Hyperhomocysteinemia in Treatment with Atypical Antipsychotics is Independent of Metabolic Syndrome

Abstract

Strong association between homocysteine (Hcy) and metabolic syndrome (MetS) is documented in individuals with schizophrenia and it is suggested that alterations in Hcy levels might be secondary to metabolic changes induced by atypical antipsychotics (AA). Serum paraoxonase (PON-1) activity, which is negatively affected by increased Hcy concentrations are lower in schizophrenia, and this may impact the development of metabolic side effects. Forty-five subjects with schizophrenia and 43 healthy volunteers, matched according to age, gender, smoking habits, and MetS predictors, were enrolled in this study to examine how Hcy level, PON-1 activity, and MetS indicators influence each other in schizophrenic individuals on AA treatment. Serum Hcy concentrations were significantly higher (15 ± 8 μmol/L vs 12 ± 3 μmol/L), and PON activity tended to be impaired (182±82 U/L vs 216 ± 110 U/L) in schizophrenia. Serum Hcy concentrations were not different between subjects with and without metabolic syndrome in study (14±4 μmol/L and 16±9 μmol/L) and control groups (12±3 μmol/L and 13±7 μmol/L), respectively. Similarly, PON and aryl esterase (AE) activities were not different between subjects with and without metabolic syndrome in study (PON: 185±100 U/L and 181±76 U/L; AE: 84±34 kU/L and 89±20 kU/L) and control (PON: 215±111 U/L and 216±113 U/L; AE: 83±27 kU/L and 88±33 kU/L) groups, respectively. . Hcy levels and MetS predictors were not statistically correlated. Results indicate that schizophrenic subjects on AA treatment have increased levels of Hcy compared to healthy controls and this is not influenced by the presence of MetS.

Keywords

• Atypical antipsychotics
• schizophrenia
• homocysteine
• metabolic syndrome

Atipik Antipsikotiklerle Tedavi Sürecinde Görülen Hiperhomosisteinemi Metabolik Sendromdan Bağımsızdır

Öz

Şizofreni olgularında homosistein (Hcy) ve metabolik sendrom (MetS) arasında güçlü ilişki olduğu bildirilmiş ve Hcy düzeylerindeki artışın atipik antipsikotikler (AA) ile uyarılan metabolik değişikliklere bağlı gelişebileceği düşünülmüştür. Artmış Hcy düzeylerinin negatif yönde etkilediği serum paraoksanaz (PON-1) aktivitesi, şizofrenili bireylerde düşük bulunmaktadır ve bu durumun metabolik yan etkilere neden olabileceği öne sürülmektedir. Bu çalışmada, AA tedavisi alan şizofreni kişilerde Hcy düzeyleri, PON-1 activitesi ve MetS indikatörlerinin birbirlerinden nasıl etkilendiğini incelemek üzere yaş, cinsiyet, sigara alışkanlığı ve MetS göstergelerine göre eşleştirilmiş 45 şizofreni olgusu ve 43 sağlıklı kontrol ile çalışıldı. Şizofreni olgularında serum Hcy düzeyleri anlamlı olarak yüksek (15 ± 8 μmol/L ve 12 ± 3 μmol/L) bulunurken, PON aktivitesinde (182±82 U/L ve 216 ± 110 U/L) azalma eğilimi olduğu gözlendi. Metabolik sendromu olan ve olmayan bireylerin Hcy konsantrasyonları arasında fark yoktu (Şizofreni grubunda sırasıyla, 14±4 μmol/L ve 16±9 μmol/L; Kontrol grubunda sırasıyla, 12±3 μmol/L and 13±7 μmol/L). Benzer şekilde, PON ve aril esteraz (AE) aktiviteleri değerlendirildiğinde metabolik sendromu olan ve olmayan şizofreni grubundaki bireylerin (PON: sırasıyla, 185±100 U/L ve 181±76 U/L; AE: sırasıyla, 84±34 kU/L ve 89±20 kU/L) ve kontrol grubundaki bireylerin (PON: sırasıyla, 215±111 U/L ve 216±113 U/L; AE: sırasıyla, 83±27 kU/L ve 88±33 kU/L) enzim aktivitelerinde fark bulunmadı.Hcy düzeyleri ile MetS göstergeleri arasında istatistiksel ilişki saptanmadı. Sonuçlara göre, AA tedavisi alan şizofreni olgularında Hcy düzeyleri sağlıklı kontrollere göre daha yüksektir ve bu durum MetS varlığından etkilenmemektedir.

Anahtar Kelimeler

• Atipik antipsikotikler
• Şizofreni
• Homosistein
• Metabolik sendrom
• Paraoksonaz

Kaynakça

1. Abdel-Salam OM, El-Shamarka M, Omara EA (2018) Brain oxidative stress and neurodegeneration in the ketamine model of schizophrenia during antipsychotic treatment: Effects of N-acetylcysteine treatment. React Oxyg Species, 6:253-266.
2. Andersson A, Lindgren A, Hultberg B (1995) Effect of thiol oxidation and thiol export from erythrocytes on determination of redox status of homocysteine and other thiols in plasma from healthy subjects and patients with cerebral infarction. Clin Chem, 41:361-366.
3. APA (1994) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Washington DC, American Psychiatric Association.
4. Bicikova M, Hampl R, Hill M, Ripova D, Mohr P, Putz Z (2011) Neuro- and immunomodulatory steroids and other biochemical markers in drug-naive schizophrenia patients and the effect of treatment with atypical antipsychotics. Neuro Endocrinol Lett, 32:141-147.
5. Brown S, Inskip H, Barraclough B (2000) Causes of the excess mortality of schizophrenia. Br J Psychiatry, 177:212-217.
6. Eckerson HW, Romson J, Wyte C, La Du BN (1983) The human serum paraoxonase polymorphism: Identification of phenotypes by their response to salts. Am J Hum Genet, 35:214-227.
7. Esteghamati A, Hafezi-Nejad N, Zandieh A, Sheikhbahaei S, Ebadi M, Nakhjavani M (2014) Homocysteine and metabolic syndrome: from clustering to additional utility in prediction of coronary heart disease. J Cardiol, 64:290-296.
8. Fe'li SN, Yassini Ardekani SM, Dehghani A (2020) Relationship between serum homocysteine and metabolic syndrome among patients with schizophrenia and bipolar disorder: A cross sectional study. Iran J Psychiatry, 4:266-273.

9. Ferretti G, Bacchetti T, Marotti E, Curatola G (2003) Effect of homocysteinylation on human high-density lipoproteins: a correlation with paraoxonase activity. Metabolism, 52:146-151.
10. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem, 18:499-502.
11. Gilca M, Piriu G, Gaman L, Delia C, Iosif L, Atanasiu V et al. (2014) A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics. Psychopharmacology (Berl), 231:4703-4710.
12. Goh XX, Tang PY, Tee SF (2022) Effects of antipsychotics on antioxidant defence system in patients with schizophrenia: A meta-analysis. Psychiatry Res, 309:114429-114437.
13. Granér M, James RW, Kahri J, Nieminen MS, Syvänne M, Taskinen MR (2006) Association of paraoxonase-1 activity and concentration with angiographic severity and extent of coronary artery disease. J Am Coll Cardiol, 47:2429-2435.
14. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. (2005) American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation, 112:2735-2752.
15. Güneş M, Camkurt MA, Bulut M, Demir S, İbiloğlu AO, Kaya MC et al. (2016) Evaluation of paraoxonase, arylesterase and malondialdehyde levels in schizophrenia patients taking typical, atypical and combined antipsychotic treatment. Clin Psychopharmacol Neurosci, 14:345-350.
16. Haagen L, Brock A (1992) A new automated method for phenotyping arylesterase (EC 3.1.1.2) based upon inhibition of enzymatic hydrolysis of 4-nitrophenyl acetate by phenyl acetate. Eur J Clin Chem Clin Biochem, 30:391-395.
17. Hennekens CH, Hennekens AR, Hollar D, Casey DE (2005) Schizophrenia and increased risk of cardiovascular disease. Am Heart J, 150:1115-1121.
18. Huang Y, Wu K, Li H, Zhou J, Xiong D, Huang X et al. (2020) Homocysteine level, body mass index and clinical correlates in Chinese Han patients with schizophrenia. Sci Rep, 10:16119.
19. Karabina SA, Lehner AN, Frank E, Parthasarathy S, Santanam N (2005) Oxidative inactivation of paraoxonase–implications in diabetes mellitus and atherosclerosis. Biochim Biophys Acta, 1725:213-221.
20. Kennedy DJ, Tang WH, Fan Y, Wu Y, Mann S, Pepoy M et al (2013) Diminished antioxidant activity of high-density lipoprotein-associated proteins in chronic kidney disease. J Am Heart Assoc, 2:e000104.
21. Kunutsor SK, Bakker SJ, James RW, Dullaart RP (2016) Serum paraoxonase-1 activity and risk of incident cardiovascular disease: The PREVEND study and meta-analysis of prospective population studies. Atherosclerosis, 245:143-154.
22. Misiak B, Frydecka D, Łaczmański Ł, Ślęzak R, Kiejna A (2014) Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients. Eur J Clin Pharmacol, 70:1433-1441.
23. Moreira EG, Boll KM, Correia DG, Soares JF, Rigobello C, Maes M (2019) Why should psychiatrists and neuroscientists worry about paraoxonase 1? Curr Neuropharmacol, 17:1004-1020.
24. Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M (2006) Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry, 11:143–149.
25. Nasallah HA, Newcomer JW (2004) Atypical antipsychotics and metabolics dysregulations: Evaluating the risk/benefit equation and improving the standard of car. J Clin Psychopharmacol, 24:7-14.
26. Nishi A, Numata S, Tajima A, Kinoshita M, Kikuchi K, Shimodera S et al. (2014) Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr Bull, 40:1154-1163.
27. Numata S, Kinoshita M, Tajima A, Nishi A, Imoto I, Ohmori T (2015) Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Med Genet, 16:54-59.
28. Obradovic M, Zaric BL, Haidara MA, Isenovic ER. (2018) Link between homocysteine and cardiovascular diseases. Curr Pharmacol Rep, 4:1-9.
29. Sarandol A, Kirli S, Akkaya C, Ocak N, Eroz E, Sarandol E (2007) Coronary artery disease risk factors in patients with schizophrenia: effects of short term antipsychotic treatment. J Psychopharmacol, 21:857-863.
30. Suematsu Y, Goto M, Park C, Nunes ACF, Jing W, Streja E et al. (2019) Association of serum paraoxonase/arylesterase activity with all-cause mortality in maintenance hemodialysis patients. J Clin Endocrinol Metab,104:4848-4856.
31. Unsal C, Albayrak Y, Albayrak N, Kuloglu M, Hashimoto K (2013) Reduced serum paraoxonase 1 (PON1) activity in patients with schizophrenia treated with olanzapine but not quetiapine. Neuropsychiatr Dis Treat, 9:1545.
32. Vuksan-Ćusa B, Jakovljević M, Sagud M, Mihaljević Peleš A, Marčinko D, Topić R et al. (2011) Metabolic syndrome and serum homocysteine in patients with bipolar disorder and schizophrenia treated with second generation antipsychotics. Psychiatry Res, 189:21-25.
33. World Health Organization (2022) Schizophrenia. https://www.who.int/news-room/fact-sheets/detail/schizophrenia. (Accessed 10.01.2022).
34. Wysokiński A, Kłoszewska I (2013) Homocysteine levels in patients with schizophrenia on clozapine monotherapy. Neurochem Res, 38:2056-2062