Abstract
Rationale
Increased levels of alanine aminotransferase (ALT) are a biomarker for metabolic syndrome (MetS), but this relationship remains unproven in patients with schizophrenia.
Objective
We assessed the relationship between aminotransferase levels and MetS in patients with schizophrenia.
Method
This pooled analysis from two open-label prospective studies included 342 patients with schizophrenia who did not meet criteria for MetS at baseline. The development of MetS was assessed at weeks 12 and 24.
Results
MetS developed in 19.1 % of patients during the 24-week follow-up period. ALT levels were significantly associated with incident MetS: for each sex-specific standard deviation increase in log ALT, the odds ratio (OR) of MetS was 1.357 (p = .006) after adjusting for age, sex, duration of illness, smoking, and previous use of antipsychotics. This result remained significant after adjusting for interim weight changes. Compared with patients in the lowest quartile, the OR of MetS in those in the highest quartile within the normal range of ALT levels was 4.276 (p = .024). However, this association was significant only in male patients. Using a cutoff value of 23.0 U/L, sensitivity and specificity were 70.6 and 68.3 %, respectively, in male patients whose ALT levels were in the normal range.
Conclusions
A prospective association between ALT levels and MetS highlights the value of ALT levels, even mild ALT elevations within the normal range, as a predictor of the MetS risk in male patients. Baseline liver function tests and monitoring should be obtained during antipsychotic treatment to identify the risk for MetS.
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References
Ader M, Kim SP, Catalano KJ, Ionut V, Hucking K, Richey JM, Kabir M, Bergman RN (2005) Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes 54:862–871
Bobes J, Arango C, Garcia-Garcia M, Rejas J (2010) Healthy lifestyle habits and 10-year cardiovascular risk in schizophrenia spectrum disorders: an analysis of the impact of smoking tobacco in the CLAMORS schizophrenia cohort. Schizophr Res 119:101–109
Boden R, Haenni A, Lindstrom L, Sundstrom J (2009) Biochemical risk factors for development of obesity in first-episode schizophrenia. Schizophr Res 115:141–145
Bonnet F, Ducluzeau PH, Gastaldelli A, Laville M, Anderwald CH, Konrad T, Mari A, Balkau B, Group RS (2011) Liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women. Diabetes 60:1660–1667
Capasso RM, Lineberry TW, Bostwick JM, Decker PA, St Sauver J (2008) Mortality in schizophrenia and schizoaffective disorder: an Olmsted County, Minnesota cohort: 1950–2005. Schizophr Res 98:287–294
Cohen D, De Hert M (2011) Endogenic and iatrogenic diabetes mellitus in drug-naive schizophrenia: the role of olanzapine and its place in the psychopharmacological treatment algorithm. Neuropsychopharmacology 36:2368–2369
De Hert M, Correll CU, Bobes J, Cetkovich-Bakmas M, Cohen D, Asai I, Detraux J, Gautam S, Moller HJ, Ndetei DM, Newcomer JW, Uwakwe R, Leucht S (2011) Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 10:52–77
De Hert M, Detraux J, van Winkel R, Yu W, Correll CU (2012) Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 8:114–126
Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44:865–873
Fleischhacker WW, Cetkovich-Bakmas M, De Hert M, Hennekens CH, Lambert M, Leucht S, Maj M, McIntyre RS, Naber D, Newcomer JW, Olfson M, Osby U, Sartorius N, Lieberman JA (2008) Comorbid somatic illnesses in patients with severe mental disorders: clinical, policy, and research challenges. J Clin Psychiatry 69:514–519
Fluss R, Faraggi D, Reiser B (2005) Estimation of the Youden index and its associated cutoff point. Biom J 47:458–472
Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM (2007) Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 49:403–414
Goessling W, Massaro JM, Vasan RS, D’Agostino RB Sr, Ellison RC, Fox CS (2008) Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 135:1935–1944
Hanley AJ, Williams K, Festa A, Wagenknecht LE, D’Agostino RB Jr, Haffner SM (2005) Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes 54:3140–3147
Hou XH, Zhu YX, Lu HJ, Chen HF, Li Q, Jiang S, Xiang KS, Jia WP (2011) Non-alcoholic fatty liver disease’s prevalence and impact on alanine aminotransferase associated with metabolic syndrome in the Chinese. J Gastroenterol Hepatol 26:722–730
Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H (2007) Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology 32:289–297
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) 230:3–13
Huang MC, Lu ML, Tsai CJ, Chen PY, Chiu CC, Jian DL, Lin KM, Chen CH (2009) Prevalence of metabolic syndrome among patients with schizophrenia or schizoaffective disorder in Taiwan. Acta Psychiatr Scand 120:274–280
Kew MC (2000) Serum aminotransferase concentration as evidence of hepatocellular damage. Lancet 355:591–592
Kim SW, Yoon JS, Kim YS, Ahn YM, Kim CE, Go HJ, Chee IS, Jung SW, Chung YC, Kim YD, Joe S, Lee J, Kwon YJ, Yoon BH, Jae YM (2012) The effect of paliperidone extended release on subjective well-being and responses in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 38:228–235
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716
Lee NY, Roh MS, Kim SH, Jung DC, Yu HY, Sung KH, Chung IW, Youn T, Kang UG, Ahn YM, Kim YS (2013) The prevalence of metabolic syndrome and its association with alanine aminotransferase in clozapine-treated Korean patients with schizophrenia. Int Clin Psychopharmacol 28:71–79
Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N (2001) Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850
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 80:19–32
Meyer JM, Stahl SM (2009) The metabolic syndrome and schizophrenia. Acta Psychiatr Scand 119:4–14
Mitchell AJ, Delaffon V, Vancampfort D, Correll CU, De Hert M (2012) Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices. Psychol Med 42:125–147
Mitchell AJ, Vancampfort D, De Herdt A, Yu W, De Hert M (2013a) Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizophr Bull 39:295–305
Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M (2013b) Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull 39:306–318
Morrato EH, Newcomer JW, Allen RR, Valuck RJ (2008) Prevalence of baseline serum glucose and lipid testing in users of second-generation antipsychotic drugs: a retrospective, population-based study of Medicaid claims data. J Clin Psychiatry 69:316–322
Morrato EH, Druss B, Hartung DM, Valuck RJ, Allen R, Campagna E, Newcomer JW (2010) Metabolic testing rates in 3 state Medicaid programs after FDA warnings and ADA/APA recommendations for second-generation antipsychotic drugs. Arch Gen Psychiatry 67:17–24
Na KS, Kim CE, Kim YS, Lee JI, Han WS, Kang UG, Park DH, Kim B, Jung HY, Yoon JS, Lim SW (2013) Effectiveness of paliperidone extended-release for patients with schizophrenia: focus on subjective improvement. Hum Psychopharmacol 28:107–116
Newcomer JW, Haupt DW, Fucetola R, Melson AK, Schweiger JA, Cooper BP, Selke G (2002) Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 59:337–345
Pan JJ, Qu HQ, Rentfro A, McCormick JB, Fisher-Hoch SP, Fallon MB (2011) Prevalence of metabolic syndrome and risks of abnormal serum alanine aminotransferase in Hispanics: a population-based study. PLoS One 6:e21515
Pramyothin P, Khaodhiar L (2010) Metabolic syndrome with the atypical antipsychotics. Curr Opin Endocrinol Diabetes Obes 17:460–466
Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607
Saha S, Chant D, McGrath J (2007) A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry 64:1123–1131
Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, Diamant M (2007) Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 191:391–396
Schneider AL, Lazo M, Ndumele CE, Pankow JS, Coresh J, Clark JM, Selvin E (2013) Liver enzymes, race, gender and diabetes risk: the Atherosclerosis Risk in Communities (ARIC) Study. Diabet Med 30:926–933
Steinvil A, Shapira I, Ben-Bassat OK, Cohen M, Vered Y, Berliner S, Rogowski O (2010) The association of higher levels of within-normal-limits liver enzymes and the prevalence of the metabolic syndrome. Cardiovasc Diabetol 9:30
Strassnig M, Brar JS, Ganguli R (2003) Nutritional assessment of patients with schizophrenia: a preliminary study. Schizophr Bull 29:393–397
Suppes T, McElroy SL, Hirschfeld R (2007) Awareness of metabolic concerns and perceived impact of pharmacotherapy in patients with bipolar disorder: a survey of 500 US psychiatrists. Psychopharmacol Bull 40:22–37
van Nimwegen LJ, Storosum JG, Blumer RM, Allick G, Venema HW, de Haan L, Becker H, van Amelsvoort T, Ackermans MT, Fliers E, Serlie MJ, Sauerwein HP (2008) Hepatic insulin resistance in antipsychotic naive schizophrenic patients: stable isotope studies of glucose metabolism. J Clin Endocrinol Metab 93:572–577
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 121:193–198
Vancampfort D, Sweers K, Probst M, Maurissen K, Knapen J, Minguet P, De Hert M (2011) Association of the metabolic syndrome with physical activity performance in patients with schizophrenia. Diabetes Metab 37:318–323
Acknowledgments
The original two study included in this pooled analysis was supported by a grant from Janssen Korea Co. Ltd. However, Janssen Korea had no involvement in the design of this analysis or interpretation of the data, writing of the report, or the decision to submit the paper for publication.
Conflict of interest
Dr. Yong Min Ahn received research grants and served as a lecturer for AstraZeneca, GlaxoSmithKline, Janssen, Lilly, Lundbeck, Otsuka, Pfizer, and Servier. Dr Jin Sang Yoon has received grant supports from Janssen, Lundbeck, and Otsuka and served as a lecturer for Janssen, Lundbeck, Otsuka, Pfizer, and GlaxoSmithKline. Dr Yong Sik Kim has received grants, research support, and/or honoraria from Novartis, Janssen, Eli Lilly, Pfizer, Sanofi-Aventis, Otsuka, AstraZeneca, Organon, GlaxoSmithKline, and Servier. All other authors have no conflicts of interest.
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Kim, E.Y., Kim, S.H., Lee, N.Y. et al. Aminotransferase levels as a prospective predictor for the development of metabolic syndrome in patients with schizophrenia. Psychopharmacology 231, 4479–4487 (2014). https://doi.org/10.1007/s00213-014-3601-7
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DOI: https://doi.org/10.1007/s00213-014-3601-7