Metabolic Consequences of Antipsychotic Therapy: Preclinical and Clinical Perspectives on Diabetes, Diabetic Ketoacidosis, and Obesity

  • David J. HealEmail author
  • Jane Gosden
  • Helen C. Jackson
  • Sharon C. Cheetham
  • Sharon L. Smith
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 212)


Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic side effects. We discuss the adverse metabolic consequences of schizophrenia, its exacerbation by a lack of social care, and the additional burden placed on patients by their medication. A critical evaluation of the animal models of antipsychotic-induced metabolic disturbances is provided with observations on their strengths and limitations. Finally, we discuss novel antipsychotic drugs with a lower propensity to increase metabolic risk and adjunctive medications to mitigate the adverse metabolic actions of the current generation of antipsychotics.


Antipsychotics Diabetes Diabetic ketoacidosis Metabolic dysfunction Obesity Weight gain 



Body mass index


Cardiovascular disease


Diabetic ketoacidosis


First-generation antipsychotic


Fasting plasma glucose


Glucagon-like peptide-1


High-density lipoprotein-cholesterol


Homeostasis model assessment of insulin resistance


International obesity task force


Low-density lipoprotein-cholesterol


Second-generation antipsychotic


Selective serotonin reuptake inhibitor


  1. Abdul-Ghani MA, DeFronzo RA (2010) Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol 2010:476279PubMedCrossRefGoogle Scholar
  2. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B et al (2006) Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring) 14:36–51CrossRefGoogle Scholar
  3. Allison DB, Fontaine KR, Heo M, Mentore JL, Cappelleri JC, Chandler LP et al (1999a) The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry 60:215–220PubMedCrossRefGoogle Scholar
  4. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC et al (1999b) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686–1696PubMedGoogle Scholar
  5. Baptista T, Tenda L, Contreras Q, Albornoz MA, Paez X, de Quijada M et al (1998) Mechanism of the neuroleptic-induced obesity in rats. Prog Neuropsychopharmacol Biol Psychiatry 22:187–198PubMedCrossRefGoogle Scholar
  6. Baptista T, de Baptista EQ, Kin NMKNY, Beaulieu S, Walker D, Joober R et al (2002a) Comparative effects of the antipsychotic sulpiride or risperidone in rats. I: Bodyweight, food intake, body composition, hormones and glucose tolerance. Brain Res 957:144–151PubMedCrossRefGoogle Scholar
  7. Baptista T, Lacrux A, Pàez X, Hernàndez L, Beaulieu S (2002b) The antipsychotic drug sulpiride does not affect bodyweight in male rats. Is insulin resistance involved? Eur J Pharmacol 447:91–98PubMedCrossRefGoogle Scholar
  8. Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis. Epidemiology, pathophysiology, and management. J Am Med Assoc 287:2570–2581CrossRefGoogle Scholar
  9. Bhole V, deVera M, Rahman MM, Krisnan E, Choi H (2010) Epidemiology of gout in women: 52-year follow up of a prospective cohort. Arthritis Rheum 62:1069–1076PubMedCrossRefGoogle Scholar
  10. Bobes J, Rejas J, Garcia-Garcia M, Rico-Villademoros F, Garcia-Portilla MP, Fernandiz I et al (2003) Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiepine or haloperidol: results of the EIRE study. Schizophr Res 62:77–82PubMedCrossRefGoogle Scholar
  11. Brown S, Birtwistle J, Roe L, Thompson C (1999) The unhealthy lifestyle of people with schizophrenia. Psychol Med 29:697–701PubMedCrossRefGoogle Scholar
  12. Chintoh AF, Mann SW, Lam TKT, Giacca A, Remington G (2008) Insulin resistance following continuous, chronic olanzapine treatment: an animal model. Schizophr Res 104:23–30PubMedCrossRefGoogle Scholar
  13. Chintoh AF, Mann SW, Lam L, Giacca A, Fletcher P, Nobrega J et al (2009) Insulin resistance and secretion in vivo: effects of different antipsychotics in an animal model. Schizophr Res 108:127–133PubMedCrossRefGoogle Scholar
  14. Chiu CC, Chen KP, Liu HC, Lu ML (2006) The early effect of olanzapine and risperidone on insulin secretion in atypical-naïve schizophrenic patients. J Clin Psychopharmacol 26:504–507PubMedCrossRefGoogle Scholar
  15. Chrzanowski WK, Marcus RN, Torbeyns A, Nyilas M, McQuade RD (2006) Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine. Psychopharmacology (Berl) 189:259–266CrossRefGoogle Scholar
  16. Church CO, Stevens DL, Fugate SE (2005) Diabetic ketoacidosis associated with aripiprazole. Diabet Med 22:1440–1443PubMedCrossRefGoogle Scholar
  17. Coccurello R, Brina D, Caprioli A, Conti R, Ghirardi O, Schepis F et al (2009) 30 Days of continuous olanzapine infusion determines energy imbalance, glucose intolerance, insulin resistance, and dyslipidemia in mice. J Clin Psychopharmacol 29:576–583PubMedCrossRefGoogle Scholar
  18. Cohen D (2004) Atypical antipsychotics and new onset diabetes mellitus. An overview of the literature. Pharmacopsychiatry 37:1–11PubMedGoogle Scholar
  19. Cohen S, Chiles J, MacNaughton A (1990) Weight gain associated with clozapine. Am J Psychiatry 147:503–504PubMedGoogle Scholar
  20. Cohn TA, Remington G, Zipursky RB, Azad A, Connolly P, Wolever TM (2006) Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: a preliminary report. Can J Psychiatry 51:382–386, Erratum in: Can J Psychiatr 2006 51:552PubMedGoogle Scholar
  21. Cooper GD, Pickvance LC, Wilding JPH, Halford JCG, Goudie AJ (2005) A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology 181:80–89PubMedCrossRefGoogle Scholar
  22. Cooper GD, Pickvance LC, Wilding JPH, Harrold JA, Halford JCG, Goudie AJ (2007) Effects of olanzapine in male rats: enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities. J Psychopharmacol 21:405–413PubMedCrossRefGoogle Scholar
  23. 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 32:428–436PubMedCrossRefGoogle Scholar
  24. Cope MB, Nagy TR, Fernández JR, Geary N, Casey DE, Allison DB (2005) Antipsychotic drug-induced weight gain: development of an animal model. Int J Obes 29:607–614CrossRefGoogle Scholar
  25. Cope MB, Li X, Jumbo-Lucioni P, DiCostanzo CA, Jamison WG, Kesterson RA et al (2009) Risperidone alters food intake, core body temperature, and locomotor activity in mice. Physiol Behav 96:457–463PubMedCrossRefGoogle Scholar
  26. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK (2009) Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. J Am Med Assoc 302:1765–1773CrossRefGoogle Scholar
  27. Daniel DG, Wozniak P, Mack RJ, McCarthy BG (1998) Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. The sertindole study group. Psychopharmacol Bull 34:61–69PubMedGoogle Scholar
  28. De Hert M, Hanssens L, van Winkel R, Wampers M, Van Eyck D, Scheen A et al (2007) A case series: evaluation of the metabolic safety of aripiprazole. Schizophr Bull 33:823–830PubMedCrossRefGoogle Scholar
  29. De Hert M, Schreurs V, Sweers K, Van Eyck D, Hanssens L, Inko S et al (2008) Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: a retrospective chart review. Schizophr Res 101:295–303PubMedCrossRefGoogle Scholar
  30. De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU (2011a) Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: a systematic review of randomised, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry 26:144–158PubMedCrossRefGoogle Scholar
  31. De Hert M, Mittoux A, he Peuskens JY (2011b) Metabolic parameters in the short- and long-term treatment of schizophrenia with sertindole and risperidone. Eur Arch Psychiatry Clin Neurosci 261:231–239PubMedCrossRefGoogle Scholar
  32. De Hert M, Detraux J, van Winkel R, Yu W, Correll CU (2011c) Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 8(2):114–126PubMedCrossRefGoogle Scholar
  33. DeFronzo RA (2010) Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard lecture 2009. Diabetologia 53:1270–1287PubMedCrossRefGoogle Scholar
  34. Editorial: Drugs causing weight gain (1974) [No authors listed] Br Med J 1:168.Google Scholar
  35. Eledrisi MS, Alshanti MS, Shah MF, Brolosy B, Jaha N (2006) Overview of the diagnosis and management of diabetic ketoacidosis. Am J Med Sci 331:243–251PubMedCrossRefGoogle Scholar
  36. Fell MJ, Marshall KM, Williams J, Neill JC (2004a) Effects of the atypical antipsychotic olanzapine on reproductive function and weight gain in female rats. J Psychopharmacol 18:149–155PubMedCrossRefGoogle Scholar
  37. Fell MJ, Neill JC, Marshall KM (2004b) Effects of the classical antipsychotic haloperidol and atypical antipsychotic risperidone on weight gain, the oestrous cycle and uterine weight in female rats. Eur Neuropsychopharmacol 14(5):385–392PubMedCrossRefGoogle Scholar
  38. Fell MJ, Gibson R, McDermott E, Sisodia G, Marshall KM, Neill JC (2005a) Investigation into the effects of the novel antipsychotic ziprasidone on weight gain and reproductive function in female rats. Behav Brain Res 160:338–343PubMedCrossRefGoogle Scholar
  39. Fell MJ, Neill JC, Rao C, Marshall KM (2005b) Effects of sub-chronic antipsychotic drug treatment on body weight and reproductive function in juvenile female rats. Psychopharmacology (Berl) 182:499–507CrossRefGoogle Scholar
  40. Fell MJ, Anjum N, Dickinson K, Marshall KM, Peltola LM, Vickers S et al (2007) The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats. Psychopharmacology (Berl) 194:221–231CrossRefGoogle Scholar
  41. Fell MJ, Neill JC, Anjum N, Peltola LM, Marshall KM (2008) Investigation into the influence of a high fat diet on antipsychotic-induced weight gain in female rats. J Psychopharmacol 22:182–186PubMedCrossRefGoogle Scholar
  42. Felson DT (1996) Weight and osteoarthritis. Am J Clin Nutr 63(3 Suppl):430S–432SPubMedGoogle Scholar
  43. Flack JM, Peters R, Shafi T, Alrefai H, Nasser SA, Crook E (2003) Prevention of hypertension and its complications: theoretical basis and guidelines for treatment. J Am Soc Nephrol 14(Suppl 2):S92–S98PubMedCrossRefGoogle Scholar
  44. Fleischhaker C, Heiser P, Hennighausen K, Herpertz-Dahlmann B, Holtkamp K, Mehler-Wex C et al (2008) Weight gain in children and adolescents during 45 weeks treatment with clozapine, olanzapine and risperidone. J Neural Transm 115:1599–1608PubMedCrossRefGoogle Scholar
  45. Gentile S (2006) Long-term treatment with atypical antipsychotics and the risk of weight gain: a literature analysis. Drug Saf 29:303–319PubMedCrossRefGoogle Scholar
  46. Goudie AJ, Smith JA, Halford JC (2002) Characterization of olanzapine-induced weight gain in rats. J Psychopharmacol 16:291–296Google Scholar
  47. Graham KA, Cho H, Brownley KA, Harp JB (2008) Early treatment-related changes in diabetes and cardiovascular disease risk markers in first episode psychosis subjects. Schizophr Res 101:1–3CrossRefGoogle Scholar
  48. Haddad P (2005) Weight change with atypical antipsychotics in the treatment of schizophrenia. J Psychopharmacol 19:16–27PubMedCrossRefGoogle Scholar
  49. Haupt DW, Fahnestock PA, Flavin KA, Schweiger JA, Steves A, Hessler MJ et al (2007) Adiposity and insulin sensitivity derived from intravenous glucose tolerance tests in antipsychotic-treated patients. Neuropsychopharmacology 32:2561–2569PubMedCrossRefGoogle Scholar
  50. Heal DJ, Cheetham SC, Fisas A, Codony X, Buschmann H (2008) Prevention of antipsychotic-induced weight-gain by the 5-HT6 agonist, E-6837. Society for Neurosciences Meeting, Abstract No. 584.12/RR85Google Scholar
  51. Henderson DC (2001) Clinical experience with insulin resistance, diabetic ketoacidosis, and type 2 diabetes mellitus in patients treated with atypical antipsychotic agents. J Clin Psychiatry 62(Suppl 27):10–14, discussion 40-1PubMedGoogle Scholar
  52. Henderson DC, Cagliero E, Copeland PM, Borba CP, Evins E, Hayden D et al (2005a) 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 62:19–28PubMedCrossRefGoogle Scholar
  53. Henderson DC, Copeland PM, Daley TB, Borba CP, Cather C, Nguyen DD et al (2005b) A double-blind, placebo-controlled trial of sibutramine for olanzapine-associated weight gain. Am J Psychiatry 162:954–962PubMedCrossRefGoogle Scholar
  54. Herman MA, Kahn BB (2006) Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J Clin Invest 116:1767–1775PubMedCrossRefGoogle Scholar
  55. Heshka S, Heymsfield S (2001) Obesity and gallstones. In: Bjorntorp P (ed) International textbook of obesity. Wiley, Chichester, pp 399–409CrossRefGoogle Scholar
  56. Hoffmann VP, Case M, Stauffer VL, Jacobson JG, Conley RR (2010) Predictive value of early changes in triglycerides and weight for longer-term changes in metabolic measures during olanzapine, ziprasidone or aripiprazole treatment for schizophrenia and schizoaffective disorder post hoc analyses of 3 randomized, controlled clinical trials. J Clin Psychopharmacol 30:656–660PubMedCrossRefGoogle Scholar
  57. 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 32:289–297PubMedCrossRefGoogle Scholar
  58. International Obesity Task Force [IOTF] (2010).
  59. Jackson HC, Bearham MS, Hutchins LJ, Mazurkiewicz SE, Needham AM, Heal DJ (1997) Investigation of the mechanisms underlying the hypophagic effects of 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat. Br J Pharmacol 121:1613–1618PubMedCrossRefGoogle Scholar
  60. Jin H, Meyer JM, Jeste DV (2002) Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Ann Clin Psychiatry 14:59–64PubMedGoogle Scholar
  61. Johnson DA, Breen M (1979) Weight gain with depot neuroleptic maintenance therapy. Acta Psychiatr Scand 59:525–528PubMedCrossRefGoogle Scholar
  62. Johnson DE, Yamazaki H, Ward KM, Schmidt AW, Lebel WS, Treadway JL et al (2005) Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perfused rat islets. Diabetes 54:1552–1558PubMedCrossRefGoogle Scholar
  63. Kalinichev M, Rourke C, Jones DN (2006) Body weights and plasma prolactin levels in female rats treated subchronically with ziprasidone versus olanzapine. Behav Pharmacol 17:289–292PubMedCrossRefGoogle Scholar
  64. Kane JM, Osuntokun O, Kryzhanovskaya LA, Xu W, Stauffer VL, Watson SB et al (2009) A 28-week, randomised, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry 70:572–581PubMedCrossRefGoogle Scholar
  65. Keck PE Jr, Calabrese JR, McQuade RD, Carson WH, Carlson BX, Rollin LM et al (2006) A randomised, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry 67:626–637PubMedCrossRefGoogle Scholar
  66. Keck PE Jr, Calabrese JR, McIntyre RS, McQuade RD, Carson WH, Eudicone JM et al (2007) Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry 68:1480–1491PubMedCrossRefGoogle Scholar
  67. Kim SH, Nikolics L, Abbasi F, Lamendola C, Link J, Reaven GM et al (2010) Relationship between body mass and insulin resistance in patients treated with second generation antipsychotic agents. J Psychiatr Res 44:493–498PubMedCrossRefGoogle Scholar
  68. Lambert BL, Cunningham FE, Miller DR, Dalack GW, Hur K (2006) Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia. Am J Epidemiol 164:672–681PubMedCrossRefGoogle Scholar
  69. Law M, Wald N, Morris J (2003) Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. Health Technol Assess 7:1–94PubMedGoogle Scholar
  70. Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M (1992) Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 149:68–72PubMedGoogle Scholar
  71. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenbeck RA, Perkins DO, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators et al (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedCrossRefGoogle Scholar
  72. Lykkegaard K, Larsen PJ, Vrang N, Bock C, Bock T, Knudsen LB (2008) The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance. Schizophr Res 103:94–103PubMedCrossRefGoogle Scholar
  73. Maayan L, Vakhrusheva J, Correll CU (2010) Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Neuropsychopharmacology 35:1520–1530PubMedCrossRefGoogle Scholar
  74. McQuade RD, Stock E, Marcus R, Jody D, Gharbia NA, Vanveggel S et al (2004) A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomised, double-blind study. J Clin Psychiatry 65:47–56PubMedGoogle Scholar
  75. Melkersson K, Jansson E (2005) The atypical antipsychotics quetiapine, risperidone and ziprasidone do not increase insulin release in vitro. Neuro Endocrinol Lett 26:205–208PubMedGoogle Scholar
  76. Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99:S18–S27CrossRefGoogle Scholar
  77. Meltzer HY, Matsubara S, Lee JC (1989) The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol Bull 25:390–392PubMedGoogle Scholar
  78. Meyer JM, Davis VG, Goff DC, McEvoy JP, Nasrallah HA, Davis SM et al (2008) Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1. Schizophr Res 101:273–286PubMedCrossRefGoogle Scholar
  79. Minet-Ringuet J, Even PC, Lacroix M, Tomé D, de Beaurepaire R (2006) A model for antipsychotic-induced obesity in the male rat. Psychopharmacology (Berl) 187:447–454CrossRefGoogle Scholar
  80. Minet-Ringuet J, Even PC, Valet P, Carpéné C, Visentin V, Prévot D et al (2007) Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Mol Psychiatry 12:562–571PubMedCrossRefGoogle Scholar
  81. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP (2001) The continuing epidemics of obesity and diabetes in the United States. J Am Med Assoc 286:1195–1200CrossRefGoogle Scholar
  82. Montani J-P, Antic V, Yang Z, Dulloo A (2002) Pathways from obesity to hypertension: from the perspective of a vicious triangle. Int J Obes 26(suppl 2):S28–S38CrossRefGoogle Scholar
  83. Mortensen PB, Juel K (1993) Mortality and causes of death in first admitted schizophrenic patients. Br J Psychiatry 163:183–189PubMedCrossRefGoogle Scholar
  84. Newcomer JW (2005) Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 19(Suppl 1):1–93PubMedGoogle Scholar
  85. Newcomer JW (2007a) Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry 68(Suppl 1):20–27PubMedGoogle Scholar
  86. Newcomer JW (2007b) Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry 68(Suppl 4):8–13PubMedGoogle Scholar
  87. Nielsen J, Skadhede S, Correll CU (2010) Antipsychotics associated with the development of type 2 diabetes in antipsychotic-naïve schizophrenia patients. Neuropsychopharmacology 35:1997–2004PubMedCrossRefGoogle Scholar
  88. Osborn DP, Levy G, Nazareth I, Petersen I, Islam A, King MB (2007) Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s general practice research database. Arch Gen Psychiatry 64:242–249PubMedCrossRefGoogle Scholar
  89. Penzner JB, Dudas M, Saito E, Olshanskiy V, Parikh UH, Kapoor S et al (2009) Lack of effect of stimulant combination with second-generation antipsychotics on weight gain, metabolic changes, prolactin levels, and sedation in youth with clinically relevant aggression or oppositionality. J Child Adolesc Psychopharmacol 19:563–573PubMedCrossRefGoogle Scholar
  90. Peroutka SJ, U’Prichard DC, Greenberg DA, Snyder SH (1977) Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology 16:549–556PubMedCrossRefGoogle Scholar
  91. Perrone JA, Chabla JM, Hallas BH, Horowitz JM, Torres G (2004) Weight loss dynamics during combined fluoxetine and olanzapine treatment. BMC Pharmacol 4:27PubMedCrossRefGoogle Scholar
  92. Pi-Sunyer X (2002) The obesity epidemic: pathophysiology and consequences of obesity. Obes Res 10(suppl 2):97S–104SPubMedCrossRefGoogle Scholar
  93. Pouzet B, Mow T, Kreilgaard M, Velschow S (2003) Chronic treatment with antipsychotics in rats as a model for antipsychotic-induced weight gain in human. Pharmacol Biochem Behav 75:133–140PubMedCrossRefGoogle Scholar
  94. Rashid P, Leonardi-Bee J, Bath P (2003) Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 34:2741–2749PubMedCrossRefGoogle Scholar
  95. Ratzoni G, Gothelf D, Brand-Gothelf A, Reidman J, Kikinzon L, Gai G et al (2002) Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study. J Am Acad Child Adolesc Psychiatry 41:337–343PubMedCrossRefGoogle Scholar
  96. Reddymasu S, Bahta E, Levine S, Manas K, Slay LE (2006) Elevated lipase and diabetic ketoacidosis associated with aripiprazole. JOP 7:303–305PubMedGoogle Scholar
  97. Reist C, Mintz J, Albers LJ, Jamal MM, Szabo S, Ozdemir V (2007) Second-generation antipsychotic exposure and metabolic-related disorders in patients with schizophrenia: an observational pharmacoepidemiology study from 1988 to 2002. J Clin Psychopharmacol 27:46–51PubMedCrossRefGoogle Scholar
  98. Reynolds GP, Kirk SL (2010) Metabolic side effects of antipsychotic drug treatment: pharmacological mechanisms. Pharmacol Ther 125:169–179PubMedCrossRefGoogle Scholar
  99. Ryan MC, Collins P, Thakore JH (2003) Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 160:284–289PubMedCrossRefGoogle Scholar
  100. Ryan MC, Flanagan S, Kinsella U, Keeling F, Thakore JH (2004) The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naïve patients with schizophrenia. Life Sci 74:1999–2008, Erratum in: Life Sci. 2004 75:2851PubMedCrossRefGoogle Scholar
  101. Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R et al (2008) Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropharmacology 33:1633–1641Google Scholar
  102. Saddichha S, Manjunatha N, Ameen S, Akhtar S (2008) Diabetes and schizophrenia—effect of disease or drug? Results from a randomized, double-blind, controlled prospective study in first-episode schizophrenia. Acta Psychiatr Scand 117:342–347PubMedCrossRefGoogle Scholar
  103. Savoy YE, Ashton MA, Miller MW, Nedza FM, Spracklin DK, Hawthorn MH (2010) Differential effects of various typical and atypical antipsychotics on plasma glucose and insulin levels in the mouse: evidence for the involvement of sympathetic regulation. Schizophr Bull 36:410–418PubMedCrossRefGoogle Scholar
  104. Scheen AJ, de Hert MA (2007) Abnormal glucose metabolism in patients treated with antipsychotics. Diabetes Metab 33:169–175PubMedCrossRefGoogle Scholar
  105. Shobo M, Yamada H, Koakutsu A, Hamada N, Fujii M, Harada K et al (2011a) Chronic treatment with olanzapine via a novel infusion pump induces adiposity in male rats. Life Sci 88:761–765PubMedCrossRefGoogle Scholar
  106. Shobo M, Yamada H, Mihara T, Kondo Y, Irie M, Harada K et al (2011b) Two models for weight gain and hyperphagia as side effects of atypical antipsychotics in male rats: validation with olanzapine and ziprasidone. Behav Brain Res 216:561–568PubMedCrossRefGoogle Scholar
  107. Silverstone T, Smith G, Goodall E (1988) Prevalence of obesity in patients receiving depot antipsychotics. Br J Psychiatry 153:214–217PubMedCrossRefGoogle Scholar
  108. Simpson GM, Weiden P, Pigott T, Murray S, Siu CO, Romano SJ (2005) Six-month, blinded, multicenter continuation study of ziprasidone versus olanzapine in schizophrenia. Am J Psychiatry 162:1535–1538PubMedCrossRefGoogle Scholar
  109. Smith GC, Chaussade C, Vickers M, Jensen J, Shepherd PR (2008a) Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat. Diabetologia 51:2309–2317PubMedCrossRefGoogle Scholar
  110. Smith M, Hopkins D, Peveler RC, Holt RIG, Woodward M, Ismail K (2008b) First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. Brit J Psychiatry 192:406–411CrossRefGoogle Scholar
  111. Smith GC, Vickers MH, Cognard E, Shepherd PR (2009) Clozapine and quetiepine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: implications for glucose metabolism and food choice behaviour. Schizophr Res 115:30–40PubMedCrossRefGoogle Scholar
  112. Sowell MO, Mukhopadhyay N, Cavazzoni P, Shankar S, Steinberg HO, Breier A et al (2002) Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo. J Clin Endocrinol Metab 87:2918–2923PubMedCrossRefGoogle Scholar
  113. Sowell MO, Mukhopadhyay N, Cavazzoni P, Carlson C, Mudaliar S, Chinnapongse S et al (2003) Evaluation of insulin sensitivity in healthy volunteers treated with olanzapine, risperidone, or placebo: a prospective, randomized study using the two-step hyperinsulinemic, euglycemic clamp. J Clin Endocrinol Metab 88:5875–5880PubMedCrossRefGoogle Scholar
  114. Spelman LM, Walsh PI, Sharifi N, Collins P, Thakore JH (2007) Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia. Diabet Med 24:481–485PubMedCrossRefGoogle Scholar
  115. Stanton JM (1995) Weight gain associated with neuroleptic medication: a review. Schizophr Bull 21:463–472PubMedGoogle Scholar
  116. Stefanidis A, Verty AN, Allen AM, Owens NC, Cowley MA, Oldfield BJ (2009) The role of thermogenesis in antipsychotic drug-induced weight gain. Obesity 17:16–24PubMedCrossRefGoogle Scholar
  117. Svensson TH (2003) Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 27:1145–1158PubMedCrossRefGoogle Scholar
  118. van den Oever IA, Raterman HG, Nurmohamed MT, Simsek S (2010) Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus. Mediators Inflamm 2010:792393PubMedGoogle Scholar
  119. Vestri HS, Maianu L, Moellering DR, Garvey WT (2007) Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology 32:765–772PubMedCrossRefGoogle Scholar
  120. Vidarsdottir S, de Leeuw van Weenen JE, Frölich M, Roelfsema F, Romijn JA, Pijl H (2010) Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab 95:118–125PubMedCrossRefGoogle Scholar
  121. Wallingford NM, Sinnayah P, Bymaster FP, Gadde KM, Krishnan RK, McKinney AA, Landbloom RP et al (2008) Zonisamide prevents olanzapine-associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 33:2922–2933PubMedCrossRefGoogle Scholar
  122. Wetterling T (2001) Bodyweight gain with atypical antipsychotics. Drug Saf 24:59–73PubMedCrossRefGoogle Scholar
  123. Wilson DR, D’Souza L, Sarkar N, Newton M, Hammond C (2003) New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophr Res 59:1–6PubMedCrossRefGoogle Scholar
  124. 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 63:856–865PubMedCrossRefGoogle Scholar
  125. Wolk R, Shamsuzzaman AS, Somers VK (2003) Obesity, sleep apnoea and hypertension. Hypertension 42:1067–1074PubMedCrossRefGoogle Scholar
  126. Wu R-R, Zhao J-P, Jin H, Shao P, Fang M-S, Guo X-F et al (2008) Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain. A randomized controlled trial. J Am Med Assoc 299:185–193CrossRefGoogle Scholar
  127. Yood MU, deLorenze G, Quesenberry CP Jr, Oliveria SA, Tsai A-L, Willey VJ et al (2009) The incidence of diabetes in atypical antipsychotic users differs according to agent—results from a multisite epidemiologic study. Pharmacoepidemiol Drug Saf 18:791–799PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • David J. Heal
    • 1
    Email author
  • Jane Gosden
    • 1
  • Helen C. Jackson
    • 1
  • Sharon C. Cheetham
    • 1
  • Sharon L. Smith
    • 1
  1. 1.RenaSci LtdNottinghamUK

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