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Pharmacopsychiatry 2013; 46(01): 1-9
DOI: 10.1055/s-0032-1321907
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

The Sex-Dependent Impact of Chronic Clozapine and Haloperidol Treatment on Characteristics of the Metabolic Syndrome in a Rat Model

M. von Wilmsdorff
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
,
M.-L. Bouvier
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
,
U. Henning
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
,
A. Schmitt
2   Department of Psychiatry, University of Göttingen, Göttingen, Germany
3   Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, São Paulo – SP, Brazil
4   Department of Psychiatry, LMU München, München, Germany
,
T. Schneider-Axmann
2   Department of Psychiatry, University of Göttingen, Göttingen, Germany
4   Department of Psychiatry, LMU München, München, Germany
,
W. Gaebel
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
› Author Affiliations
Further Information

Publication History

received 07 February 2012
revised 28 June 2012

accepted 11 July 2012

Publication Date:
22 August 2012 (online)

Also available at
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Abstract

Introduction:

An increased risk for metabolic syndrome has been described for patients with psychotic disorders. Antipsychotic drugs possibly contribute to metabolic changes.

Methods:

Haloperidol or clozapine was orally fed to male and female Sprague Dawley rats for 12 weeks, and body weight gain, food and water intake were measured. The serum levels of fasting glucose, HbA1c, triglycerides, cholesterol, HDL and LDL, insulin, leptin, adiponectin and ghrelin were determined. Gonadal and perirenal fat pads were removed and weighed.

Results:

We found increased body weight in the male clozapine group, but decreased ones in the male haloperidol group. Clozapine-treated male and female animals had higher fasting glucose, adiponectin, leptin, ghrelin, cholesterol, HDL and LDL levels, whereas haloperidol caused increased levels of insulin and decreased values of HbA1c, cholesterol, HDL and LDL.

Conclusion:

Both antipsychotic drugs cause sex-dependent metabolic changes, which are risk factors for the metabolic syndrome, be it hyperinsulinemia under haloperidol treatment or hyperglycemia, hyperleptinemia and hyperlipidemia under clozapine.

Key words

clozapine - haloperidol - metabolic syndrome - sex-dependence
 

  • References

  • 1 Henderson DC. Schizophrenia and comorbid metabolic disorders. J Clin Psychiatry 2005; 66 (Suppl. 06) 11-20
    PubMedGoogle Scholar
  • 2 Sacks FM. Metabolic syndrome: epidemiology and consequences. J Clin Psychiatry 2004; 65 (Suppl. 18) 3-12
    PubMedGoogle Scholar
  • 3 Jones LE, Carney CP. Increased risk for metabolic syndrome in persons seeking care for mental disorders. Ann Clin Psychiatry 2006; 18: 149-155
    CrossrefPubMedGoogle Scholar
  • 4 McEvoy JP, Meyer JM, Goff DC et al. 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 2005; 80: 19-32
    CrossrefPubMedGoogle Scholar
  • 5 Casey DE, Haupt DW, Newcomer JW et al. Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry 2004; 65 (Suppl. 07) 4-18
    CrossrefPubMedGoogle Scholar
  • 6 Guo JJ, Keck Jr PE, Corey-Lisle PK et al. Risk of diabetes mellitus associated with atypical antipsychotic use among patients with bipolar order: A retrospective, population-based, case-control study. J Clin Psychiatry 2006; 67: 1055-1061
    CrossrefPubMedGoogle Scholar
  • 7 Thakore JH, Mann JN, Vlahos I et al. Increased visceral fat distribution in drug-naïve and drug-free patients with schizophrenia. Int J Obesity 2002; 26: 137-141
    CrossrefPubMedGoogle Scholar
  • 8 Ryan MC, Collins P, Thakore JH. Impaired fasting glucose tolerance in first-episode, drug-naïve patients with schizophrenia. Am J Psychiatry 2003; 160: 284-289
    CrossrefPubMedGoogle Scholar
  • 9 Arranz B, Rosel P, Ramirez N et al. Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but not in antipsychotic-naïve first-episode schizophrenia patients. J Clin Psychiatry 2004; 65: 1335-1342
    CrossrefPubMedGoogle Scholar
  • 10 Sengupta S, Parrilla-Escobar MA, Klink R et al. Are metabolic indices different between drug-naïve first-episode psychosis patients and healthy controls?. Schizophr Res 2008; 102: 329-336
    CrossrefPubMedGoogle Scholar
  • 11 Wu MK, Huang CY, Liou YJ et al. Glucose-insulin homeostasis, lipid profiles and GH-IGF-IGFBP axis in clozapine-treated schizophrenic obesity versus non-psychiatric obesity. Int J Obesity 2008; 32: 436-442
    CrossrefPubMedGoogle Scholar
  • 12 Baptista T, La Cruz A, Mendoza S et al. Endocrine and metabolic abnormalities involved in the obesity associated to typical antipsychotic drug administration. Pharmacopsychiatry 2001; 34: 223-231
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Bergman RN, Ader M. Atypical antipsychotics and glucose homeostasis. J Clin Psychiatry 2005; 66: 504-514
    PubMedGoogle Scholar
  • 14 De Hert MA, van Winkel R, van Eyck D et al. Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophr Res 2006; 83: 87-93
    CrossrefPubMedGoogle Scholar
  • 15 Lamberti JS, Olson D, Crilly JF et al. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 2006; 163: 1273-1276
    CrossrefPubMedGoogle Scholar
  • 16 Brixner DI, Said Q, Corey-Lisle PK et al. Naturalistic impact of second-generation antipsychotics on weight gain. Am Pharmacother 2006; 40: 626-632
    PubMedGoogle Scholar
  • 17 Melkersson KI, Dahl ML. Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics of clozapine and olanzapine in patients on treatment with therapeutic doses. Psychopharmacology 2003; 170: 157-166
    CrossrefPubMedGoogle Scholar
  • 18 Henderson DC, Cagiero E, Copeland PM et al. Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry 2005; 62: 19-28
    CrossrefPubMedGoogle Scholar
  • 19 Ascher-Svanum H, Stensland M, Zhao Z et al. Acute weight gain, gender, and therapeutic response to antipsychotics in the treatment of patients with schizophrenia. BMC Psychiatry 2005; 5: 3-16
    CrossrefPubMedGoogle Scholar
  • 20 Wu RR, Zhao JP, Zhai JG et al. Sex difference in effects of typical and atypical antipsychotics on glucose-insulin homeostasis and lipid metabolism in first-episode schizophrenia. J Clin Psychopharmacol 2007; 27: 374-379
    CrossrefPubMedGoogle Scholar
  • 21 Shehata M, Kamel MA. Protective effect of antioxidant adjuvant treatment with hormone replacement therapy against cardiovascular diseases in ovariectomized rats. Endocr Regul 2008; 42: 69-75
    PubMedGoogle Scholar
  • 22 Demissie M, Lazic M, Foecking EM et al. Transient prenatal androgen exposure produces metabolic syndrome in adult female rats. Am J Physiol Endocrinol Metab 2008; 295: E262-E268
    CrossrefPubMedGoogle Scholar
  • 23 Pouzet B, Mow T, Kreilgaard M et al. Chronic treatment with antipsychotics in rats as a model for antipsychotic-induced weight gain in human. Pharmacol Biochem Behav 2003; 75: 133-140
    CrossrefPubMedGoogle Scholar
  • 24 Cooper GD, Harrold JA, Halford JCG et al. Chronic clozapine treatment in female rats does not induce weight gain or metabolic abnormalities but enhances adiposity: Implications for animal models of antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 428-436
    CrossrefPubMedGoogle Scholar
  • 25 Choi S, Disilvio B, Unangst J et al. Effect of chronic infusion of alanzapine and clozapine on food intake and body weight gain in male and female rats. Life Sci 2007; 81: 1024-1030
    CrossrefPubMedGoogle Scholar
  • 26 Wiley JL. Antipsychotic-induced suppression of locomotion in juvenile, adolescent and adult rats. Eur J Pharmacol 2008; 578: 216-221
    CrossrefPubMedGoogle Scholar
  • 27 Baptista T, Parada M, Hernandez L. Long term administration of some antipsychotic drugs increases body weight and feeding in rats. Are D2 dopamine receptors involved?. Pharmacol Biochem Behav 1987; 27: 399-405
    CrossrefPubMedGoogle Scholar
  • 28 Baptista T, de Baptista EA, Ying Kin NMK et al. Comparative effects of the antipsychotics sulpiride or risperidone in rats I. bodyweight, food intake, body composition, hormones and glucose tolerance. Brain Res 2002; 957: 144-151
    CrossrefPubMedGoogle Scholar
  • 29 Wilmsdorff M, Bouvier ML, Henning U et al. The impact of antipsychotic drugs on food intake and body weight and on leptin levels in blood and hypothalamic ob-r leptin receptor expression in wistar rats. Clinics 2010; 65: 1-10
    CrossrefPubMedGoogle Scholar
  • 30 Mercer JG, Archer ZA. Diet-induced obesity in the Sprague-Dawley rat: dietary manipulations and their effect on hypothalamic neuropeptide energy balance systems. Biochem Soc Trans 2005; 33: 1068-1072
    CrossrefPubMedGoogle Scholar
  • 31 Assié MB, Carilla-Durand E, Bardin L et al. The antipsychotics clozapine and olanzapine increase plasma glucose and corticosterone levels in rats: comparison with aripiprazole, ziprasidone, bifeprunox and F15063. Eur J Pharmacol 2008; 592: 160-166
    CrossrefPubMedGoogle Scholar
  • 32 Tulipano G, Rizzetti C, Bianchi I et al. Clozapine-induced alteration of glucose homeostasis in the rat: contribution of hypothalamic-pituitary-adrenal axis activation. Neuroendocrinology 2007; 85: 61-70
    CrossrefPubMedGoogle Scholar
  • 33 Minet-Ringuet J, Even PC, Goubern M et al. Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermic alteration. Appetite 2006; 46: 254-262
    CrossrefPubMedGoogle Scholar
  • 34 Minet-Ringuet J, Even PC, Lacroix M et al. A model for antipsychotic-induced obesity in the male rat. Psychopharmacology 2006; 187: 447-454
    CrossrefPubMedGoogle Scholar
  • 35 Boyda HN, Tse L, Procyshyn RM et al. Preclinical models of antipsychotic drug-induced metabolic side effects. Trends Pharmacol Sci 2010; 31: 484-497
    CrossrefPubMedGoogle Scholar
  • 36 Wiley JL, Evans RL. Evaluation of age and sex differences in locomotion and catalepsy during repeated administration of haloperidol and clozapine in adolescent and adult rats. Pharmacol Res 2008; 58: 240-246
    CrossrefPubMedGoogle Scholar
  • 37 Lemieux H, Blier P, Dutil JD. Do digestive enzymes set a physiological limit on growth rate and food conversion efficiency in the Atlantic cod (Gadus morhua)?. Fish Physiol Biochem 1999; 20: 293-303
    CrossrefPubMedGoogle Scholar
  • 38 Kapur S, Wadenberg ML, Remington G. Are animal studies of antipsychotics appropriately dosed? Lessons from the bedside to the bench. Can J Psychiatry 2000; 45: 241-246
    PubMedGoogle Scholar
  • 39 Perez-Costas E, Guidetti P, Melendez-Ferro M et al Neuroleptics and animal models: Feasibility of oral treatment monitored by plasma levels and receptor occupancy assays. J Neural Transm 2008; 115: 745-753
    CrossrefPubMedGoogle Scholar
  • 40 Remington G, Mann S, McCormick P et al. Modeling chronic olanzapine exposure using osmotic minipumps: pharmacological limitations. Pharmacol Biochem Behav 2011; 100: 86-89
    CrossrefPubMedGoogle Scholar
  • 41 Lightfoot JT. Sex hormones regulation of rodent physical activity: a review. Int J Biol Sci 2008; 4: 126-132
    PubMedGoogle Scholar
  • 42 Kühn ER, Bellon K, Huybrechts L et al Endocrine differences between the Wistar and Sprague Dawley laboratory rat: influence of cold adaption. Horm Metabol Res 1983; 15: 491-498
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Cacho J, Sevillano J, de Castro J et al. Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague Dawley rats. Am J Physiol Endocrinol Metab 2008; 295: E1269-E1276
    CrossrefPubMedGoogle Scholar
  • 44 Chovan JP, Yu E, Ring SC. Metabolic differences between Sprague Dawley and Wistar Han male rats. ISSX Poster and oral presentations 2007
    PubMedGoogle Scholar
  • 45 Gao X, Zhao A, Zhou M et al. GC/MS-based urinary metabolomics reveals systematic differences in metabolism and ethanol response between Sprague-Dawley and Wistar rats. Metabolomics 2011; 7: 363-374
    CrossrefPubMedGoogle Scholar
  • 46 Jassim G, Skrede S, Vázques MJ et al. Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat. Psychopharmacology 2012; 219: 783-794
    CrossrefPubMedGoogle Scholar
  • 47 Sertié AL, Suzuki AM, Sertié RAL et al. Effects of antipsychotics with different weight gain liabilities on human in vitro models of adipose tissue differentiation and metabolism. Prog Neuro-Psychopharmacol Biol Psychiatry 2011; 35: 1884-1890
    CrossrefPubMedGoogle Scholar
  • 48 Newcomer JW, Haupt DW, Fucetola R et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 2002; 59: 337-345
    CrossrefPubMedGoogle Scholar
  • 49 Jang I, Hwang D, Lee J et al. Physiological difference between dietary obesity-susceptible and obesity-resistant Sprague Dawley rats in response to moderate high fat diet. Exp Anim 2003; 52: 99-107
    CrossrefPubMedGoogle Scholar
  • 50 Leibowitz KL, Chang GQ, Pamy PS et al. Weight gain model in prepupertal rats: prediction and phenotyping of obesity-prone animals at normal body weight. Int J Obesity 2007; 31: 1210-1221
    CrossrefPubMedGoogle Scholar
  • 51 Yang SJ, Denbow DM. Interaction of leptin and nitric oxide on food intake in broilers and Leghorns. Physiol Behav 2007; 92: 651-657
    CrossrefPubMedGoogle Scholar
  • 52 Calapai G, Caputi AP. Nitric oxide and drinking behavior. Regul Pept 1996; 66: 117-121
    CrossrefPubMedGoogle Scholar
  • 53 Murashita M, Kusumi I, Hosoda H et al. Acute administration of clozapine concurrently increases blood glucose and circulating plasma ghrelin levels in rats. Psychoneuroendocrinology 2007; 32: 777-784
    CrossrefPubMedGoogle Scholar
  • 54 Esen-Danaci A, Sarandöl A, Taneli F et al. Effects of second generation antipsychotics on leptin and ghrelin. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1434-1438
    CrossrefPubMedGoogle Scholar
  • 55 Giovambattista A, Piermaria J, Suescun MO et al. Direct effect of ghrelin on leptin production by cultured rat white adipocytes. Obesity 2006; 14: 19-38
    CrossrefPubMedGoogle Scholar
  • 56 Hanssens L, van Winkel R, Wampers M et al. A cross-sectional evaluation of adiponectin plasma levels in patients with schizophrenia and schizoaffective disorder. Schizophr Res 2008; 106: 308-314
    CrossrefPubMedGoogle Scholar
  • 57 Hägg S, Söderberg S, Ahrén B et al. Leptin concentrations are increased in subjects treated with clozapine or conventional antipsychotics. J Clin Psychiatry 2001; 62: 843-848
    CrossrefPubMedGoogle Scholar
  • 58 Emsley R, Turner JH, Schronen J et al. Effects of quetiapine and haloperidol on body mass index and glycaemic control: a long-term, randomized, controlled trial. Int J Neuropsychopharmacol 2005; 8: 175-182
    CrossrefPubMedGoogle Scholar
  • 59 Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol Clin Exp 2008; 23: 27-41
    CrossrefPubMedGoogle Scholar
  • 60 Chae BJ, Kang BJ. The effect of clozapine on blood glucose metabolism. Hum Psychopharmacol 2001; 16: 265-271
    CrossrefPubMedGoogle Scholar
  • 61 Smith GC, Chaussade C, Vickers M et al. Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat. Diabetologica 2008; 51: 2309-2317
    CrossrefPubMedGoogle Scholar
  • 62 Best L, Yates AP, Reynolds GP. Actions of antipsychotic drugs on pancreatic β-cell function: contrasting effects of clozapine and haloperidol. J Psychopharmacol 2005; 19: 597-601
    CrossrefPubMedGoogle Scholar
  • 63 Lindenmayer JP, Czobor P, Volavka J et al. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry 2003; 160: 290-296
    CrossrefPubMedGoogle Scholar
  • 64 Kimura F, Natsusaka J, Endo Y et al. Effect of dose of fat and fat content of the maintenance diet on postprandial serum triglyceride in rats. J Oleo Science 2004; 53: 515-520
    PubMedGoogle Scholar
  • 65 Stairs DJ, Prendergast MA, Bardo MT. Environmental-induced differences in corticosterone and glucocorticoid receptor blockade of amphetamine self-administration in rats. Psychopharmacology 2011; 218: 293-301
    CrossrefPubMedGoogle Scholar
  • 66 Zhuravliova E, Barbakadze T, Zaalishvili E et al Social isolation in rats inhibits oxidative metabolism, decreases the content of mitochondrial K-Ras and activates mitochondrial hexokinase. Behav Brain Res 2009; 205: 377-383
    CrossrefPubMedGoogle Scholar
  • 67 Munetsuna E, Hattori M, Komatsu S et al. Social isolation stimulates hippocampal estradiol synthesis. Biochem Biophys Res Commun 2009; 379: 480-484
    CrossrefPubMedGoogle Scholar
  • 68 Héliès JM, Diane A, Langlois A et al. Comparison of fat storage between Fischer 344 and obesity-resistant Lou/C rats fed different diets. Obesity Res 2005; 13: 3-10
    CrossrefPubMedGoogle Scholar
  • 69 Wu B, Du Y, Liu C et al. Effect of repeated fasting/reffeding on body weight weight control and energy balance regulation in rats. Wei Sheng Yan Jiu 2010; 39: 601-605
    PubMedGoogle Scholar
  • 70 Ghibaudi L, Cook J, Farley C et al. Fat intake affects adiposity, comorbidity factors, and energy metabolism of Sprague Dawley rats. Obesity Res 2002; 10: 956-963
    CrossrefPubMedGoogle Scholar
  • 71 Eckel LA, Houpt TA, Geary N. Spontaneous meal patterns in female rats with and without access to running wheels. Physiol Behav 2000; 70: 397-405
    CrossrefPubMedGoogle Scholar