Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-23T08:10:55.511Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  31 December 2018

Julie R. Larsen Open the ORCID record for Julie R. Larsen [Opens in a new window] ,
Camilla K. Svensson ,
Louise Vedtofte ,
Mathilde Lund Jakobsen ,
Hans Søe Jespersen ,
Michelle I. Jakobsen ,
Kamuran Koyuncu ,
Ole Schjerning ,
Jimmi Nielsen  and
Claus T. Ekstrøm
...Show all authors
Julie R. Larsen
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Camilla K. Svensson
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Louise Vedtofte
Affiliation:
Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
Mathilde Lund Jakobsen
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Hans Søe Jespersen
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Michelle I. Jakobsen
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Kamuran Koyuncu
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Ole Schjerning
Affiliation:
Psychiatry, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
Jimmi Nielsen
Affiliation:
Psychiatry, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
Claus T. Ekstrøm
Affiliation:
Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
Jens J. Holst
Affiliation:
NNF Center for Basic Metabolic Research, and Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
Christoph U. Correll
Affiliation:
Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, USA Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA Charité Universitätsmedizin, Department of Child and Adolescent Psychiatry, Berlin, Germany
Tina Vilsbøll
Affiliation:
Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences; University of Copenhagen, Copenhagen, Denmark Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
Anders Fink-Jensen*
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences; University of Copenhagen, Copenhagen, Denmark
*
*Address for correspondence: Anders Fink-Jensen, Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, Edel Sauntes Allé 10, DK-2100 Copenhagen O, Denmark. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Antipsychoticglucose metabolismmetabolic syndromeprediabetesschizophrenia
Type
Original Research
Information
CNS Spectrums , Volume 24 , Issue 4 , August 2019 , pp. 441 - 452
Copyright
© Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

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.

References

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): 295–301.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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): 441–445.CrossRefGoogle ScholarPubMed
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): 452–464.CrossRefGoogle ScholarPubMed
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): 52–77.CrossRefGoogle ScholarPubMed
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): 339–347.CrossRefGoogle ScholarPubMed
Ward, M, Druss, B. The epidemiology of diabetes in psychotic disorders. Lancet Psychiatry. 2015; 2(5): 431–451.CrossRefGoogle ScholarPubMed
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): 166–174.CrossRefGoogle ScholarPubMed
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): 163–180.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
van Os, J, Kapur, S. Schizophrenia. Lancet 2009; 374(9690): 635–645.CrossRefGoogle ScholarPubMed
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): 31–41.CrossRefGoogle ScholarPubMed
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): 951–962.CrossRefGoogle ScholarPubMed
Correll, CU, Lencz, T, Malhotra, AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011; 17(2): 97–107.CrossRefGoogle ScholarPubMed
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): 789–796.CrossRefGoogle ScholarPubMed
Allison, DB, Mentore, JL, Heo, M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999; 156(11): 1686–1696.Google ScholarPubMed
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): 114–126.CrossRefGoogle ScholarPubMed
Deng, C. Effects of antipsychotic medications on appetite, weight, and insulin resistance. Endocrinol Metab Clin North Am. 2013; 42(3): 545–563.CrossRefGoogle ScholarPubMed
Kahn, SE, Cooper, ME, Del, PS. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014; 383(9922): 1068–1083.CrossRefGoogle ScholarPubMed
Nathan, DM. Diabetes: advances in diagnosis and treatment. JAMA. 2015; 314(10): 1052–1062.CrossRefGoogle ScholarPubMed
Lebovitz, HE. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes. 2001; 109(Suppl 2): S135–S148.CrossRefGoogle ScholarPubMed
Long, MT, Fox, CS. The Framingham Heart Study—67 years of discovery in metabolic disease. Nat Rev Endocrinol. 2016; 12(3): 177–183.CrossRefGoogle ScholarPubMed
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): 433–438.CrossRefGoogle ScholarPubMed
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): 997–1002.CrossRefGoogle ScholarPubMed
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): 343–346.CrossRefGoogle ScholarPubMed
Zhang, Q, Deng, C, Huang, XF. The role of ghrelin signalling in second-generation antipsychotic-induced weight gain. Psychoneuroendocrinology. 2013; 38(11): 2423–2438.CrossRefGoogle ScholarPubMed
Manu, P, Correll, CU, Wampers, M, et al. Insulin secretion in patients receiving clozapine, olanzapine, quetiapine and risperidone. Schizophr Res. 2013; 143(2–3): 358–362.CrossRefGoogle ScholarPubMed
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): 247–259.CrossRefGoogle ScholarPubMed
Mayfield, K, Siskind, D, Winckel, K, et al. Glucagon-like peptide-1 agonists combating clozapine-associated obesity and diabetes. J Psychopharmacol. 2016; 30(3): 227–236.CrossRefGoogle ScholarPubMed
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): 2309–2317.CrossRefGoogle ScholarPubMed
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):128–133.CrossRefGoogle ScholarPubMed
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): 241–249.CrossRefGoogle ScholarPubMed
Holst, JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007; 87(4): 1409–1439.CrossRefGoogle ScholarPubMed
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): 719–728.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; 1992.Google Scholar
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text revision. Washington, DC: American Psychiatric Association; 2000.Google Scholar
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): 658–661.CrossRefGoogle ScholarPubMed
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): 2519–2524.CrossRefGoogle ScholarPubMed
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): 1919–1926.CrossRefGoogle ScholarPubMed
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): 42–46.CrossRefGoogle ScholarPubMed
Busner, J, Targum, SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007; 4(7): 28–37.Google ScholarPubMed
Aas, IH. Global Assessment of Functioning (GAF): properties and frontier of current knowledge. Ann Gen Psychiatry. 2010; 9: 20.CrossRefGoogle ScholarPubMed
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): 791–804.CrossRefGoogle Scholar
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): 460–466.CrossRefGoogle ScholarPubMed
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): 1350–1363.CrossRefGoogle ScholarPubMed
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): 1041–1050.CrossRefGoogle ScholarPubMed
Eckel, RH, Alberti, KG, Grundy, SM, Zimmet, PZ. The metabolic syndrome. Lancet 2010; 375(9710): 181–183.CrossRefGoogle ScholarPubMed
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): 1109–1117.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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): 409–413.CrossRefGoogle ScholarPubMed
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): 2513–2525.CrossRefGoogle ScholarPubMed
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): 965–972.CrossRefGoogle ScholarPubMed
Ahren, B, Larsson, H. Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations. Diabetologia. 2001; 44(11): 1998–2003.CrossRefGoogle ScholarPubMed
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): 500–503.CrossRefGoogle ScholarPubMed
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): 274–285.CrossRefGoogle ScholarPubMed
Anstee, QM, Targher, G, Day, CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013; 10(6): 330–344.CrossRefGoogle ScholarPubMed
Sinclair, A, Dunning, T, Rodriguez-Manas, L. Diabetes in older people: new insights and remaining challenges. Lancet Diabetes Endocrinol. 2015; 3(4): 275–285.CrossRefGoogle ScholarPubMed
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): 717–748.CrossRefGoogle ScholarPubMed
Supplementary material: File

Larsen et al. supplementary material

Figures S1-S2

Download Larsen et al. supplementary material(File)
File 56.5 KB