Background: Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance.
Objective: To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs.
Methods: All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed.
Results: Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20–12.73), an increase in weight (OR 2.36, 95% CI 1.76–3.17), male gender (OR 1.27, 95% CI 1.11–1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61–2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33–1.99) or buspirone (OR 2.24, 95% CI 1.33–3.77).
Conclusion: Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.
The authors have no financial or other conflicts of interest that are directly relevant to the contents of the manuscript.
The authors are indebted to the national centres mentioned in this study, who contributed data. The opinions and conclusions, however, are not necessarily those of the various centres nor of the WHO.
Waddington JL, O’Callaghan E. What makes an antipsychotic agent ‘atypical’? conserving the definition. CNS Drugs 1997; 7: 341–6CrossRefGoogle Scholar
Popli AP, Konicki PE, Jurjus GJ, et al. Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997; 58: 108–11PubMedCrossRefGoogle Scholar
Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998; 44: 778–83PubMedCrossRefGoogle Scholar
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
Melkersson KI, Hulting A-L, 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
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
Bettinger TL, Mendelson SC, Dorson PG, et al. Olanzapine-induced glucose dysregulation. Ann Pharmacother 2000; 34: 865–7PubMedCrossRefGoogle Scholar
Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999; 60: 358–63PubMedCrossRefGoogle Scholar
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
Ghaeli P, Dufresne RL. Serum triglyceride levels in patients treated with clozapine. Am J Health Syst Pharm 1996; 53: 2079–81PubMedGoogle Scholar
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
Gaulin BD, Markowitz JS, Caley CF, et al. Clozapine-associated elevation in serum triglycerides. Am J Psychiatry 1999; 156: 1270–2PubMedGoogle Scholar
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
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
Melamed Y, Mazeh D, Elizur A. Risperidone treatment for a patient suffering from schizophrenia and IDDM [letter]. Can J Psychiatry 1998; 43: 956PubMedGoogle Scholar
Bate A, Lindquist M, Edwards IR, et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 1998; 54: 315–21PubMedCrossRefGoogle Scholar
Orre R, Lansner A, Bate A, et al. Bayesian neural networks with confidence estimations applied to data mining. Comput Stat Data Anal 2000; 34: 473–93CrossRefGoogle Scholar
Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002; 16: 77–89PubMedCrossRefGoogle Scholar
Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686–96PubMedGoogle Scholar
Isojärvi JIT, Rättyä J, Myllylä VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998; 43: 446–51PubMedCrossRefGoogle Scholar
Goodnick PJ, Henry JH, Buki VM. Treatment of depression in diabetes mellitus. J Clin Psychiatry 1995; 56: 128–36PubMedGoogle Scholar
Petty KJ. Hyperglycemia associated with paroxetine [letter]. Ann Intern Med 1996; 125: 782PubMedGoogle Scholar
Erenmemisoglu A, Ozdogan UK, Saraymen R, et al. Effect of some antidepressants on glycaemia and insulin levels of normoglycaemic and alloxan-induced hypeglycemic mice. J Pharm Pharmacol 1999; 51: 741–3PubMedCrossRefGoogle Scholar
Yamada J, Sugimoto Y, Inoue K. Selective serotonin reuptake inhibitors fluoxetine and fluvoxamine induce hyperglycemia by different mechanisms. Eur J Pharmacol 1999; 382: 211–5PubMedCrossRefGoogle Scholar
Good MI. Lethal interaction of clozapine and buspirone? Am J Psychiatry 1997; 154: 1472–3PubMedGoogle Scholar
Uvnäs-Moberg K, Ahlenius S, Alster P, et al. Effects of selective serotonin and dopamine agonists on plasma levels of glucose, insulin and glucagon in the rat. Neuroendocrinology 1996; 63: 269–74PubMedCrossRefGoogle Scholar