circadian regulation of corticotropin-releasing hormone secretion , 1997, Biological Psychiatry.

[9]  C. Hammen.  Stress and depression. , 2005, Annual review of clinical psychology.

[10]  Harry Hemingway,et al.  Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. , 1999, BMJ.

[11]  Angela L. Lee,et al.  Stress and depression: possible links to neuron death in the hippocampus. , 2002, Bipolar disorders.

[12]  E. Sprague,et al.  The association of elevated plasma cortisol and early atherosclerosis as demonstrated by coronary angiography. , 1977, Atherosclerosis.

[13]  Shumei Yang,et al.  Inhibitory effect of glucocorticoid on coronary artery endothelial function. , 2002, American journal of physiology. Heart and circulatory physiology.

[14]  M. Trimble.  Anticonvulsant-Induced Psychiatric Disorders , 1996, Drug safety.

[15]  D. Webb,et al.  Cortisol inhibits cholinergic vasodilation in the human forearm. , 2000, American journal of hypertension.

[16]  W. Rand,et al.  Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. , 2001, Journal of the American College of Cardiology.

[17]  H. Burger,et al.  Differing effects of low-dose estrogen–progestin therapy and pravastatin in postmenopausal hypercholesterolemic women , 2002, Climacteric : the journal of the International Menopause Society.

[18]  J. Lekakis,et al.  Oral L-arginine improves endothelial dysfunction in patients with essential hypertension. , 2002, International journal of cardiology.

[19]  R. Newcombe,et al.  Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. , 1998, Circulation.

[20]  T. Mitsui,et al.  Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction , 2003, Circulation research.

[21]  E. Nabel,et al.  Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. , 1990, Journal of the American College of Cardiology.

[22]  D. Celermajer,et al.  Cigarette Smoking Is Associated With Dose‐Related and Potentially Reversible Impairment of Endothelium‐Dependent Dilation in Healthy Young Adults , 1993, Circulation.

[23]  V. Moskvina,et al.  Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment. , 2005, Journal of the American College of Cardiology.

[24]  E. Nabel,et al.  Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. , 1989, Circulation.

[25]  A. Steiger,et al.  Nocturnal secretion of prolactin and cortisol and the sleep EEG in patients with major endogenous depression during an acute episode and after full remission , 1997, Psychiatry Research.

[26]  C. Jones,et al.  Arterial endothelial function is impaired in treated depression , 2002, Heart.

[27]  J. Whitworth,et al.  Cushing, cortisol, and cardiovascular disease. , 2000, Hypertension.

[28]  B. Walker.  Cortisol and cardiovascular disease , 2007 .

[29]  M W Ramsey,et al.  Endothelium and inelastic arteries: an early marker of vascular dysfunction in non-insulin dependent diabetes , 1996, BMJ.

[30]  A. Quyyumi,et al.  Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. , 1990, The New England journal of medicine.

[31]  I. Ferrier,et al.  A Combined Study of Cortisol, ACTH and Dexamethasone Concentrations in Major Depression , 1987, British Journal of Psychiatry.

[32]  G. Watts,et al.  Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia , 1992, The Lancet.

[33]  M. Rubenfire,et al.  Abnormal brachial artery flow-mediated vasodilation in young adults with major depression. , 2001, The American journal of cardiology.

[34]  A. Sherwood,et al.  Depression as a Risk Factor for Coronary Artery Disease: Evidence, Mechanisms, and Treatment , 2004, Psychosomatic medicine.

[35]  I. Miyamori,et al.  11beta-hydroxysteroid dehydrogenase in cultured human vascular cells. Possible role in the development of hypertension. , 1999, Hypertension.

[36]  C. Jones,et al.  Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide. , 2001, Clinical science.

[37]  R. Rugulies.  Depression as a predictor for coronary heart disease. a review and meta-analysis. , 2002, American journal of preventive medicine.