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Asymmetric dimethylarginine levels in patients with schizophrenia
Psychiatry Research 227 (2015) 369–370
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Asymmetric dimethylarginine levels in patients with schizophrenia To the Editors: In the recent study by Zincir et al. (2014), the authors investigated asymmetric dimethylarginine (ADMA) levels in patients with first episode schizophrenia. They found ADMA levels in schizophrenia patients were higher than in controls and the level of ADMA decreased with antipsychotic treatment. This study gives important information to clinicians about the link between first episode schizophrenia and ADMA. However, we have some minor comments about this article. Firstly, the diagnosis of schizophrenia in these patients should have been performed according to DSM-IV-TR Van Os and Kapur (2009) criteria, which includes patients who have had schizophrenia-like psychotic disorder for at least 6 months. Key exclusion criteria should include a DSM-IV-TR diagnosis other than schizophrenia, uncontrolled thyroid function abnormalities, a history of seizures, neuroleptic malignant syndrome, clinically relevant tardive dyskinesia, or other medical condition that would expose the patient to undue risk or interfere with study assessments. Secondly, new inflammatory markers have been identified in recent years for many conditions. One of the major endotheliumderived vasoactive mediators is nitric oxide (NO). A growing body of data indicates that one of the endogenous NO synthase inhibitors is ADMA. The free radical (oxidative stress) theory of aging assumes that aging occurs as a result of damage to cell constituents and connective tissues by free radicals arising from oxygen-associated reactions. Schizophrenia has been associated with oxidative stress and chronic inflammation, both of which also appear to reciprocally induce each other in a positive feedback manner. When compared with age-matched healthy controls, schizophrenia patients have higher levels of markers of oxidative cellular damage such as protein carbonyls, products of lipid peroxidation, and DNA hydroxylation. Potential confounders such as antipsychotic medication, smoking, socio-economic status and unhealthy lifestyle make it impossible to solely attribute the earlier onset of aging-related changes or oxidative stress to having a diagnosis of schizophrenia. Elevated levels of markers of oxidative stress have been reported in schizophrenia patients relative to healthy controls (Okusaga, 2014). ADMA may be responsible for endothelial vasodilator dysfunction in many individuals with coronary and peripheral arterial diseases and in those with atherosclerotic risk factors, particularly hypertension (Cakar et al., 2015), diabetes mellitus, hypercholesterolemia (Kurtoglu et al., 2014), hyperhomocysteinemia, smoking, and aging (Böger, 2003). Furthermore, renal failure is one of the most important prognostic variable in
http://dx.doi.org/10.1016/j.psychres.2015.02.018 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
patients with cardiovascular disease (Balta et al., 2013). ADMA is eliminated from the body via renal excretion. The serum creatinine level and an accurate function test such as the glomerular filtration rate (GFR) provide knowledge about renal function. A mild reduction in GFR is associated with an increased plasma level of ADMA. It would have been useful if the authors had mentioned these factors. The authors reported that plasma ADMA levels were analyzed by using high performance liquid chromatography (HPLC). This novel assay allows the rapid, reproducible, sensitive determination of ADMA compared with the ELISA method (Böger, 2003), but many assays are time-consuming and costly, and they deliver quite unstable results which are not suitable to differentiate ADMA from symmetric dimethylarginine (SDMA), monomethylarginine, and other methylated arginine analogs. The authors did not determine other arginine derivatives such as SDMA and Larginine or assess endothelial function. For this reason, HPLC coupled to mass spectrometric detection (LC–MS/MS) has a clear advantage as the current gold standard for differentiation between ADMA and the other methylated arginine derivatives; however, this method is not widely available, and the equipment is relatively expensive (Böger et al., 2009). In conclusion, because ADMA is clearly tightly related to oxidative-inflammatory mechanisms of schizophrenia, it may be very helpful to consider some of the above factors in future studies.
References Balta, S., Demirkol, S., Arslan, Z., Sahin, M.A., Yesil, F.G., Kucuk, U., 2013. The relation between decreased glomerular filtration rate and nonvalvular atrial fibrillation. Cardiology 124 (4), 219. Böger, R.H., 2003. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovascular Research 59 (4), 824–833. Böger, R.H., Maas, R., Schulze, F., Schwedhelm, E., 2009. Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality— an update on patient populations with a wide range of cardiovascular risk. Pharmacological Research 60 (6), 481–487. Cakar, M., Bulucu, F., Karaman, M., Ay, S.A., Kurt, O., Balta, S., Demirkol, S., Sarlak, H., Akhan, M., Altun, B., Yaman, H., Arslan, E., Demirbas, S., Saglam, K., 2015. Asymmetric dimethylarginine and augmentation ındex in newly diagnosed patients with hypertension. Angiology 66 (1), 43–48. Kurtoglu, E., Balta, S., Sincer, I., Altas, Y., Atas, H., Yilmaz, M., Korkmaz, H., Erdem, K., Akturk, E., Demirkol, S., Can, C., 2014. Comparision of effects of rosuvastatin versus atorvastatin treatment on plasma levels of asymmetric dimethylarginine in patients with hyperlipidemia having coronary artery disease. Angiology 65 (9), 788–793. Okusaga, O.O., 2014. Accelerated aging in schizophrenia patients: the potential role of oxidative stress. Aging and Disease 5 (4), 256–262. Van Os, J., Kapur, S, 2009. Schizophrenia. Lancet 374 (9690), 635–645. Zincir, S., Zincir, S.B., Doruk, A., Erdem, M., Celik, C., Ak, M., Garip, B., Yükselir, C., Karaahmetoğlu, B., 2014. Asymmetric dimethylarginine (ADMA) and treatment response relationship in male patients with first-episode schizophrenia: a controlled study. Psychiatry Research 220 (1–2), 76–80.
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Letter to the Editor / Psychiatry Research 227 (2015) 369–370
Sevket Balta n, Mustafa Aparci, Cengiz Ozturk Department of Cardiology, Eskisehir Military Hospital, Eskisehir, Turkey E-mail address: [email protected] (S. Balta) Ertugrul Kurtoglu Department of Cardiology, Malatya State Hospital, Malatya, Turkey
n Correspondence to: Department of Cardiology, Eskisehir Military Hospital, 26020 Eskişehir, Turkey. Tel.: þ 90 222 220 45 30; fax: þ 90 222 230 34 33.
Abdullah Bolu Department of Psychiatry, Eskisehir Military Hospital, Eskisehir, Turkey Received 11 September 2014 6 December 2014 9 February 2015
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Asymmetric dimethylarginine levels in patients with schizophrenia To the Editors: In the recent study by Zincir et al. (2014), the authors investigated asymmetric dimethylarginine (ADMA) levels in patients with first episode schizophrenia. They found ADMA levels in schizophrenia patients were higher than in controls and the level of ADMA decreased with antipsychotic treatment. This study gives important information to clinicians about the link between first episode schizophrenia and ADMA. However, we have some minor comments about this article. Firstly, the diagnosis of schizophrenia in these patients should have been performed according to DSM-IV-TR Van Os and Kapur (2009) criteria, which includes patients who have had schizophrenia-like psychotic disorder for at least 6 months. Key exclusion criteria should include a DSM-IV-TR diagnosis other than schizophrenia, uncontrolled thyroid function abnormalities, a history of seizures, neuroleptic malignant syndrome, clinically relevant tardive dyskinesia, or other medical condition that would expose the patient to undue risk or interfere with study assessments. Secondly, new inflammatory markers have been identified in recent years for many conditions. One of the major endotheliumderived vasoactive mediators is nitric oxide (NO). A growing body of data indicates that one of the endogenous NO synthase inhibitors is ADMA. The free radical (oxidative stress) theory of aging assumes that aging occurs as a result of damage to cell constituents and connective tissues by free radicals arising from oxygen-associated reactions. Schizophrenia has been associated with oxidative stress and chronic inflammation, both of which also appear to reciprocally induce each other in a positive feedback manner. When compared with age-matched healthy controls, schizophrenia patients have higher levels of markers of oxidative cellular damage such as protein carbonyls, products of lipid peroxidation, and DNA hydroxylation. Potential confounders such as antipsychotic medication, smoking, socio-economic status and unhealthy lifestyle make it impossible to solely attribute the earlier onset of aging-related changes or oxidative stress to having a diagnosis of schizophrenia. Elevated levels of markers of oxidative stress have been reported in schizophrenia patients relative to healthy controls (Okusaga, 2014). ADMA may be responsible for endothelial vasodilator dysfunction in many individuals with coronary and peripheral arterial diseases and in those with atherosclerotic risk factors, particularly hypertension (Cakar et al., 2015), diabetes mellitus, hypercholesterolemia (Kurtoglu et al., 2014), hyperhomocysteinemia, smoking, and aging (Böger, 2003). Furthermore, renal failure is one of the most important prognostic variable in
http://dx.doi.org/10.1016/j.psychres.2015.02.018 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
patients with cardiovascular disease (Balta et al., 2013). ADMA is eliminated from the body via renal excretion. The serum creatinine level and an accurate function test such as the glomerular filtration rate (GFR) provide knowledge about renal function. A mild reduction in GFR is associated with an increased plasma level of ADMA. It would have been useful if the authors had mentioned these factors. The authors reported that plasma ADMA levels were analyzed by using high performance liquid chromatography (HPLC). This novel assay allows the rapid, reproducible, sensitive determination of ADMA compared with the ELISA method (Böger, 2003), but many assays are time-consuming and costly, and they deliver quite unstable results which are not suitable to differentiate ADMA from symmetric dimethylarginine (SDMA), monomethylarginine, and other methylated arginine analogs. The authors did not determine other arginine derivatives such as SDMA and Larginine or assess endothelial function. For this reason, HPLC coupled to mass spectrometric detection (LC–MS/MS) has a clear advantage as the current gold standard for differentiation between ADMA and the other methylated arginine derivatives; however, this method is not widely available, and the equipment is relatively expensive (Böger et al., 2009). In conclusion, because ADMA is clearly tightly related to oxidative-inflammatory mechanisms of schizophrenia, it may be very helpful to consider some of the above factors in future studies.
References Balta, S., Demirkol, S., Arslan, Z., Sahin, M.A., Yesil, F.G., Kucuk, U., 2013. The relation between decreased glomerular filtration rate and nonvalvular atrial fibrillation. Cardiology 124 (4), 219. Böger, R.H., 2003. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovascular Research 59 (4), 824–833. Böger, R.H., Maas, R., Schulze, F., Schwedhelm, E., 2009. Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality— an update on patient populations with a wide range of cardiovascular risk. Pharmacological Research 60 (6), 481–487. Cakar, M., Bulucu, F., Karaman, M., Ay, S.A., Kurt, O., Balta, S., Demirkol, S., Sarlak, H., Akhan, M., Altun, B., Yaman, H., Arslan, E., Demirbas, S., Saglam, K., 2015. Asymmetric dimethylarginine and augmentation ındex in newly diagnosed patients with hypertension. Angiology 66 (1), 43–48. Kurtoglu, E., Balta, S., Sincer, I., Altas, Y., Atas, H., Yilmaz, M., Korkmaz, H., Erdem, K., Akturk, E., Demirkol, S., Can, C., 2014. Comparision of effects of rosuvastatin versus atorvastatin treatment on plasma levels of asymmetric dimethylarginine in patients with hyperlipidemia having coronary artery disease. Angiology 65 (9), 788–793. Okusaga, O.O., 2014. Accelerated aging in schizophrenia patients: the potential role of oxidative stress. Aging and Disease 5 (4), 256–262. Van Os, J., Kapur, S, 2009. Schizophrenia. Lancet 374 (9690), 635–645. Zincir, S., Zincir, S.B., Doruk, A., Erdem, M., Celik, C., Ak, M., Garip, B., Yükselir, C., Karaahmetoğlu, B., 2014. Asymmetric dimethylarginine (ADMA) and treatment response relationship in male patients with first-episode schizophrenia: a controlled study. Psychiatry Research 220 (1–2), 76–80.
370
Letter to the Editor / Psychiatry Research 227 (2015) 369–370
Sevket Balta n, Mustafa Aparci, Cengiz Ozturk Department of Cardiology, Eskisehir Military Hospital, Eskisehir, Turkey E-mail address: [email protected] (S. Balta) Ertugrul Kurtoglu Department of Cardiology, Malatya State Hospital, Malatya, Turkey
n Correspondence to: Department of Cardiology, Eskisehir Military Hospital, 26020 Eskişehir, Turkey. Tel.: þ 90 222 220 45 30; fax: þ 90 222 230 34 33.
Abdullah Bolu Department of Psychiatry, Eskisehir Military Hospital, Eskisehir, Turkey Received 11 September 2014 6 December 2014 9 February 2015