Advertisement

Psychopharmacology

, Volume 231, Issue 10, pp 2211–2218 | Cite as

Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype

  • Yi Zhang
  • Meijuan Chen
  • Jun Chen
  • Zhiguo Wu
  • Shunying Yu
  • Yiru Fang
  • Chen Zhang
Original Investigation

Abstract

Rationale

Metabolic syndrome (MetS) has consistently been identified as an adverse effect of long-term treatment with atypical antipsychotics (AAPs) such as clozapine. Elevated serum homocysteine concentration has been found to act as an independent risk factor for MetS, and catechol-O-methyltransferase (COMT) catalyzes the homocysteine metabolism. We accordingly hypothesized that COMT dysregulation may confer the susceptibility to MetS induced by AAPs, potentially in a gender-specific manner, because the interaction effects of COMT and gender have been consistently reported.

Objectives

This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment.

Methods

A total of 468 schizophrenia patients taking clozapine were divided into two groups, those experiencing MetS and non-MetS. We genotyped three functional variants (rs4633, rs4680, and rs4818) in COMT and measured the serum levels of fasting homocysteine, glucose, triglyceride (TG), and high-density lipoprotein cholesterol.

Results

MetS was found in 202/468 (43.2 %) of all the patients, with 40.2 % prevalence (138/343) in males and 51.2 % (64/125) in females. Patients with MetS had notably higher metabolic parameters than those without MetS. The mean levels of homocysteine in patients with MetS were significantly higher than those without MetS. We found a positive association between the rs4680 polymorphism and the serum triglyceride levels (corrected P = 0.024). Further analysis revealed that the rs4680 Met allele was significantly associated with increased triglyceride levels among female patients (P = 0.009), but not among males (P = 0.07).

Conclusions

Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients.

Keyword

Clozapine COMT Metabolic syndrome Triglyceride Association 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81000581), the Shanghai Science & Technology Development Foundation (12140904200), the China Postdoctoral Science Foundation (2013M530410), and the National Key Clinical Disciplines at Shanghai Mental Health Center (OMA-MH, 2011-873).

Conflict of interest

None.

Supplementary material

213_2013_3410_MOESM1_ESM.doc (30 kb)
Fig. S1 (DOC 30.5 kb)
213_2013_3410_MOESM2_ESM.doc (76 kb)
Table S1 (DOC 76.0 kb)
213_2013_3410_MOESM3_ESM.doc (41 kb)
Table S2 (DOC 41.0 kb)

References

  1. Alberti KG, Zimmet P, Shaw J (2005) The metabolic syndrome—a new worldwide definition. Lancet 366:1059–1062PubMedCrossRefGoogle Scholar
  2. Araki A, Sako Y (1987) Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 422:43–52PubMedCrossRefGoogle Scholar
  3. Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Leucht S (2010) Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev: CD006633Google Scholar
  4. Backhed F (2009) Changes in intestinal microflora in obesity: cause or consequence? J Pediatr Gastroenterol Nutr 48(Suppl 2):S56–S57PubMedCrossRefGoogle Scholar
  5. Bao YQ, Lu JX, Wang C, Yang M, Li HT, Zhang XY, Zhu JH, Lu HJ, Jia WP, Xiang KS (2008) Optimal waist circumference cutoffs for abdominal obesity in Chinese. Atherosclerosis 201:378–384PubMedCrossRefGoogle Scholar
  6. Bialecka M, Kurzawski M, Roszmann A, Robowski P, Sitek EJ, Honczarenko K, Gorzkowska A, Budrewicz S, Mak M, Jarosz M, Golab-Janowska M, Koziorowska-Gawron E, Drozdzik M, Slawek J (2012) Association of COMT, MTHFR, and SLC19A1(RFC-1) polymorphisms with homocysteine blood levels and cognitive impairment in Parkinson's disease. Pharmacogenet Genomics 22:716–724PubMedCrossRefGoogle Scholar
  7. Burghardt KJ, Pilsner JR, Bly MJ, Ellingrod VL (2012) DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences. Epigenomics 4:261–268PubMedCentralPubMedCrossRefGoogle Scholar
  8. Cai J, Zhang W, Yi Z, Lu W, Wu Z, Chen J, Yu S, Fang Y, Zhang C (2013) Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive-compulsive symptoms. Psychopharmacology (Berl) 230:49–55CrossRefGoogle Scholar
  9. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75:807–821PubMedCentralPubMedCrossRefGoogle Scholar
  10. Clarke R, Collins R, Lewington S, Donald A, Alfthan G, Tuomilehto J, Arnesen E, Bonaa K, Blacher J, Boers GHJ, Bostom A, Bots ML, Grobee DE, Brattstrom L, Breteler MMB, Hofman A, Chambers JC, Kooner JS, Coull BM, Evans RW, Kuller LH, Evers S, Folsom AR, Freyburger G, Parrot F, Genst J, Dalery K, Graham IM, Daly L, Hoogeveen EK, Kostense PJ, Stehouwer CDA, Hopknis PN, Jacques P, Selhub J, Luft FC, Jungers P, Lindgren A, Lolin YI, Loehrer F, Fowler B, Mansoor MA, Malinow MR, Ducimetiere P, Nygard O, Refsum H, Vollset SE, Ueland PM, Omenn GS, Beresford SAA, Roseman JM, Parving HH, Gall MA, Perry IJ, Ebraham SB, Shaper AG, Robinson K, Jacobsen DW, Schwartz SM, Siscovick DS, Stampfer MJ, Henekens CH, Feskens EJM, Kromhout D, Ubbink J, Elwood P, Pickering J, Verhoef P, von Eckardstein A, Schulte H, Assmann G, Wald N, Law MR, Whincup PH, Wilcken DEL, Sherliker P, Linksted P, Smith GD, Witteman JCM, Israelsson B, Sexton G, Wu LL, Joubran R, Norrving B, Hultberg B, Andersson A, Johansson BB, Bergmark C, Svardal AM, Evans AE, Pancharuniti N, Lewis CA, Holman R, Stratton I, Johnston C, Morris J, Collaboration HS (2002) Homocysteine and risk of ischemic heart disease and stroke—a meta-analysis. JAMA 288:2015–2022CrossRefGoogle Scholar
  11. Comasco E, Hellgren C, Sundstrom-Poromaa I (2012) Influence of catechol-O-methyltransferase Val158Met polymorphism on startle response in the presence of high estradiol levels. Eur Neuropsychopharmacol 23:629–635PubMedCrossRefGoogle Scholar
  12. Davey KJ, O'Mahony SM, Schellekens H, O'Sullivan O, Bienenstock J, Cotter PD, Dinan TG, Cryan JF (2012) Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters. Psychopharmacology (Berl) 221:155–169CrossRefGoogle Scholar
  13. De Hert M, Schreurs V, Sweers K, Van Eyck D, Hanssens L, Sinko S, Wampers M, Scheen A, Peuskens J, van Winkel R (2008) Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: a retrospective chart review. Schizophr Res 101:295–303PubMedCrossRefGoogle Scholar
  14. Ellingrod VL, Miller DD, Taylor SF, Moline J, Holman T, Kerr J (2008) Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants. Schizophr Res 98:47–54PubMedCentralPubMedCrossRefGoogle Scholar
  15. Falchi M, Wilson SG, Paximadas D, Swaminathan R, Spector TD (2008) Quantitative linkage analysis for pancreatic B-cell function and insulin resistance in a large twin cohort. Diabetes 57:1120–1124PubMedCrossRefGoogle Scholar
  16. Fatemi SH, Folsom TD (2007) Catechol-O-methyltransferase gene regulation in rat frontal cortex. Mol Psychiatry 12:322–323PubMedCrossRefGoogle Scholar
  17. Fatemi SH, Folsom TD, Reutiman TJ, Novak J, Engel RH (2012) Comparative gene expression study of the chronic exposure to clozapine and haloperidol in rat frontal cortex. Schizophr Res 134:211–218PubMedCrossRefGoogle Scholar
  18. Gao S, Hu Z, Cheng J, Zhou W, Xu Y, Xie S, Liu S, Li Z, Guo J, Dong J, Huang M (2012) Impact of catechol-o-methyltransferase polymorphisms on risperidone treatment for schizophrenia and its potential clinical significance. Clin Biochem 45:787–792PubMedCrossRefGoogle Scholar
  19. Gellekink H, Muntjewerff JW, Vermeulen SHHM, Hermus ARMM, Blom HJ, den Heijer M (2007) Catechol-O-methyltransferase genotype is associated with plasma total homocysteine levels and may increase venous thrombosis risk. Thromb Haemost 98:1226–1231PubMedGoogle Scholar
  20. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Spertus JA, Costa F (2005) Diagnosis and management of the metabolic syndrome—an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 112:2735–2752PubMedCrossRefGoogle Scholar
  21. Gupta M, Bhatnagar P, Grover S, Kaur H, Baghel R, Bhasin Y, Chauhan C, Verma B, Manduva V, Mukherjee O, Purushottam M, Sharma A, Jain S, Brahmachari SK, Kukreti R (2009) Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics 10:385–397PubMedCrossRefGoogle Scholar
  22. Guven A, Inanc F, Kilinc M, Ekerbicer H (2005) Plasma homocysteine and lipoprotein (a) levels in Turkish patients with metabolic syndrome. Heart Vessels 20:290–295PubMedCrossRefGoogle Scholar
  23. Hajer GR, van der Graaf Y, Olijhoek JK, Verhaar MC, Visseren FL (2007) Levels of homocysteine are increased in metabolic syndrome patients but are not associated with an increased cardiovascular risk, in contrast to patients without the metabolic syndrome. Heart 93:216–220PubMedCentralPubMedCrossRefGoogle Scholar
  24. Hu S, Yao M, Peterson BS, Xu D, Hu J, Tang J, Fan B, Liao Z, Yuan T, Li Y, Yue W, Wei N, Zhou W, Huang M, Xu Y (2013) A randomized, 12-week study of the effects of extended-release paliperidone (paliperidone ER) and olanzapine on metabolic profile, weight, insulin resistance, and beta-cell function in schizophrenic patients. Psychopharmacology (Berl) 230:3–13CrossRefGoogle Scholar
  25. Jassim G, Skrede S, Vazquez MJ, Wergedal H, Vik-Mo AO, Lunder N, Dieguez C, Vidal-Puig A, Berge RK, Lopez M, Steen VM, Ferno J (2012) Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat. Psychopharmacology (Berl) 219:783–794CrossRefGoogle Scholar
  26. Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de Mari M, Livrea P (2005) Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients. Mov Disord 20:69–72PubMedCrossRefGoogle Scholar
  27. Lott SA, Burghardt PR, Burghardt KJ, Bly MJ, Grove TB, Ellingrod VL (2013) The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia. Pharmacogenomics J 13:264–271PubMedCentralPubMedCrossRefGoogle Scholar
  28. McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, Meltzer HY, Hsiao J, Scott Stroup T, Lieberman JA (2005) Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 80:19–32PubMedCrossRefGoogle Scholar
  29. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 163:600–610PubMedCrossRefGoogle Scholar
  30. Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M (2013) Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull 39:306–318PubMedCentralPubMedCrossRefGoogle Scholar
  31. Monneret D, Tamisier R, Ducros V, Garrel C, Levy P, Baguet JP, Faure P, Pepin JL (2012) The impact of obstructive sleep apnea on homocysteine and carotid remodeling in metabolic syndrome. Respir Physiol Neurobiol 180:298–304PubMedCrossRefGoogle Scholar
  32. Muller T (2008) Role of homocysteine in the treatment of Parkinson's disease. Expert Rev Neurother 8:957–967PubMedCrossRefGoogle Scholar
  33. Nissinen E, Nissinen H, Larjonmaa H, Vaananen A, Helkamaa T, Reenila I, Rauhala P (2005) The COMT inhibitor, entacapone, reduces levodopa-induced elevations in plasma homocysteine in healthy adult rats. J Neural Transm 112:1213–1221PubMedCrossRefGoogle Scholar
  34. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE (1997) Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337:230–236PubMedCrossRefGoogle Scholar
  35. Ou JJ, Xu Y, Chen HH, Fan X, Gao K, Wang J, Guo XF, Wu RR, Zhao JP (2013) Comparison of metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia. Psychopharmacology (Berl) 225:627–635CrossRefGoogle Scholar
  36. Papaleo F, Erickson L, Liu G, Chen J, Weinberger DR (2012) Effects of sex and COMT genotype on environmentally modulated cognitive control in mice. Proc Natl Acad Sci U S A 109:20160–20165PubMedCentralPubMedCrossRefGoogle Scholar
  37. Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607PubMedCrossRefGoogle Scholar
  38. Ryu S, Oh S, Cho EY, Nam HJ, Yoo JH, Park T, Joo YH, Kwon JS, Hong KS (2011) Interaction between genetic variants of DLGAP3 and SLC1A1 affecting the risk of atypical antipsychotics-induced obsessive-compulsive symptoms. Am J Med Genet Part B Neuropsychiatr Genet 156B:949–959CrossRefGoogle Scholar
  39. Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98PubMedCrossRefGoogle Scholar
  40. Shield AJ, Thomae BA, Eckloff BW, Wieben ED, Weinshilboum RM (2004) Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 9:151–160PubMedCrossRefGoogle Scholar
  41. Tenorio-Laranga J, Mannisto PT, Karayiorgou M, Gogos JA, Garcia-Horsman JA (2009) Sex-dependent compensated oxidative stress in the mouse liver upon deletion of catechol O-methyltransferase. Biochem Pharmacol 77:1541–1552PubMedCrossRefGoogle Scholar
  42. van Winkel R, Rutten BP, Peerbooms O, Peuskens J, van Os J, De Hert M (2010) MTHFR and risk of metabolic syndrome in patients with schizophrenia. Schizophr Res 121:193–198PubMedCrossRefGoogle Scholar
  43. Vaya A, Rivera L, Hernandez-Mijares A, de la Fuente M, Sola E, Romagnoli M, Alis R, Laiz B (2012) Homocysteine levels in morbidly obese patients: its association with waist circumference and insulin resistance. Clin Hemorheol Microcirc 52:49–56PubMedGoogle Scholar
  44. Voutilainen S, Tuomainen TP, Korhonen M, Mursu J, Virtanen JK, Happonen P, Alfthan G, Erlund I, North KE, Mosher MJ, Kauhanen J, Tiihonen J, Kaplan GA, Salonen JT (2007) Functional COMT Val158Met polymorphism, risk of acute coronary events and serum homocysteine: the Kuopio ischaemic heart disease risk factor study. PLoS One 2:e181PubMedCentralPubMedCrossRefGoogle Scholar
  45. Wu RR, Zhao JP, Liu ZN, Zhai JG, Guo XF, Guo WB, Tang JS (2006) Effects of typical and atypical antipsychotics on glucose-insulin homeostasis and lipid metabolism in first-episode schizophrenia. Psychopharmacology (Berl) 186:572–578CrossRefGoogle Scholar
  46. Yan H, Chen JD, Zheng XY (2013) Potential mechanisms of atypical antipsychotic-induced hypertriglyceridemia. Psychopharmacology (Berl) 229:1–7CrossRefGoogle Scholar
  47. Yi ZH, Zhang C, Wu ZG, Hong W, Li ZZ, Fang YR, Yu SY (2011) Lack of effect of brain derived neurotrophic factor (BDNF) Val66Met polymorphism on early onset schizophrenia in Chinese Han population. Brain Res 1417:146–150PubMedCrossRefGoogle Scholar
  48. Zarkesh M, Faam B, Daneshpour MS, Azizi F, Hedayati M (2012) The relationship between metabolic syndrome, cardiometabolic risk factors and inflammatory markers in a Tehranian population: the Tehran lipid and glucose study. Intern Med 51:3329–3335PubMedGoogle Scholar
  49. Zhang JP, Malhotra AK (2011) Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol 7:9–37PubMedCentralPubMedCrossRefGoogle Scholar
  50. Zhang C, Fang YR, Xie B, Cheng WH, Du YS, Wang DX, Yu SY (2010) No genetic association between dopamine D1 receptor gene and [early onset] schizophrenia. Psychiatry Res 177:350–353PubMedCrossRefGoogle Scholar
  51. Zhang C, Li ZZ, Shao Y, Xie B, Du YS, Fang YR, Yu SY (2011) Association study of tryptophan hydroxylase-2 gene in schizophrenia and its clinical features in Chinese Han population. J Mol Neurosci 43:406–411PubMedCrossRefGoogle Scholar
  52. Zhang Y, Chen M, Wu Z, Chen J, Yu S, Fang Y, Zhang C (2013) Association study of Val66Met polymorphism in brain-derived neurotrophic factor gene with clozapine-induced metabolic syndrome: preliminary results. PLoS One 8:e72652PubMedCentralPubMedCrossRefGoogle Scholar
  53. Zhou H, Guo ZR, Yu LG, Hu XS, Xu BH, Liu HB, Wu M, Zhou ZY (2010) Evidence on the applicability of the ATPIII, IDF and CDS metabolic syndrome diagnostic criteria to identify CVD and T2DM in the Chinese population from a 6.3-year cohort study in mid-eastern China. Diabetes Res Clin Pract 90:319–325PubMedCrossRefGoogle Scholar
  54. Zoccolella S, Iliceto G, deMari M, Livrea P, Lamberti P (2007) Management of L-Dopa related hyperhomocysteinemia: catechol-O-methyltransferase (COMT) inhibitors or B vitamins? Results from a review. Clin Chem Lab Med 45:1607–1613PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Schizophrenia Program, Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.Division of Mood Disorders, Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina
  3. 3.Department of Genetics, Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina
  4. 4.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan ProvinceKunming Institute of ZoologyKunmingChina

Personalised recommendations