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High prevalence of prediabetes and metabolic abnormalities in overweight or obese schizophrenia patients treated with clozapine or olanzapine

  • Julie R. Larsen (a1), Camilla K. Svensson (a1), Louise Vedtofte (a2), Mathilde Lund Jakobsen (a1), Hans Søe Jespersen (a1), Michelle I. Jakobsen (a1), Kamuran Koyuncu (a1), Ole Schjerning (a3), Jimmi Nielsen (a3), Claus T. Ekstrøm (a4), Jens J. Holst (a5), Christoph U. Correll (a6) (a7) (a8), Tina Vilsbøll (a2) (a9) (a10) and Anders Fink-Jensen (a1) (a9)...



To assess the prevalence of prediabetes and metabolic abnormalities among overweight or obese clozapine- or olanzapine-treated schizophrenia patients, and to identify characteristics of the schizophrenia group with prediabetes.


A cross-sectional study assessing the presence of prediabetes and metabolic abnormalities in schizophrenia clozapine- or olanzapine-treated patients with a body mass index (BMI) ≥27 kg/m2. Procedures were part of the screening process for a randomized, placebo-controlled trial evaluating liraglutide vs placebo for improving glucose tolerance. For comparison, an age-, sex-, and BMI-matched healthy control group without psychiatric illness and prediabetes was included. Prediabetes was defined as elevated fasting plasma glucose and/or impaired glucose tolerance and/or elevated glycated hemoglobin A1c.


Among 145 schizophrenia patients (age = 42.1 years; males = 59.3%) on clozapine or olanzapine (clozapine/olanzapine/both: 73.8%/24.1%/2.1%), prediabetes was present in 69.7% (101 out of 145). While schizophrenia patients with and without prediabetes did not differ regarding demographic, illness, or antipsychotic treatment variables, metabolic abnormalities (waist circumference: 116.7±13.7 vs 110.1±13.6 cm, P = 0.007; triglycerides: 2.3±1.4 vs 1.6±0.9 mmol/L, P = 0.0004) and metabolic syndrome (76.2% vs 40.9%, P<0.0001) were significantly more pronounced in schizophrenia patients with vs without prediabetes. The age-, sex-, and BMI-matched healthy controls had significantly better glucose tolerance compared to both groups of patients with schizophrenia. The healthy controls also had higher levels of high-density lipoprotein compared to patients with schizophrenia and prediabetes.


Prediabetes and metabolic abnormalities were highly prevalent among the clozapine- and olanzapine-treated patients with schizophrenia, putting these patients at great risk for later type 2 diabetes and cardiovascular disease. These results stress the importance of identifying and adequately treating prediabetes and metabolic abnormalities among clozapine- and olanzapine-treated patients with schizophrenia.


Corresponding author

*Address for correspondence: Anders Fink-Jensen, Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Edel Sauntes Allé 10, DK-2100 Copenhagen O, Denmark. (Email:


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We thank Bente Bennike, Signe Foghsgaard, Susie Brøndum, Britt Marie Droob, Lene Bruus Albæk, and Sonja Snel for their assistance in the trial.

The study is an investigator-university initiated study (IIS), which received the liraglutide and the liraglutide placebo pens from Novo Nordisk A/S together with an unrestricted grant. The study received additional funding from the Capital Region Psychiatry Research Group and the foundation of King Christian X.



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1.Hjorthoj, C, Sturup, AE, McGrath, JJ, Nordentoft, M. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017; 4(4): 295301.
2.Lawrence, D, Hancock, KJ, Kisely, S. The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ. 2013; 346: f2539.
3.Kelly, AC, Sheitman, BB, Hamer, RM, et al. A naturalistic comparison of the long-term metabolic adverse effects of clozapine versus other antipsychotics for patients with psychotic illnesses. J Clin Psychopharmacol. 2014; 34(4): 441445.
4.Henderson, DC, Vincenzi, B, Andrea, NV, Ulloa, M, Copeland, PM. Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry. 2015; 2(5): 452464.
5.De Hert, M, Correll, CU, Bobes, J, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry. 2011; 10(1): 5277.
6.Vancampfort, D, Stubbs, B, Mitchell, AJ, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry. 2015; 14(3): 339347.
7.Ward, M, Druss, B. The epidemiology of diabetes in psychotic disorders. Lancet Psychiatry. 2015; 2(5): 431451.
8.Vancampfort, D, Correll, CU, Galling, B, et al. Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis. World Psychiatry. 2016; 15(2): 166174.
9.Correll, CU, Solmi, M, Veronese, N, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry. 2017; 16(2): 163180.
10.Stubbs, B, Koyanagi, A, Veronese, N, et al. Physical multimorbidity and psychosis: comprehensive cross sectional analysis including 242,952 people across 48 low- and middle-income countries. BMC Med. 2016; 14(1): 189.
11.van Os, J, Kapur, S. Schizophrenia. Lancet 2009; 374(9690): 635645.
12.Leucht, S, Corves, C, Arbter, D, Engel, RR, Li, C, Davis, JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009; 373(9657): 3141.
13.Leucht, S, Cipriani, A, Spineli, L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013; 382(9896): 951962.
14.Correll, CU, Lencz, T, Malhotra, AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011; 17(2): 97107.
15.Kane, J, Honigfeld, G, Singer, J, Meltzer, H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988; 45(9): 789796.
16.Allison, DB, Mentore, JL, Heo, M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999; 156(11): 16861696.
17.De Hert, M, Detraux, J, van Winkel, R, Yu, W, Correll, CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011; 8(2): 114126.
18.Deng, C. Effects of antipsychotic medications on appetite, weight, and insulin resistance. Endocrinol Metab Clin North Am. 2013; 42(3): 545563.
19.Kahn, SE, Cooper, ME, Del, PS. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014; 383(9922): 10681083.
20.Nathan, DM. Diabetes: advances in diagnosis and treatment. JAMA. 2015; 314(10): 10521062.
21.Lebovitz, HE. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes. 2001; 109(Suppl 2): S135S148.
22.Long, MT, Fox, CS. The Framingham Heart Study—67 years of discovery in metabolic disease. Nat Rev Endocrinol. 2016; 12(3): 177183.
23.Grundy, SM, Brewer, HB Jr, Cleeman, JI, Smith, SC Jr, Lenfant, C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004; 109(3): 433438.
24.Reaven, GM, Lieberman, JA, Sethuraman, G, et al. In search of moderators and mediators of hyperglycemia with atypical antipsychotic treatment. J Psychiatr Res. 2009; 43(11): 9971002.
25.Yamamoto, N, Yamanaka, G, Takasugi, E, et al. Lifestyle intervention reversed cognitive function in aged people with diabetes mellitus: two-year follow up. Diabetes Res Clin Pract. 2009; 85(3): 343346.
26.Zhang, Q, Deng, C, Huang, XF. The role of ghrelin signalling in second-generation antipsychotic-induced weight gain. Psychoneuroendocrinology. 2013; 38(11): 24232438.
27.Manu, P, Correll, CU, Wampers, M, et al. Insulin secretion in patients receiving clozapine, olanzapine, quetiapine and risperidone. Schizophr Res. 2013; 143(2–3): 358362.
28.Galling, B, Roldan, A, Nielsen, RE, et al. Type 2 diabetes mellitus in youth exposed to antipsychotics: a systematic review and meta-analysis. JAMA Psychiatry. 2016; 73(3): 247259.
29.Mayfield, K, Siskind, D, Winckel, K, et al. Glucagon-like peptide-1 agonists combating clozapine-associated obesity and diabetes. J Psychopharmacol. 2016; 30(3): 227236.
30.Smith, GC, Chaussade, C, Vickers, M, Jensen, J, Shepherd, PR. Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat. Diabetologia. 2008; 51(12): 23092317.
31.Smith, GC, Zhang, ZY, Mulvey, T, et al. Clozapine directly increases insulin and glucagon secretion from islets: implications for impairment of glucose tolerance. Schizophr Res. 2014; 157(1–3):128133.
32.Smith, GC, Vickers, MH, Shepherd, PR. Olanzapine effects on body composition, food preference, glucose metabolism and insulin sensitivity in the rat. Arch Physiol Biochem. 2011; 117(4): 241249.
33.Holst, JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007; 87(4): 14091439.
34.Larsen, JR, Vedtofte, L, Jakobsen, MSL, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017; 74(7): 719728.
35.Larsen, JR, Vedtofte, L, Holst, JJ, et al. Does a GLP-1 receptor agonist change glucose tolerance in patients treated with antipsychotic medications? Design of a randomised, double-blinded, placebo-controlled clinical trial. BMJ Open. 2014; 4(3): e004227.
36.World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; 1992.
37.American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text revision. Washington, DC: American Psychiatric Association; 2000.
38.Orskov, C, Wettergren, A, Holst, JJ. Biological effects and metabolic rates of glucagon-like peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993; 42(5): 658661.
39.Lindgren, O, Carr, RD, Deacon, CF, et al. Incretin hormone and insulin responses to oral versus intravenous lipid administration in humans. J Clin Endocrinol Metab. 2011; 96(8): 25192524.
40.Wewer Albrechtsen, NJ, Hartmann, B, Veedfald, S, et al. Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels? Diabetologia. 2014; 57(9): 19191926.
41.Wilkinson, G, Hesdon, B, Wild, D, et al. Self-report quality of life measure for people with schizophrenia: the SQLS. Br J Psychiatry. 2000; 177(1): 4246.
42.Busner, J, Targum, SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007; 4(7): 2837.
43.Aas, IH. Global Assessment of Functioning (GAF): properties and frontier of current knowledge. Ann Gen Psychiatry. 2010; 9: 20.
44.Saunders, JB, Aasland, OG, Babor, TF, de la Fuente, JR, Grant, M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption—II. Addiction 1993; 88(6): 791804.
45.Manu, P, Correll, CU, van Winkel, R, Wampers, M, De Hert, M. Prediabetes in patients treated with antipsychotic drugs. J Clin Psychiatry 2012; 73(4): 460466.
46.Correll, CU, Robinson, DG, Schooler, NR, et al. Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA Psychiatry. 2014; 71(12): 13501363.
47.Simon, V, van Winkel, R, De Hert, M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review. J Clin Psychiatry. 2009; 70(7): 10411050.
48.Eckel, RH, Alberti, KG, Grundy, SM, Zimmet, PZ. The metabolic syndrome. Lancet 2010; 375(9710): 181183.
49.Cederberg, H, Stancakova, A, Yaluri, N, Modi, S, Kuusisto, J, Laakso, M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015; 58(5): 11091117.
50.Ohkuma, T, Iwase, M, Fujii, H, et al. Dose- and time-dependent association of smoking and its cessation with glycemic control and insulin resistance in male patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry. PLoS One. 2015; 10(3): e0122023.
51.Manu, P, Tsang, J, Napolitano, BA, Lesser, ML, Correll, CU. Predictors of insulin resistance in the obese with metabolic syndrome. Eur J Intern Med. 2010; 21(5): 409413.
52.Faerch, K, Torekov, SS, Vistisen, D, et al. GLP-1 Response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: The ADDITION-PRO Study. Diabetes. 2015; 64(7): 25132525.
53.Calanna, S, Christensen, M, Holst, JJ, et al. Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia. 2013; 56(5): 965972.
54.Ahren, B, Larsson, H. Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations. Diabetologia. 2001; 44(11): 19982003.
55.Rettenbacher, MA, Baumgartner, S, Eder-Ischia, U, et al. Association between antipsychotic-induced elevation of liver enzymes and weight gain: a prospective study. J Clin Psychopharmacol. 2006; 26(5): 500503.
56.Vernon, G, Baranova, A, Younossi, ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011; 34(3): 274285.
57.Anstee, QM, Targher, G, Day, CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013; 10(6): 330344.
58.Sinclair, A, Dunning, T, Rodriguez-Manas, L. Diabetes in older people: new insights and remaining challenges. Lancet Diabetes Endocrinol. 2015; 3(4): 275285.
59.Cooper, SJ, Reynolds, GP, Barnes, T, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol. 2016; 30(8): 717748.


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High prevalence of prediabetes and metabolic abnormalities in overweight or obese schizophrenia patients treated with clozapine or olanzapine

  • Julie R. Larsen (a1), Camilla K. Svensson (a1), Louise Vedtofte (a2), Mathilde Lund Jakobsen (a1), Hans Søe Jespersen (a1), Michelle I. Jakobsen (a1), Kamuran Koyuncu (a1), Ole Schjerning (a3), Jimmi Nielsen (a3), Claus T. Ekstrøm (a4), Jens J. Holst (a5), Christoph U. Correll (a6) (a7) (a8), Tina Vilsbøll (a2) (a9) (a10) and Anders Fink-Jensen (a1) (a9)...


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