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Nitric oxide-related biomarkers for depression-induced cardiovascular risk
S390
P.2.b. Mood disorders and treatment − Affective disorders (clinical)
P.2.b.018 Nitric oxide-related biomarkers for depression-induced cardiovascular risk O. Amouzadeh-Ghadikolai1 ° , A. Baranyi2 , H.B. Rothenh¨ausler2 , S. Theokas2 , C. Robier3 , M. Baranyi2 , M. Koppitz2 , G. Reicht4 , P. Hlade1 , A. Meinitzer5 1 Hospital of the Brothers of St. John of God, Department of Psychiatry, Graz, Austria; 2 Medical University of Graz, Department of Psychiatry, Graz, Austria; 3 Hospital of the Brothers of St. John of God, Central Laboratory, Graz, Austria; 4 Hospital of the Brothers of St. John of God, Department of Internal Medicine, Graz, Austria; 5 Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria Background: Endothelial dysfunction is associated with increased cardiovascular risk and is defined by the reduced bioavailability of nitric oxide, which plays an important role in flow-mediated vasodilatation, aggregation of platelets, adhesion of monocytes and leukocytes to the endothelium, smooth muscle cell proliferation, oxidation of low density lipoprotein (LDL), and vascular inflammation by suppressing the expression and activity of chemokines and adhesion molecules [1−4]. In addition, major depression is also a well-known risk factor for cardiovascular diseases and increased mortality following myocardial infarction [5]. However, biomarkers of increased cardiovascular risk during depressive episodes have not been identified to date. The aim of this prospective study was to evaluate, whether nitric oxiderelated factors for endothelial dysfunction, such as global arginine bioavailability, arginase activity, L-arginine/ADMA ratio and the arginine metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine might be biomarkers for depressioninduced cardiovascular risk. Methods: In 71 in-patients with major depression and 48 healthy controls the Global Arginine Bioavailability Ratio (GABR), arginase activity (arginine/ornithine ratio), the L-arginine/ADMA ratio, ADMA, and symmetric dimethylarginine were determined by high-pressure liquid chromatography. Psychiatric (Sociodemographic Questionaire, Hamilton Depression Scale, Beck Depression Inventory) and laboratory assessments were obtained at baseline at the time of in-patient admittance and at the time of hospital discharge. Results: Primarily patients suffering from major depression had a global arginine bioavailability (GABR: Mann– Whitney U: 1561.5; p = 0.69), arginase activity (Mann–Whitney U-Test: 1544.5; p = 0.621) and L-arginine/ADMA ratio (t = −0.631 df = 114; p = 0.529) similar to those of healthy controls without a history of psychiatric disorders. After a first improvement of depression, a significant decrease in arginase activity (L-arginine to ornithine ratio) in patients suffering from major depression was observed at the time of hospital discharge (Wilcoxon Test: Z = −2.057; p = 0.04). In addition, there was a trend for increased global arginine bioavailability and a significant increase of the L-arginine/ADMA ratio in depressive patients at the time of hospital discharge [GABR: Wilcoxon Test: Z = −1.814; p = 0.07; L-arginine/ADMA ratio: t(paired) = −2.257, df = 56; p = 0.028). In patients with major depression the ADMA concentrations were significantly elevated in comparison with healthy participants (t = 2.052, df = 116; p = 0.042). Even after a short-term improvement of depression at the time of discharge from a psychiatric hospital, ADMA levels remained nearly unchanged [t(paired) = 1.057, df = 56; p = 0.295]. Symmetric dimethylarginine concentrations were significantly lower in patients with major
depression than those of healthy controls (Mann–Whitney-U-Test: 1172.5; p = 0.005). Conclusions: Our study results are evidence that in patients with major depression ADMA and symmetric dimethylarginine might be biomarkers to indicate an increased cardiovascular threat due to depression-triggered nitric oxide reduction. GABR, the L-arginine/ADMA ratio and arginase activity might be indicators of therapy success and increased nitric oxide production after remission. References [1] Halcox, J.P., Schenke, W.H., Zalos, G., Mincemoyer, R., Prasad, A., Waclawiw, M.A., et al., 2002. Prognostic value of coronary vascular endothelial dysfunction. Circulation 106(6), 653–658. [2] Rajapakse, N.W., Mattson, D.L., 2009. Role of L-arginine in nitric oxide production in health and hypertension. Clin Exp Pharmacol Physiol. 36(3), 249–255. [3] Wolf, A., Zalpour, C., Theilmeier, G., Wang, B.Y., Ma, A., Anderson, B., et al., 1997. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 29(3), 479–485. [4] B¨oger, R.H., Bode-B¨oger, S.M., Kienke, S., Stan, A.C., Nafe, R., Fr¨olich, J.C., 1998. Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits. Atherosclerosis. 1998; 136(1): 67−77. [5] Barth, J., Schumacher, M., Herrmann-Lingen, C., 2004. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med. 66(6), 802–813.
P.2.b.019 New insights in the kynurenine pathway of interferon-a-induced depression O. Amouzadeh-Ghadikolai1 ° , A. Baranyi2 , A. Meinitzer3 , R.J. Breitenecker4 , R. Stauber5 , H.B. Rothenh¨ausler2 1 Hospital of the Brothers of St. John of God, Department of Psychiatry, Graz, Austria; 2 Medical University of Graz, Department of Psychiatry, Graz, Austria; 3 Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria; 4 Alpen-Adria Universit¨ at Klagenfurt, Department of Innovation Management and Entrepreneurship, Klagenfurt, Austria; 5 Medical University of Graz, Division of Gastroenterology and Hepatology Department of Internal Medicine, Graz, Austria Background: Treatment of chronic forms of hepatitis C is based on a standard combination therapy of pegylated interferon-a (IFNa) and ribavirin. The effectiveness of the antiviral therapy has greatly improved in the last years, and the overall rate of sustained virological response is clearly above 50%. However, many patients develop a IFN-a-induced depressive symptomatology. Minor depressive episodes have been observed through detailed examination in 30% to 60% of all patients treated with IFN-a. 20 to 30% of patients even develop the full symptomatology of a major depression. The biological pathways of this side effect are still mostly unknown. However, we do know that IFN-a increases the activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that is responsible for the breakdown of tryptophan to kynurenine. This results in an increase of kynurenine and in reduced concentration of tryptophan that is available for serotonin synthesis. Kynurenine crosses the blood-brain barrier and is broken down into the neurotoxic metabolites 3-hydroxykynurenines and quinolinic acid, which has agonistic properties on the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is a glutamate receptor, and overstimulation leads to neuronal damage. Kynurenic acid is synthesized by the enzyme kynurenine aminotransferase. It is a metabolite of
P.2.b. Mood disorders and treatment − Affective disorders (clinical)
P.2.b.018 Nitric oxide-related biomarkers for depression-induced cardiovascular risk O. Amouzadeh-Ghadikolai1 ° , A. Baranyi2 , H.B. Rothenh¨ausler2 , S. Theokas2 , C. Robier3 , M. Baranyi2 , M. Koppitz2 , G. Reicht4 , P. Hlade1 , A. Meinitzer5 1 Hospital of the Brothers of St. John of God, Department of Psychiatry, Graz, Austria; 2 Medical University of Graz, Department of Psychiatry, Graz, Austria; 3 Hospital of the Brothers of St. John of God, Central Laboratory, Graz, Austria; 4 Hospital of the Brothers of St. John of God, Department of Internal Medicine, Graz, Austria; 5 Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria Background: Endothelial dysfunction is associated with increased cardiovascular risk and is defined by the reduced bioavailability of nitric oxide, which plays an important role in flow-mediated vasodilatation, aggregation of platelets, adhesion of monocytes and leukocytes to the endothelium, smooth muscle cell proliferation, oxidation of low density lipoprotein (LDL), and vascular inflammation by suppressing the expression and activity of chemokines and adhesion molecules [1−4]. In addition, major depression is also a well-known risk factor for cardiovascular diseases and increased mortality following myocardial infarction [5]. However, biomarkers of increased cardiovascular risk during depressive episodes have not been identified to date. The aim of this prospective study was to evaluate, whether nitric oxiderelated factors for endothelial dysfunction, such as global arginine bioavailability, arginase activity, L-arginine/ADMA ratio and the arginine metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine might be biomarkers for depressioninduced cardiovascular risk. Methods: In 71 in-patients with major depression and 48 healthy controls the Global Arginine Bioavailability Ratio (GABR), arginase activity (arginine/ornithine ratio), the L-arginine/ADMA ratio, ADMA, and symmetric dimethylarginine were determined by high-pressure liquid chromatography. Psychiatric (Sociodemographic Questionaire, Hamilton Depression Scale, Beck Depression Inventory) and laboratory assessments were obtained at baseline at the time of in-patient admittance and at the time of hospital discharge. Results: Primarily patients suffering from major depression had a global arginine bioavailability (GABR: Mann– Whitney U: 1561.5; p = 0.69), arginase activity (Mann–Whitney U-Test: 1544.5; p = 0.621) and L-arginine/ADMA ratio (t = −0.631 df = 114; p = 0.529) similar to those of healthy controls without a history of psychiatric disorders. After a first improvement of depression, a significant decrease in arginase activity (L-arginine to ornithine ratio) in patients suffering from major depression was observed at the time of hospital discharge (Wilcoxon Test: Z = −2.057; p = 0.04). In addition, there was a trend for increased global arginine bioavailability and a significant increase of the L-arginine/ADMA ratio in depressive patients at the time of hospital discharge [GABR: Wilcoxon Test: Z = −1.814; p = 0.07; L-arginine/ADMA ratio: t(paired) = −2.257, df = 56; p = 0.028). In patients with major depression the ADMA concentrations were significantly elevated in comparison with healthy participants (t = 2.052, df = 116; p = 0.042). Even after a short-term improvement of depression at the time of discharge from a psychiatric hospital, ADMA levels remained nearly unchanged [t(paired) = 1.057, df = 56; p = 0.295]. Symmetric dimethylarginine concentrations were significantly lower in patients with major
depression than those of healthy controls (Mann–Whitney-U-Test: 1172.5; p = 0.005). Conclusions: Our study results are evidence that in patients with major depression ADMA and symmetric dimethylarginine might be biomarkers to indicate an increased cardiovascular threat due to depression-triggered nitric oxide reduction. GABR, the L-arginine/ADMA ratio and arginase activity might be indicators of therapy success and increased nitric oxide production after remission. References [1] Halcox, J.P., Schenke, W.H., Zalos, G., Mincemoyer, R., Prasad, A., Waclawiw, M.A., et al., 2002. Prognostic value of coronary vascular endothelial dysfunction. Circulation 106(6), 653–658. [2] Rajapakse, N.W., Mattson, D.L., 2009. Role of L-arginine in nitric oxide production in health and hypertension. Clin Exp Pharmacol Physiol. 36(3), 249–255. [3] Wolf, A., Zalpour, C., Theilmeier, G., Wang, B.Y., Ma, A., Anderson, B., et al., 1997. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 29(3), 479–485. [4] B¨oger, R.H., Bode-B¨oger, S.M., Kienke, S., Stan, A.C., Nafe, R., Fr¨olich, J.C., 1998. Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits. Atherosclerosis. 1998; 136(1): 67−77. [5] Barth, J., Schumacher, M., Herrmann-Lingen, C., 2004. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med. 66(6), 802–813.
P.2.b.019 New insights in the kynurenine pathway of interferon-a-induced depression O. Amouzadeh-Ghadikolai1 ° , A. Baranyi2 , A. Meinitzer3 , R.J. Breitenecker4 , R. Stauber5 , H.B. Rothenh¨ausler2 1 Hospital of the Brothers of St. John of God, Department of Psychiatry, Graz, Austria; 2 Medical University of Graz, Department of Psychiatry, Graz, Austria; 3 Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria; 4 Alpen-Adria Universit¨ at Klagenfurt, Department of Innovation Management and Entrepreneurship, Klagenfurt, Austria; 5 Medical University of Graz, Division of Gastroenterology and Hepatology Department of Internal Medicine, Graz, Austria Background: Treatment of chronic forms of hepatitis C is based on a standard combination therapy of pegylated interferon-a (IFNa) and ribavirin. The effectiveness of the antiviral therapy has greatly improved in the last years, and the overall rate of sustained virological response is clearly above 50%. However, many patients develop a IFN-a-induced depressive symptomatology. Minor depressive episodes have been observed through detailed examination in 30% to 60% of all patients treated with IFN-a. 20 to 30% of patients even develop the full symptomatology of a major depression. The biological pathways of this side effect are still mostly unknown. However, we do know that IFN-a increases the activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that is responsible for the breakdown of tryptophan to kynurenine. This results in an increase of kynurenine and in reduced concentration of tryptophan that is available for serotonin synthesis. Kynurenine crosses the blood-brain barrier and is broken down into the neurotoxic metabolites 3-hydroxykynurenines and quinolinic acid, which has agonistic properties on the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is a glutamate receptor, and overstimulation leads to neuronal damage. Kynurenic acid is synthesized by the enzyme kynurenine aminotransferase. It is a metabolite of