Drugs

, Volume 64, Issue 7, pp 701–723

Adverse Metabolic Effects Associated with Atypical Antipsychotics

Literature Review and Clinical Implications
Review Article

Abstract

Adverse metabolic effects, such as diabetes mellitus, lipid abnormalities and weight gain, have increasingly been recognised with the use of the newer, so-called atypical antipsychotic drugs. This article reviews the current literature in the field and attempts to answer the question of whether the atypical antipsychotics differ in their effects on glucose-insulin homeostasis and lipid metabolism. It also addresses how then to manage the use of the atypical antipsychotics that do interfere with these metabolic systems. Differences in effects of atypical antipsychotics on leptin levels are also summarised and put into context; bodyweight gain associated with atypical antipsychotics is reviewed elsewhere.

In summary, there are no large controlled trials published quantifying the prevalence of adverse effects on glucose-insulin homeostasis and lipid metabolism in patients receiving atypical antipsychotics. Nevertheless, the published articles and case reports reviewed in this article give a fairly good view of those adverse effects occurring with clozapine, olanzapine and risperidone, whereas little data are available regarding quetiapine, ziprasidone and zotepine, and no data exist for amisulpride and aripiprazole. Estimated rankings of the atypical agents, based on the available literature, show that the relative risk of glucose intolerance/diabetes mellitus, hyperlipidaemia and hyperleptinaemia is highest for clozapine and olanzapine, moderately high for quetiapine, rather low for risperidone and lowest for ziprasidone. Since adverse metabolic effects of atypical antipsychotics may have a negative influence on both the antipsychotic treatment outcome as well as the physical health of the patient, these effects have to be recognised and adequately managed. In this review, recommendations for prevention and treatment of the adverse metabolic effects are outlined.

References

  1. 1.
    Hiles BW. Hyperglycemia and glucosuria following chlorpromazine therapy [letter]. JAMA 1956; 162: 1651CrossRefGoogle Scholar
  2. 2.
    Cooperberg AA, Eidlow S. Haemolytic anaemia, jaundice and diabetes mellitus following chlorpromazine therapy. CMAJ 1956; 75: 746–9Google Scholar
  3. 3.
    Amdisen A. Diabetes mellitus as a side effect of treatment with tricyclic neuroleptics. Acta Psychiatr Scand 1964; 40 (180 Suppl.): 411–4PubMedCrossRefGoogle Scholar
  4. 4.
    Korenyi C, Lowenstein B. Chlorpromazine induced diabetes. Dis Nerv Syst 1968; 29: 827–8PubMedGoogle Scholar
  5. 5.
    Schwarz L, Munoz R. Blood sugar levels in patients treated with chlorpromazine. Am J Psychiatry 1968; 125: 253–5PubMedGoogle Scholar
  6. 6.
    Thonnard-Neumann E. Phenothiazines and diabetes in hospitalized women. Am J Psychiatry 1968; 124: 978–82PubMedGoogle Scholar
  7. 7.
    Mefferd RB, Labrosse EH, Gawienowski AM, et al. Influence of chlorpromazine on certain biochemical variables of chronic male schizophrenics. J Nerv Ment Dis 1958; 127: 167–79PubMedCrossRefGoogle Scholar
  8. 8.
    Clark ML, Ray TS, Paredes A, et al. Chlorpromazine in women with chronic schizophrenia: the effect on cholesterol levels and cholesterol-behavior relationships. Psychosom Med 1967; 29: 634–42PubMedGoogle Scholar
  9. 9.
    Clark M, Dubowski K, Colmore J. The effect of chlorpromazine on serum cholesterol in chronic schizophrenic patients. Clin Pharm Ther 1970; 11: 883–9Google Scholar
  10. 10.
    Taylor DM, McAskill R. Atypical antipsychotics and weight gain: a systematic review. Acta Psychiatr Scand 2000; 101: 416–32PubMedCrossRefGoogle Scholar
  11. 11.
    Russell JM, Mackell JA. Bodyweight gain associated with atypical antipsychotics: epidemiology and therapeutic implications. CNS Drugs 2001; 15: 537–51PubMedCrossRefGoogle Scholar
  12. 12.
    Sussman N. Review of atypical antipsychotics and weight gain. J Clin Psychiatry 2001; 62 (23 Suppl.): 5–12PubMedCrossRefGoogle Scholar
  13. 13.
    Wetterling T. Bodyweight gain with atypical antipsychotics: a comparative review. Drug Saf 2001; 24: 59–73PubMedCrossRefGoogle Scholar
  14. 14.
    Nasrallah H. A review of the effect of atypical antipsychotics on weight. Psychoneuroendocrinology 2003; 28: 83–96PubMedCrossRefGoogle Scholar
  15. 15.
    Keck P, Buffenstein A, Ferguson J, et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology 1998; 140: 173–84PubMedCrossRefGoogle Scholar
  16. 16.
    Daniel DG, Zimbroff DL, Potkin SG, et al. Ziprasidone 80 mg/ day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Neuropsychopharmacology 1999; 20: 491–505PubMedCrossRefGoogle Scholar
  17. 17.
    Kingsbury SJ, Fayek M, Trufasiu D, et al. The apparent effects of ziprasidone on plasma lipids and glucose. J Clin Psychiatry 2001; 62: 347–9PubMedCrossRefGoogle Scholar
  18. 18.
    Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001; 62: 92–100PubMedCrossRefGoogle Scholar
  19. 19.
    Zimmet PZ. Kelly West Lecture 1991. Challenges in diabetes epidemiology: from West to the rest. Diabetes Care 1992; 15: 232–52PubMedGoogle Scholar
  20. 20.
    Olefsky JM. Insulin resistance. In: Porte D, Sherwin RS, editors. Diabetes mellitus. 5th ed. Stamford (CT): Appleton & Lange, 1997: 513–52Google Scholar
  21. 21.
    Comi RJ. Drug-induced diabetes mellitus. In: LeRoith D, Taylor SI, Olefsky JM, editors. Diabetes mellitus: a fundamental and clinical text. Philadelphia (PA): Lippincott Williams & Wilkins, 2000: 582–8Google Scholar
  22. 22.
    Yazici KM, Erbas T, Yazici AH. The effect of clozapine on glucose metabolism. Exp Clin Endocrinol Diabetes 1998; 106: 475–7PubMedCrossRefGoogle Scholar
  23. 23.
    Hägg S, Joelsson L, Mjörndal T, et al. Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications. J Clin Psychiatry 1998; 59: 294–9PubMedCrossRefGoogle Scholar
  24. 24.
    Melkersson KI, Hulting AL, Brismar KE. Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry 1999; 60: 783–91PubMedCrossRefGoogle Scholar
  25. 25.
    Melkersson KI, Dahl ML. Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses. Psychopharmacology 2003; 170: 157–66PubMedCrossRefGoogle Scholar
  26. 26.
    Chae B-J, Kang B-J. The effect of clozapine on blood glucose metabolism. Hum Psychopharmacol Clin Exp 2001; 16: 265–71CrossRefGoogle Scholar
  27. 27.
    Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 2000; 157: 975–81PubMedCrossRefGoogle Scholar
  28. 28.
    Leonard P, Halley A, Browne S. Prevalence of obesity, lipid and glucose abnormalities in outpatients prescribed clozapine. Ir Med J 2002; 95: 119–20PubMedGoogle Scholar
  29. 29.
    Sernyak MJ, Gulanski B, Leslie DL, et al. Undiagnosed hyperglycemia in clozapine-treated patients with schizophrenia. J Clin Psychiatry 2003; 64: 605–8PubMedCrossRefGoogle Scholar
  30. 30.
    Lund BC, Perry PJ, Brooks JM, et al. Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry 2001; 58: 1172–6PubMedCrossRefGoogle Scholar
  31. 31.
    Wang PS, Glynn RJ, Ganz DA, et al. Clozapine use and risk of diabetes mellitus. J Clin Psychopharmacol 2002; 22: 236–43PubMedCrossRefGoogle Scholar
  32. 32.
    Melkersson KI, Hulting AL, Brismar KE. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry 2000; 61: 742–9PubMedCrossRefGoogle Scholar
  33. 33.
    Lindenmayer J-P, Smith RC, Singh A, et al. Hyperglycemia in patients with schizophrenia who are treated with olanzapine [letter]. J Clin Psychopharmacol 2001; 21: 351–3PubMedCrossRefGoogle Scholar
  34. 34.
    Biswas PN, Wilton LV, Pearce GL, et al. The pharmacovigilance of olanzapine: results of a post-marketing surveillance study on 8858 patients in England. J Psychopharmacol 2001; 15: 265–71CrossRefGoogle Scholar
  35. 35.
    Reinstein MJ, Sirotovskaya LA, Jones LE, et al. Effect of clozapine-quetiapine combination therapy on weight and glycaemic control: preliminary findings. Clin Drug Invest 1999; 18: 99–104CrossRefGoogle Scholar
  36. 36.
    Melamed Y, Mazeh D, Elizur A. Risperidone treatment for a patient suffering from schizophrenia and IDDM [letter]. Can J Psychiatry 1998; 43: 956PubMedGoogle Scholar
  37. 37.
    Madhusoodanan S, Brenner R, Araujo L, et al. Efficacy of risperidone treatment for psychoses associated with schizophrenia, schizoaffective disorder, bipolar disorder, or senile dementia in 11 geriatric patients: a case series. J Clin Psychiatry 1995; 56: 514–8PubMedGoogle Scholar
  38. 38.
    Diagnostic and statistical manual of mental disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association, 1994Google Scholar
  39. 39.
    Melkersson KI, Hulting AL. Insulin and leptin levels in patients with schizophrenia or related psychoses: a comparison between different antipsychotic agents. Psychopharmacology 2001; 154: 205–12PubMedCrossRefGoogle Scholar
  40. 40.
    Diagnostic and statistical manual of mental disorders, DSM-III-R. 3rd rev. ed. Washington, DC: American Psychiatric Association, 1987Google Scholar
  41. 41.
    Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 2002; 59: 337–45PubMedCrossRefGoogle Scholar
  42. 42.
    International classification of diseases. 9th rev. Geneva: World Health Organization, 1977Google Scholar
  43. 43.
    Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002; 159: 561–6PubMedCrossRefGoogle Scholar
  44. 44.
    Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcome after 1 year. J Clin Psychiatry 2002; 63: 425–33PubMedCrossRefGoogle Scholar
  45. 45.
    Koro CE, Fedder DO, L’Italien GJ, et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ 2002; 325: 243–8PubMedCrossRefGoogle Scholar
  46. 46.
    Gianfrancesco FD, Grogg AL, Mahmoud RA, et al. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry 2002; 63: 920–30PubMedCrossRefGoogle Scholar
  47. 47.
    Wirshing DA, Boyd JA, Meng LR, et al. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry 2002; 63: 856–65PubMedCrossRefGoogle Scholar
  48. 48.
    Hedenmalm K, Hägg S, Ståhl M, et al. Glucose intolerance with atypical antipsychotics. Drug Saf 2002; 25: 1107–16PubMedCrossRefGoogle Scholar
  49. 49.
    Sowell MO, Mukhopadhyay N, Cavazzoni P, et al. Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo. J Clin Endocrinol Metab 2002; 87: 2918–23PubMedCrossRefGoogle Scholar
  50. 50.
    Caro JJ, Ward A, Levinton C, et al. The risk of diabetes during olanzapine use compared with risperidone use: a retrospective database analysis. J Clin Psychiatry 2002; 63: 1135–9PubMedCrossRefGoogle Scholar
  51. 51.
    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: 290–6PubMedCrossRefGoogle Scholar
  52. 52.
    Croarkin PE, Jacobs KM, Bain BK. Diabetic ketoacidosis associated with risperidone treatment [letter]? Psychosomatics 2000; 41: 369–70PubMedCrossRefGoogle Scholar
  53. 53.
    Procyshyn RM, Pande S, Tse G. New-onset diabetes mellitus associated with quetiapine [letter]. Can J Psychiatry 2000; 45: 668–9PubMedGoogle Scholar
  54. 54.
    Haupt DW, Newcomer JW. Risperidone-associated diabetic ketoacidosis [letter]. J Psychosomatics 2001; 42: 279–80CrossRefGoogle Scholar
  55. 55.
    Mallya A, Chawla P, Boyer SK, et al. Resolution of hyperglycemia on risperidone discontinuation: a case report [letter]. J Clin Psychiatry 2002; 63: 453–4PubMedCrossRefGoogle Scholar
  56. 56.
    George K, Alberti MM. Diabetic acidosis, hyperosmolar coma, and lactic acidosis. In: Becker KL, editor. Principles and practice of endocrinology and metabolism. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2001: 1438–51Google Scholar
  57. 57.
    Von Hayek D, Hüttl V, Reiss J, et al. Hyperglycaemia and ketoacidosis on olanzapine [in German]. Nervenarzt 1999; 70: 836–7CrossRefGoogle Scholar
  58. 58.
    Zajecka JM, Weisler R, Sachs G, et al. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry 2002; 63: 1148–55PubMedCrossRefGoogle Scholar
  59. 59.
    Meatherall R, Younes J. Fatality from olanzapine induced hyperglycemia. J Forensic Sci 2002; 47: 893–6PubMedGoogle Scholar
  60. 60.
    Koren W, Kreis Y, Duchowiczny K, et al. Lactic acidosis and fatal myocardial failure due to clozapine. Ann Pharmacother 1997; 31: 168–70PubMedGoogle Scholar
  61. 61.
    Fertig MK, Brooks VG, Shelton PS, et al. Hyperglycemia associated with olanzapine [letter]. J Clin Psychiatry 1998; 59: 687–9PubMedCrossRefGoogle Scholar
  62. 62.
    Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998; 44: 778–83PubMedCrossRefGoogle Scholar
  63. 63.
    Goldstein LE, Sporn J, Brown S, et al. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics 1999; 40: 438–43PubMedCrossRefGoogle Scholar
  64. 64.
    Rigalleau V, Gatta B, Bonnaud S, et al. Diabetes as a result of atypical anti-psychotic drugs: a report of three cases. Diabet Med 2000; 17: 484–6PubMedCrossRefGoogle Scholar
  65. 65.
    Ananth J, Gunatilake S, Aquino S, et al. Are African American patients at a higher risk for olanzapine-induced glucose intolerance [letter]? Psychopharmacology 2001; 157: 324–5PubMedCrossRefGoogle Scholar
  66. 66.
    Bechara CI, Goldman-Levine JD. Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy 2001; 21: 1444–7PubMedCrossRefGoogle Scholar
  67. 67.
    Bonanno DG, Davydov L, Botts SR. Olanzapine-induced diabetes mellitus. Ann Pharmacother 2001; 35: 563–5PubMedCrossRefGoogle Scholar
  68. 68.
    Domon SE, Webber JC. Hyperglycemia and hypertriglyceridemia secondary to olanzapine. J Child Adolesc Psychopharmacol 2001; 11: 285–8PubMedCrossRefGoogle Scholar
  69. 69.
    Kropp S, Emrich HM. Olanzapine-related hyperglycemia in a nondiabetic woman [letter]. Can J Psychiatry 2001; 46: 457PubMedGoogle Scholar
  70. 70.
    Seaburg HL, McLendon BM, Doraiswamy PM. Olanzapine-associated severe hyperglycemia, ketonuria, and acidosis: case report and review of literature. Pharmacotherapy 2001; 21: 1448–54PubMedCrossRefGoogle Scholar
  71. 71.
    Van Meter SA, Seaburg H, McLendon B, et al. Olanzapine, new-onset diabetes mellitus, and risk for insulin overdose [letter]. J Clin Psychiatry 2001; 62: 993–4PubMedCrossRefGoogle Scholar
  72. 72.
    Melkersson K, Hulting AL. Recovery from new-onset diabetes in a schizophrenic man after withdrawal of olanzapine. Psychosomatics 2002; 43: 67–70PubMedCrossRefGoogle Scholar
  73. 73.
    Opp D, Hildebrandt C. Olanzapine-associated type 2 diabetes mellitus [letter]. Schizophr Res 2002; 56: 195–6PubMedCrossRefGoogle Scholar
  74. 74.
    Riccitelli G, Baker N. Weight gain and hyperglycemia associated with olanzapine [letter]. Aust N Z J Psychiatry 2002; 36: 270–1PubMedGoogle Scholar
  75. 75.
    Spivak B, Alamy SS, Jarskog LF, et al. Ziprasidone alternative for olanzapine-induced hyperglycemia [letter]. Am J Psychiatry 2002; 159: 1606PubMedCrossRefGoogle Scholar
  76. 76.
    Stoner SC, Dubisar BM, Khan R, et al. Severe hypertriglyceridemia associated with olanzapine [letter]. J Clin Psychiatry 2002; 63: 948–9PubMedCrossRefGoogle Scholar
  77. 77.
    Abdullah N, Voronovitch L, Taylor S, et al. Olanzapine and quick-response hyperglycemia [letter]. Psychosomatics 2003; 44: 175–6PubMedCrossRefGoogle Scholar
  78. 78.
    Gatta B, Rigalleau V, Gin H. Diabetic ketoacidosis with olanzapine treatment [letter]. Diabetes Care 1999; 22: 1002–3PubMedCrossRefGoogle Scholar
  79. 79.
    Lindenmayer JP, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus [letter]. Am J Psychiatry 1999; 156: 1471PubMedGoogle Scholar
  80. 80.
    Paizis M, Cavaleri S, Schwarz ME, et al. Acute-onset diabetic ketoacidosis during olanzapine treatment in a patient without pretreatment obesity or treatment-associated weight gain. Prim Psychiatry 1999; 6: 37–8Google Scholar
  81. 81.
    Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001; 14: 278–82PubMedGoogle Scholar
  82. 82.
    Ragucci KR, Wells BJ. Olanzapine-induced diabetic ketoacidosis. Ann Pharmacother 2001; 35: 1556–8PubMedCrossRefGoogle Scholar
  83. 83.
    Selva KA, Scott SM. Diabetic ketoacidosis associated with olanzapine in an adolescent patient. J Pediatr 2001; 138: 936–8PubMedCrossRefGoogle Scholar
  84. 84.
    Johnson RP, Al-Taher MT, Madlock LE, et al. Increasing insulin dose for olanzapine-related diabetes [letter]. Am J Psychiatry 2002; 159: 150–1PubMedCrossRefGoogle Scholar
  85. 85.
    Straker D, Mendelowitz A, Karlin L. Near fatal ketoacidosis with olanzapine treatment. Psychosomatics 2002; 43: 339–40PubMedCrossRefGoogle Scholar
  86. 86.
    Wilson DR, D’Souza L, Sarkar N, et al. New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophr Res 2002; 59: 1–6CrossRefGoogle Scholar
  87. 87.
    Roefaro J, Mukherjee SM. Olanzapine-induced hyperglycemic nonketonic coma. Ann Pharmacother 2001; 35: 300–2PubMedCrossRefGoogle Scholar
  88. 88.
    Ober SK, Hudak R, Rusterholtz A. Hyperglycemia and olanzapine [letter]. Am J Psychiatry 1999; 156: 970PubMedGoogle Scholar
  89. 89.
    Bettinger TL, Mendelson SC, Dorson PG, et al. Olanzapine-induced glucose dysregulation. Ann Pharmacother 2000; 34: 865–7PubMedCrossRefGoogle Scholar
  90. 90.
    Malyuk R, Gibson B, Procyshyn RM, et al. Olanzapine associated weight gain, hyperglycemia and neuroleptic malignant syndrome: case report. Int J Geriatr Psychiatry 2002; 17: 326–8PubMedCrossRefGoogle Scholar
  91. 91.
    Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain. Acta Psychiatr Scand 2002; 105: 235–7PubMedCrossRefGoogle Scholar
  92. 92.
    Kamran A, Doraiswamy PM, Jane JL, et al. Severe hyperglycemia associated with high doses of clozapine [letter]. Am J Psychiatry 1994; 151: 1395PubMedGoogle Scholar
  93. 93.
    Popli AP, Konicki PE, Jurjus GJ, et al. Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997; 58: 108–11PubMedCrossRefGoogle Scholar
  94. 94.
    Dickson RA, Hogg L. Pregnancy of a patient treated with clozapine. Psychiatr Serv 1998; 49: 1081–3PubMedGoogle Scholar
  95. 95.
    Thompson J, Chengappa KNR, Good CB, et al. Hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria occurring early in clozapine treatment. Int Clin Psychopharmacol 1998; 13: 95–8PubMedCrossRefGoogle Scholar
  96. 96.
    Isakov I, Klesmer J, Masand PS. Insulin-resistant hyperglycemia induced by clozapine [letter]. Psychosomatics 2000; 41: 373–4PubMedCrossRefGoogle Scholar
  97. 97.
    Wehring H, Alexander B, Perry PJ. Diabetes mellitus associated with clozapine therapy. Pharmacotherapy 2000; 20: 844–7PubMedCrossRefGoogle Scholar
  98. 98.
    Wu G, Dias P, Wu C, et al. Hyperglycemia, hyperlipidemia, and periodic paralysis: a case report of new side effects of clozapine. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24: 1395–400PubMedCrossRefGoogle Scholar
  99. 99.
    Koval MS, Rames LJ, Christie S. Diabetic ketoacidosis associated with clozapine treatment [letter]. Am J Psychiatry 1994; 151: 1520–1PubMedGoogle Scholar
  100. 100.
    Kostakoglu AE, Yazici KM, Erbas T, et al. Ketoacidosis as a side-effect of clozapine: a case report. Acta Psychiatr Scand 1996; 93: 217–8PubMedCrossRefGoogle Scholar
  101. 101.
    Peterson GA, Byrd SL. Diabetic ketoacidosis from clozapine and lithium cotreatment [letter]. Am J Psychiatry 1996; 153: 737–8PubMedGoogle Scholar
  102. 102.
    Pierides M. Clozapine monotherapy and ketoacidosis [letter]. Br J Psychiatry 1997; 171: 90–1PubMedCrossRefGoogle Scholar
  103. 103.
    Ai D, Roper TA, Riley JA. Diabetic ketoacidosis and clozapine. Postgrad Med J 1998; 74: 493–4PubMedCrossRefGoogle Scholar
  104. 104.
    Colli A, Cocciolo M, Francobandiera G, et al. Diabetic ketoacidosis associated with clozapine treatment [letter]. Diabetes Care 1999; 22: 176–7PubMedCrossRefGoogle Scholar
  105. 105.
    Maule S, Giannella R, Lanzio M, et al. Diabetic ketoacidosis with clozapine treatment [letter]. Diabetes Nutr Metab 1999; 12: 187–8PubMedGoogle Scholar
  106. 106.
    Mohan D, Gordon H, Hindley N, et al. Schizophrenia and diabetes mellitus [letter]. Br J Psychiatry 1999; 174: 180–1PubMedCrossRefGoogle Scholar
  107. 107.
    Smith H, Kenney-Herbert J, Knowles L. Clozapine-induced diabetic ketoacidosis [letter]. Aust N Z J Psychiatry 1999; 33: 120–1PubMedCrossRefGoogle Scholar
  108. 108.
    Avram AM, Patel V, Taylor HC, et al. Euglycemic clamp study in clozapine-induced diabetic ketoacidosis. Ann Pharmacother 2001; 35: 1381–7PubMedCrossRefGoogle Scholar
  109. 109.
    Nicolai J, Smith SJ, Keunen RWM. Simultaneous side effects of both clozapine and valproate [letter]. Intensive Care Med 2001; 27: 943PubMedCrossRefGoogle Scholar
  110. 110.
    Kristensen SH, Porksen NK. Clozapine and diabetic ketoacidosis [in Danish]. Ugeskr Laeger 2003; 165: 475–6PubMedGoogle Scholar
  111. 111.
    Short JA, Nolan JA. Neuroleptic malignant syndrome and hyperosmolar, non-ketotic hyperglycaemic coma. Pract Diabetes Int 1995; 12: 138–9CrossRefGoogle Scholar
  112. 112.
    Sobel M, Jaggers ED, Franz MA. New-onset diabetes mellitus associated with the initiation of quetiapine treatment [letter]. J Clin Psychiatry 1999; 60: 556–7PubMedCrossRefGoogle Scholar
  113. 113.
    Domon SE, Cargile CS. Quetiapine-associated hyperglycemia and hypertriglyceridemia [letter]. J Am Acad Child Adolesc Psychiatry 2002; 41: 495–6PubMedCrossRefGoogle Scholar
  114. 114.
    Wirshing DA, Pierre JM, Eyeler J, et al. Risperidone-associated new-onset diabetes. Biol Psychiatry 2001; 50: 148–9PubMedCrossRefGoogle Scholar
  115. 115.
    Yang SH, McNeely MJ. Rhabdomyolysis, pancreatitis and hyperglycemia with ziprasidone [letter]. Am J Psychiatry 2002; 159: 1435PubMedCrossRefGoogle Scholar
  116. 116.
    Mir S, Taylor D. Atypical antipsychotics and hyperglycaemia. Int Clin Psychopharmacol 2001; 16: 63–74PubMedCrossRefGoogle Scholar
  117. 117.
    Liebzeit KA, Markowitz JS, Caley CF. New onset diabetes and atypical antipsychotics. Eur Neuropsychopharmacol 2001; 11: 25–32PubMedCrossRefGoogle Scholar
  118. 118.
    Jin H, Meyer JM, Jeste DV. 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 2002; 14: 59–64PubMedGoogle Scholar
  119. 119.
    Ananth J, Venkatesh R, Burgoyne K, et al. Atypical antipsychotic drug use and diabetes. Psychother Psychosom 2002; 71: 244–54PubMedCrossRefGoogle Scholar
  120. 120.
    Koller E, Schneider B, Bennett K, et al. Clozapine-associated diabetes. Am J Med 2001; 111: 716–23PubMedCrossRefGoogle Scholar
  121. 121.
    Koller EA, Doraiswamy PM. Olanzapine-associated diabetes mellitus. Pharmacotherapy 2002; 22: 841–52PubMedCrossRefGoogle Scholar
  122. 122.
    Koller EA, Cross JT, Doraiswamy PM, et al. Risperidone-associated diabetes melllitus: a pharmacovigilance study. Pharmacotherapy 2003; 23: 735–44PubMedCrossRefGoogle Scholar
  123. 123.
    Ishigooka J, Murasaki M, Miura S. Efficacy and safety of olanzapine, an atypical antipsychotic, in patients with schizophrenia: results of an open-label multicenter study in Japan. Psychiatry Clin Neurosci 2001; 55: 353–63PubMedCrossRefGoogle Scholar
  124. 124.
    O’Neil MJ, Smith A, Heckelman PE, editors. The Merck Index: an encyclopedia of chemicals, drugs, and biologicals. 13th ed. Whitehouse Station (NJ): Merck & Co, 2001Google Scholar
  125. 125.
    Ghaeli P, Dufresne RL. Serum triglyceride levels in patients treated with clozapine. Am J Health Syst Pharm 1996; 53: 2079–81PubMedGoogle Scholar
  126. 126.
    Spivak B, Roitman S, Vered Y, et al. Diminished suicidal and aggressive behavior, high plasma norepinephrine levels, and serum triglyceride levels in chronic neuroleptic-resistant schizophrenic patients maintained on clozapine. Clin Neuro-pharmacol 1998; 21: 245–50Google Scholar
  127. 127.
    Dursun SM, Szemis A, Andrews H, et al. The effects of clozapine on levels of total cholesterol and related lipids in serum of patients with schizophrenia: a prospective study. J Psychiatry Neurosci 1999; 24: 453–5PubMedGoogle Scholar
  128. 128.
    Gaulin BD, Markowitz JS, Caley CF, et al. Clozapine-associated elevation in serum triglycerides. Am J Psychiatry 1999; 156: 1270–2PubMedGoogle Scholar
  129. 129.
    Spivak B, Lamschtein C, Talmon Y, et al. The impact of clozapine treatment on serum lipids in chronic schizophrenic patients. Clin Neuropharmacol 1999; 22: 98–101PubMedCrossRefGoogle Scholar
  130. 130.
    Wiltfang J, Schenk-Dapra B, Stiens G, et al. Clozapine-associated elevation of plasma cholinesterase. Eur Arch Psychiatry Clin Neurosci 2001; 251: 269–71PubMedCrossRefGoogle Scholar
  131. 131.
    Pande S, Procyshyn RM, Nazerali M, et al. Do triglycerides modulate the effectiveness of clozapine? Int Clin Psychopharmacol 2002; 17: 197–9PubMedCrossRefGoogle Scholar
  132. 132.
    Osser DN, Najarian DM, Dufresne RL. Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry 1999; 60: 767–70PubMedCrossRefGoogle Scholar
  133. 133.
    Sheitman BB, Bird PM, Binz W, et al. Olanzapine-induced elevation of plasma triglyceride levels [letter]. Am J Psychiatry 1999; 156: 1471–2PubMedGoogle Scholar
  134. 134.
    Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001; 21: 369–74PubMedCrossRefGoogle Scholar
  135. 135.
    Nguyen M, Murphy T. Olanzapine and hypertriglyceridemia [letter]. J Am Acad Child Adolesc Psychiatry 2001; 40: 133PubMedCrossRefGoogle Scholar
  136. 136.
    Martin A, L’Ecuyer S. Triglyceride, cholesterol and weight changes among risperidone-treated youths: a retrospective study. Eur Child Adolesc Psychiatry 2002; 11: 129–33PubMedCrossRefGoogle Scholar
  137. 137.
    Cohen S, Fitzgerald B, Okos A, et al. Weight, lipids, glucose, and behavioral measures with ziprasidone treatment in a population with mental retardation. J Clin Psychiatry 2003; 64: 60–2PubMedCrossRefGoogle Scholar
  138. 138.
    Wetterling T. Hyperlipidemia: side-effect of the treatment with an atypical antipsychotic (zotepine) [in German]? Psychiatr Prax 2002; 29: 438–40PubMedCrossRefGoogle Scholar
  139. 139.
    Ghaeli P, Dufresne RL. Elevated serum triglycerides with clozapine resolved with risperidone in four patients. Pharmacotherapy 1999; 19: 1099–101PubMedCrossRefGoogle Scholar
  140. 140.
    Koro CE, Fedder DO, L’Italien GJ, et al. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry 2002; 59: 1021–6PubMedCrossRefGoogle Scholar
  141. 141.
    Atmaca M, Kuloglu M, Tezcan E, et al. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J Clin Psychiatry 2003; 64: 598–604PubMedCrossRefGoogle Scholar
  142. 142.
    Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–32PubMedCrossRefGoogle Scholar
  143. 143.
    Woods SC, Kaiyala K, Porte D, et al. Food intake and energy balance. In: Porte D, Sherwin RS, editors. Diabetes mellitus. 5th ed. Stamford (CT): Appleton & Lange, 1997: 175–92Google Scholar
  144. 144.
    Shimabukuro M, Koyama K, Chen G, et al. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A 1997; 94: 4637–41PubMedCrossRefGoogle Scholar
  145. 145.
    Friedman JM. Leptin, leptin receptors, and the control of body weight. Nutr Rev 1998; 56: S38–46PubMedCrossRefGoogle Scholar
  146. 146.
    Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879–84PubMedCrossRefGoogle Scholar
  147. 147.
    Segal KR, Landt M, Klein S. Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 1996; 45: 988–91PubMedCrossRefGoogle Scholar
  148. 148.
    Haffner SM, Miettinen H, Mykkänen L, et al. Leptin concentrations and insulin sensitivity in normoglycemic men. Int J Obes Relat Metab Disord 1997; 21: 393–9PubMedCrossRefGoogle Scholar
  149. 149.
    Girard J. Is leptin the link between obesity and insulin resistance? Diabetes Metab 1997; 23: 16–24PubMedGoogle Scholar
  150. 150.
    Kolaczynski JW, Nyce MR, Considine RV, et al. Acute and chronic effect of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes 1996; 45: 699–701PubMedCrossRefGoogle Scholar
  151. 151.
    Tanizawa Y, Okuya S, Ishihara H, et al. Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic beta cells. Endocrinology 1997; 138: 4513–6PubMedCrossRefGoogle Scholar
  152. 152.
    Seufert J, Kieffer TJ, Leech CA, et al. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. J Clin Endocrinol Metab 1999; 84: 670–6PubMedCrossRefGoogle Scholar
  153. 153.
    Brömel T, Blum WF, Ziegler A, et al. Serum leptin levels increase rapidly after initiation of clozapine therapy. Mol Psychiatry 1998; 3: 76–80PubMedCrossRefGoogle Scholar
  154. 154.
    Hinze-Selch D, Deuschle M, Weber B, et al. Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight. Psychopharmacology (Berl) 2000; 149: 163–9CrossRefGoogle Scholar
  155. 155.
    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: 843–8PubMedCrossRefGoogle Scholar
  156. 156.
    Monteleone P, Fabrazzo M, Tortorella A, et al. Pronounced, early increase in circulating leptin predicts lower weight gain during clozapine treatment. J Clin Psychopharmacol 2002; 22: 424–6PubMedCrossRefGoogle Scholar
  157. 157.
    International classification of diseases. 10th rev. Geneva: World Health Organization, 1992Google Scholar
  158. 158.
    Eder U, Mangweth B, Ebenbichler C, et al. Association of olanzapine-induced weight gain with an increase in body fat. Am J Psychiatry 2001; 158: 1719–22PubMedCrossRefGoogle Scholar
  159. 159.
    Kraus T, Haack M, Schuld A, et al. Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 1999; 156: 312–4PubMedGoogle Scholar
  160. 160.
    Herran A, Garcia-Unzueta MT, Amado JA, et al. Effects of long-term treatment with antipsychotics on serum leptin levels. Br J Psychiatry 2001; 179: 59–62PubMedCrossRefGoogle Scholar
  161. 161.
    Atmaca M, Kuloglu M, Tezcan E, et al. Weight gain, serum leptin and triglyceride levels in patients with schizophrenia on antipsychotic treatment with quetiapine, olanzapine and haloperidol [letter]. Schizophr Res 2003; 60: 99–100PubMedCrossRefGoogle Scholar
  162. 162.
    Klarlund JK, Cherniak AD, Conway BR, et al. Mechanisms of insulin action. In: Porte D, Sherwin RS, editors. Diabetes mellitus. 5th ed. Stamford (CT): Appleton & Lange, 1997: 75–93Google Scholar
  163. 163.
    Harris M, Cahill G. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28: 1039–57Google Scholar
  164. 164.
    Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–607PubMedCrossRefGoogle Scholar
  165. 165.
    Melkersson K, Khan A, Hilding A, et al. Different effects of antipsychotic drugs on insulin release in vitro. Eur Neuropsychopharmacol 2001; 11: 327–32PubMedCrossRefGoogle Scholar
  166. 166.
    Melkersson K. Clozapine and olanzapine, but not conventional antipsychotics, increase insulin release in vitro. Eur Neuropsychopharmacol 2004; 14: 115–9PubMedCrossRefGoogle Scholar
  167. 167.
    Hauner H, Röhrig K, Hedebrand J, et al. No evidence for a direct effect of clozapine on fat-cell formation and production of leptin and other fat-cell-derived factors. Mol Psychiatry 2003; 8: 258–9PubMedCrossRefGoogle Scholar
  168. 168.
    Melkersson K, Hulting A-L, Brismar K. Reply: body weight gain, insulin, and leptin in olanzapine-treated patients [letter]. J Clin Psychiatry 2001; 62: 903–4Google Scholar
  169. 169.
    Mukherjee S, Decina P, Bocola V, et al. Diabetes mellitus in schizophrenic patients. Comphr Psychiatry 1996; 37: 68–73CrossRefGoogle Scholar
  170. 170.
    Gopalaswamy AK, Morgan R. Too many chronic mentally disabled patients are too fat. Acta Psychiatr Scand 1985; 72: 254–8PubMedCrossRefGoogle Scholar
  171. 171.
    Allison DB, Fontaine KR, Heo M, et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry 1999; 60: 215–20PubMedCrossRefGoogle Scholar
  172. 172.
    Kelly C, McCreadie RG. Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland. Am J Psychiatry 1999; 156: 1751–7PubMedGoogle Scholar
  173. 173.
    Braceland FJ, Meduna LJ, Vaichulis JA. Delayed action of insulin in schizophrenia. Am J Psychiatry 1945; 102: 108–10Google Scholar
  174. 174.
    Ryan MCM, Collins P, Thakore JH. Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 2003; 160: 284–9PubMedCrossRefGoogle Scholar
  175. 175.
    Depres JP. Visceral obesity: a component of the insulin resistance-dyslipidemic syndrome. Can J Cardiol 1994; 10: 17B-22BGoogle Scholar
  176. 176.
    Haupt DW, Newcomer JW. Hyperglycemia and antipsychotic medications. J Clin Psychiatry 2001; 62 Suppl. 27: 15–26PubMedGoogle Scholar
  177. 177.
    Lindenmayer J-P, Nathan A-M, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001; 62 Suppl. 23: 30–8PubMedGoogle Scholar
  178. 178.
    McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001; 46: 273–81PubMedGoogle Scholar
  179. 179.
    Meyer JM. Effects of atypical antipsychotics on weight and serum lipid levels. J Clin Psychiatry 2001; 62 Suppl. 27: 27–34PubMedGoogle Scholar
  180. 180.
    Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002; 16: 77–89PubMedCrossRefGoogle Scholar
  181. 181.
    Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA 2001; 286: 1945–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Sollentuna Psychiatric Polyclinic and Department of Molecular MedicineKarolinska InstituteStockholmSweden
  2. 2.Department of Medical Sciences, Clinical PharmacologyUniversity HospitalUppsalaSweden
  3. 3.Psychiatric PolyclinicSollentuna HospitalSollentunaSweden

Personalised recommendations