Abstract
Rationale
The antipsychotic drug, olanzapine, often induces weight gain and glucose metabolism disturbances, which may result from feeding pattern abnormalities.
Objectives
The objectives of the study were to examine the effects of a chronic olanzapine treatment on feeding patterns in the rat and to investigate a potential time-related association between feeding patterns and the appearance of glucose metabolism abnormalities and adiposity.
Methods
Male rats were treated with olanzapine (2 mg/kg/day), haloperidol (1 mg/kg/day) or a control solution (drugs mixed with the food). In experiment 1, treatments lasted 26 days and feeding patterns were measured on day 21. In experiment 2, treatments lasted for 46 days, and an oral glucose tolerance test (OGTT) was realised on day 31. At the end of both experiments, plasma parameters and body composition were analysed.
Results
In experiment 1, olanzapine-treated animals showed increased meal number, decreased ingestion rate, meal size and inter-meal interval, and no change in total food intake. Plasma glucose, OGTT and body composition were not altered. In experiment 2, after 31 days of treatment, fasting blood glucose was increased and OGTT indicated an insulin resistance. After 46 days of treatment, hyperglycaemia was aggravated (compared to 31 days), and adiposity was increased in olanzapine-treated animals. In both experiments, the haloperidol-treated rats did not differ from the control ones.
Conclusion
Chronic olanzapine treatment produces changes in feeding patterns, in a way consistent with an increased incentive drive to eat. As a whole, the results raise the hypothesis that long-term alteration of feeding pattern by olanzapine may predispose to disturbances in the regulation of energy metabolism.
Similar content being viewed by others
References
Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B, Lynch CJ (2006) Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring) 14:36–51
Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686–1696
American Diabetes Association, American Psychiatric Association (2004) Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 27:596–601
Arjona AA, Zhang SX, Adamson B, Wurtman RJ (2004) An animal model of antipsychotic-induced weight gain. Behav Brain Res 152:121–127
Baptista T (1999) Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand 100:3–16
Baptista T, de Baptista EA, Lalonde J, Plamondon J, Kin NM, Beaulieu S, Joober R, Richard D (2004) Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection. Prog Neuropsychopharmacol Biol Psychiatry 28:1305–1311
Bellisle F, McDevitt R, Prentice AM (1997) Meal frequency and energy balance. Br J Nutr 77(Suppl 1):S57–S70
Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale W, Sawchenko PE (1992) The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J Comp Neurol 319:218–245
Burstein M, Morlin R (1970) Precipitation of serum lipoproteins by anionic detergents in the presence of bivalent cations. Rev Eur Etud Clin Biol 15:109–113
Bushe CJ, Leonard BE (2007) Blood glucose and schizophrenia: a systematic review of prospective randomized clinical trials. J Clin Psychiatry 68:1682–1690
Chagnon YC, Merette C, Bouchard RH, Emond C, Roy MA, Maziade M (2004) A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses. Mol Psychiatry 9:1067–1074
Chagnon YC, Bureau A, Gendron D, Bouchard RH, Merette C, Roy MA, Maziade M (2007) Possible association of the pro-melanin-concentrating hormone gene with a greater body mass index as a side effect of the antipsychotic olanzapine. Am J Med Genet B Neuropsychiatr Genet 144B:1063–1069
Clifton PG, Rusk IN, Cooper SJ (1991) Effects of dopamine D1 and dopamine D2 antagonists on the free feeding and drinking patterns of rats. Behav Neurosci 105:272–281
Cooper GD, Pickavance LC, Wilding JP, Halford JC, Goudie AJ (2005) A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology (Berl) 181:80–89
Cooper GD, Pickavance LC, Wilding JP, Harrold JA, Halford JC, Goudie AJ (2007) Effects of olanzapine in male rats: enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities. J Psychopharmacol 21:405–413
Cooper GD, Harrold JA, Halford JC, Goudie AJ (2008) 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 32:428–436
Cooper G, Goudie A, Halford J (2009) Acute effects of olanzapine on behavioural expression including the behavioural satiety sequence in female rats. J Psychopharmacol (in press). doi:10.1177/0269881109102543
Davoodi N, Kalinichev M, Korneev SA, Clifton PG (2009) Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine. Psychopharmacology (Berl) 203:693–702
Dunlop BW, Sternberg M, Phillips LS, Andersen J, Duncan E (2003) Disturbed glucose metabolism among patients taking olanzapine and typical antipsychotics. Psychopharmacol Bull 37:99–117
Fell MJ, Anjum N, Dickinson K, Marshall KM, Peltola LM, Vickers S, Cheetham S, Neill JC (2007) The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats. Psychopharmacology (Berl) 194:221–231
Feurte S, Tome D, Gietzen DW, Even PC, Nicolaidis S, Fromentin G (2002) Feeding patterns and meal microstructure during development of a taste aversion to a threonine devoid diet. Nutr Neurosci 5:269–278
Fossati P, Prencipe L (1982) Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 28:2077–2080
Gebhardt S, Haberhausen M, Krieg JC, Remschmidt H, Heinzel-Gutenbrunner M, Hebebrand J, Theisen FM (2007) Clozapine/olanzapine-induced recurrence or deterioration of binge eating-related eating disorders. J Neural Transm 114:1091–1095
Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, Marsh DJ, Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ (2005) The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci 25:2933–2940
Gothelf D, Falk B, Singer P, Kairi M, Phillip M, Zigel L, Poraz I, Frishman S, Constantini N, Zalsman G, Weizman A, Apter A (2002) Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic in patients treated with olanzapine. Am J Psychiatry 159:1055–1057
Goudie AJ, Cooper GD, Halford JC (2005) Antipsychotic-induced weight gain. Diabetes Obes Metab 7:478–487
Hartfield AW, Moore NA, Clifton PG (2003) Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat. Psychopharmacology (Berl) 167:115–122
Henderson DC, Doraiswamy PM (2008) Prolactin-related and metabolic adverse effects of atypical antipsychotic agents. J Clin Psychiatry 69(Suppl 1):32–44
Kalinichev M, Rourke C, Daniels AJ, Grizzle MK, Britt CS, Ignar DM, Jones DN (2005) Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olanzapine on body weight and prolactin secretion in female rats. Psychopharmacology (Berl) 182:220–231
Kelly DL, Conley RR, Love RC, Morrison JA, McMahon RP (2008) Metabolic risk with second-generation antipsychotic treatment: a double-blind randomized 8-week trial of risperidone and olanzapine. Ann Clin Psychiatry 20:71–78
Kluge M, Schuld A, Himmerich H, Dalal M, Schacht A, Wehmeier PM, Hinze-Selch D, Kraus T, Dittmann RW, Pollmacher T (2007) Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study. J Clin Psychopharmacol 27:662–666
Lee MD, Clifton PG (2002) Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol. Pharmacol Biochem Behav 71:147–154
Lindenmayer JP, Czobor P, Volavka J, Citrome L, Sheitman B, McEvoy JP, Cooper TB, Chakos M, Lieberman JA (2003) Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry 160:290–296
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419
Minet-Ringuet J, Even PC, Guesdon B, Tome D, de Beaurepaire R (2005) Effects of chronic neuroleptic treatments on nutrient selection, body weight, and body composition in the male rat under dietary self-selection. Behav Brain Res 163:204–211
Minet-Ringuet J, Even PC, Goubern M, Tome D, de Beaurepaire R (2006a) Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermogenic alteration. Appetite 46:254–262
Minet-Ringuet J, Even PC, Lacroix M, Tome D, de Beaurepaire R (2006b) A model for antipsychotic-induced obesity in the male rat. Psychopharmacology (Berl) 187:447–454
Minet-Ringuet J, Even PC, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007) Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Mol Psychiatry 12:562–571
Nahon JL (2006) The melanocortins and melanin-concentrating hormone in the central regulation of feeding behavior and energy homeostasis. C R Biol 329:623–638 discussion 653-5
Newcomer JW (2007) Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry 68(Suppl 4):8–13
Newcomer JW, Haupt DW (2006) The metabolic effects of antipsychotic medications. Can J Psychiatry 51:480–491
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
Ortega-Alvaro A, Gibert-Rahola J, Mico JA (2006) Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats. Prog Neuropsychopharmacol Biol Psychiatry 30:104–111
Rashidi MR, Mahboob S, Sattarivand R (2003) Effects of nibbling and gorging on lipid profiles, blood glucose and insulin levels in healthy subjects. Saudi Med J 24:945–948
Richmond W (1973) Preparation and properties of a cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem 19:1350–1356
Roerig JL, Mitchell JE, de Zwaan M, Crosby RD, Gosnell BA, Steffen KJ, Wonderlich SA (2005) A comparison of the effects of olanzapine and risperidone versus placebo on eating behaviors. J Clin Psychopharmacol 25:413–418
Trinder P (1969) Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol 22:158–161
Wallingford NM, Sinnayah P, Bymaster FP, Gadde KM, Krishnan RK, McKinney AA, Landbloom RP, Tollefson GD, Cowley MA (2008) Zonisamide prevents olanzapine-associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 33:2922–2933
Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC (2002) The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry 63:856–865
Acknowledgements
Montserrat Victoriano was in part supported by a grant from the Servier Laboratories (France). We thank Valérie Delbouis for her practical assistance during the study and Angélique Foucault-Simonin for animal care and help with dissection.
Ethical standards
The authors declare that the experiments comply with the current laws of the country in which they were performed.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Victoriano, M., Hermier, D., Even, P.C. et al. Early perturbation in feeding behaviour and energy homeostasy in olanzapine-treated rats. Psychopharmacology 206, 167–176 (2009). https://doi.org/10.1007/s00213-009-1593-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-009-1593-5