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ZYPREXA® (olanzapine)

Anti-psychotics including Clozapine, olanzapine, Quetiapine, and risperidone have been reported to increase the risks of elevated blood sugar and diabetes. There is a very significant literature database that suggests that olanzapine (Zyprexa®) seriously increases the risk of hyperglycemia, diabetic ketoacidosis, and death. While the induction of Type 2 diabetes may be reversible after discontinuing the drug, untreated diabetic ketoacidosis is fatal. On March 1, 2004, Eli Lilly, the manufacturer of Zyprexa®, proclaimed a safety alert and indicated a label change for the drug warning against possible increased risk of hyperglycemia and diabetes in patients taking this medication. Possible mechanisms for this adverse reaction include excessive weight gain associated with insulin resistance, inhibition of glucose transport, alpha-2-adrenergic inhibition of insulin release, and blockade of pancreatic beta-cell 5HT[1A] receptors. Dr. Parent has consulted on a Zyprexa® death case and has opined that there is a causal relationship between Zyprexa® and diabetic ketoacidosis with subsequent death. Dr. Parent believes that there is sufficient support in the published literature for the construction of a causation report that will survive a Daubert challenge. Selected references on this subject are provided below.

Selected References

Ai, D., Roper, T. A. and Riley, J. A., Diabetic ketoacidosis and clozapine. Postgraduate Medical Journal, 74(874), 493-494 (1998).

Ananth, J., Parameswaran, S. and Gunatilake, S., Side effects of atypical antipsychotic drugs. Current Pharmaceutical Design, 10(18), 2219-2229 (2004).

Avella, J., Wetli, C. V., Wilson, J. C., Katz, M. and Hahn, T., Fatal olanzapine-induced hyperglycemic ketoacidosis. American Journal of Forensic Medicine and Pathology, 25(2), 172-175 (2004).

Bechara, C. I. and Goldman-Levine, J. D., Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy, 21(11), 1444-1447(2001).

Bettinger, T. L., Mendelson, S. C., Dorson, P. G. and Crismon, M. L., Olanzapine-induced glucose dysregulation. Annals of Pharmacotherapy, 34(7-8), 865-867 (2000).

Bonanno, D. G., Davydov, L. and Botts, S. R., Olanzapine-induced diabetes mellitus. Annals of Pharmacotherapy, 35(5), 563-565 (2001).

Chue, P. and Singer, P., A review of olanzapine-associated toxicity and fatality in overdose. Journal of Psychiatry and Neuroscience, 28(4), 253-261 (2003).

Conley, R. R. and Mahmoud, R., A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. American Journal of Psychiatry, 158(5), 765-774 (2001).

Courvoisie, H. E., Cooke, D. W. and Riddle, M. A., Olanzapine-induced diabetes in a seven-year-old boy. Journal of Child and Adolescent Psychopharmacology, 14(4), 612-616 (2004).

Doucette, D. E., Grenier, J. P. and Robertson, P. S., Olanzapine-induced acute pancreatitis. Annals of Pharmacotherapy, 34(10), 1128-1131 (2000).

Fertig, M. K., Brooks, V. G., Shelton, P. S. and English, C. W., Hyperglycemia associated with olanzapine. Journal of Clinical Psychiatry, 59(12), 687-689 (1998).

Gatta, B., Rigalleau, V. and Gin, H., Diabetic ketoacidosis with olanzapine treatment. Diabetes Care, 22(6), 1002-1003 (1999).

Gerber, J. E. and Cawthon, B., Overdose and death with olanzapine: two case reports. American Journal of Forensic Medicine and Pathology, 21(3), 249-251 (2000).

Goldstein, L. E., Sporn, J., Brown, S., Kim, H., Finkelstein, J., Gaffey, G. K., Sachs, G. and Stern, T. A., New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics, 40(5), 438-443 (1999).

Haupt, D. W. and Newcomer, J. W., Hyperglycemia and antipsychotic medications. Journal of Clinical Psychiatry, 62(Suppl 27), 15-26; discussion 40-41 (2001).

Henderson, D. C., Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? Central Nervous System Drugs, 16(2), 77-89 (2002).

Howes, O. D. and Rifkin, L., Diabetic keto-acidotic (DKA) coma following olanzapine initiation in a previously euglycaemic woman and successful continued therapy with olanzapine. Journal of Psychopharmacology, 18(3), 435-437 (2004).

Jin, H., Meyer, J. M. and Jeste, D. V., Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Annals of Clinical Psychiatry, 14(1), 59-64 (2002).

Johnson, R. P., Al-Taher, M. T., Madlock, L. E., Guo, M. and Nasdahl, C. S., Increasing insulin
dose for olanzapine-related diabetes. American Journal of Psychiatry, 159(1), 150-151 (2002).

Kamran, A., Doraiswamy, P. M., Jane, J. L., Hammett, E. B. and Dunn, L., Severe hyperglycemia associated with high doses of clozapine. American Journal of Psychiatry, 151(9), 1395 (1994).

Keskiner, A., el-Toumi, A. and Bousquet, T., Psychotropic drugs, diabetes and chronic mental patients. Psychosomatics, 14(3), 176-181 (1973).

Koller, E., Schneider, B., Bennett, K. and Dubitsky, G., Clozapine-associated diabetes. American Journal of Medicine, 111(9), 716-723 (2001).

Koller, E., Malozowski, S. and Doraiswamy, P. M., Atypical antipsychotic drugs and hyperglycemia in adolescents. Journal of the American Medical Association, 286(20), 2547-2548 (2001).

Koller, E. A. and Doraiswamy, P. M., Olanzapine-associated diabetes mellitus. Pharmacotherapy, 22(7), 841-852 (2002).

Koro, C. E., Fedder, D. O., L'Italien, G. J., Weiss, S. S., Magder, L. S., Kreyenbuhl, J., Revicki, D. A. and Buchanan, R. W., Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. British Medical Journal, 325(7358), 243-247 (2002).

Kostakoglu, A. E., Yazici, K. M., Erbas, T. and Guvener, N., Ketoacidosis as a side-effect
of clozapine: a case report. Acta Psychiatrica Scandinavica, 93(3), 217-218 (1996).

Koval, M. S., Rames, L. J. and Christie, S., Diabetic ketoacidosis associated with clozapine treatment. American Journal of Psychiatry, 151(10), 1520-1521 (1994).

Kropp, S., Emrich, H. M., Bleich, S. and Degner, D., Olanzapine-related hyperglycemia in
a nondiabetic woman. Canadian Journal of Psychiatry, 46(5), 457 (2001).

Kyriazis, I. A., Korovesis, K., Bashir, S., Liakouras, A. and Partheniou, C., Diabetic ketoacidosis and severe dyslipidemia in an adult psychotic man with olanzapine  treatment. Journal of Clinical Psychopharmacology, 26(1), 92-94 (2006).

Leslie, D. L. and Rosenheck, R. A., Incidence of newly diagnosed diabetes attributable toatypical antipsychotic medications. American Journal of Psychiatry, 161(9), 1709-1711 (2004).

Liebzeit, K. A., Markowitz, J. S. and Caley, C. F., New onset diabetes and atypical antipsychotics. European Neuropsychopharmacology, 11(1), 25-32 (2001).

Lindenmayer, J. P. and Patel, R., Olanzapine-induced ketoacidosis with diabetes mellitus. American Journal of Psychiatry, 156(9), 1471 (1999).

Lund, B. C., Perry, P. J., Brooks, J. M. and Arndt, S., Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Archives of General Psychiatry, 58(12), 1172-1176 (2001).

Marinow, A., Diabetes in chronic schizophrenia. Diseases of the Nervous System, 32(11), 777-778 (1971).

Meatherall, R. and Younes, J., Fatality from olanzapine induced hyperglycemia. Journal of Forensic Sciences, 47(4), 893-896 (2002).

Merrick, T. C., Felo, J. A. and Jenkins, A. J., Tissue distribution of olanzapine in a postmortem case. American Journal of Forensic Medicine and Pathology, 22(3), 270-274 (2001).

Muench, J. and Carey, M., Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. Journal of the American Board of Family Practice, 14(4), 278-282 (2001).

Mukherjee, S., Decina, P., Bocola, V., Saraceni, F. and Scapicchio, P. L., Diabetes mellitus in schizophrenic patients. Comprehensive Psychiatry, 37(1), 68-73 (1996).

Newcomer, J. W., Second-generation (atypical) antipsychotics and metabolic effects:  a comprehensive literature review. CNS Drugs, 19(Suppl 1), 1-93 (2005).

Ober, S. K., Hudak, R. and Rusterholtz, A., Hyperglycemia and olanzapine. American Journal of  Psychiatry, 156(6), 970 (1999).

Popli, A. P., Konicki, P. E., Jurjus, G. J., Fuller, M. A. and Jaskiw, G. E., Clozapine and associated diabetes mellitus. Journal of Clinical Psychiatry, 58(3), 108-111 (1997).

Ragucci, K. R. and Wells, B. J., Olanzapine-induced diabetic ketoacidosis. Annals of Pharmacotherapy, 35(12), 1556-1558 (2001).

Rigalleau, V., Gatta, B., Bonnaud, S., Masson, M., Bourgeois, M. L., Vergnot, V. and Gin, H., Diabetes as a result of atypical anti-psychotic drugs--a report of three cases. Diabetes Medicine, 187(6), 484-486 (2000).

Roefaro, J., Mukherjee, S. M., Olanzapine-lnduced hyperglycemic nonketonic coma. Annals of Pharmacotherapy, 35(3), 300-302 (2001).

Seaburg, H. L., McLendon, B. M. and Doraiswamy, P. M., Olanzapine-associated severe hyperglycemia, ketonuria, and acidosis: case report and review of literature. Pharmacotherapy, 21(11), 1448-1454 (2001).

Selva, K. A. and Scott, S. M., Diabetic ketoacidosis associated with olanzapine in an adolescent patient. Journal of Pediatrics, 138(6), 936-938 (2001).

Sernyak, M. J., Leslie, D. L., Alarcon, R. D., Losonczy, M. F. and Rosenheck, R., Association of
diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. American Journal of Psychiatry, 159(4), 561-566 (2002).

Sheitman, B. B., Bird, P. M., Binz, W., Akinli, L. and Sanchez, C., Olanzapine-induced
elevation of plasma triglyceride levels. American Journal of Psychiatry, 156(9), 1471-1472

Sowell, M., Mukhopadhyay, N., Cavazzoni, P., Carlson, C., Mudaliar, S., Chinnapongse, S., Ray, A., Davis, T., Breier, A., Henry, R. R. and Dananberg, J., Evaluation of insulin sensitivity in healthy volunteers treated with olanzapine, risperidone, or placebo: a prospective, randomized study using the two-step hyperinsulinemic, euglycemic clamp. Journal of Clinical Endocrinology and Metabolism, 88(12), 5875-5880 (2003).

Straker, D., Mendelowitz, A. and Karlin, L., Near fatal ketoacidosis with olanzapine treatment. Psychosomatics, 43(4), 339-340 (2002).

Tavakoli, S. A. and Arguisola, M. S., Diabetic ketoacidosis in a patient treated with olanzapine, valproic acid, and venlafaxine. Southern Medical Journal, 96(7), 729-730 (2003).

Torrey, E. F. and Swalwell, C. I., Fatal olanzapine-induced ketoacidosis. American Journal of Psychiatry, 160(12), 2241 (2003).

Tsuchiyama, N., Ando, H., Ota, T., Sakurai, M. and Takamura, T., Modulating effects of olanzapine on the development of diabetic ketoacidosis. Diabetes Medicine, 21(3), 300-301 (2004).

Van Meter, S. A., Seaburg, H., McLendon, B. and Doraiswamy, P. M., Olanzapine, new-onset diabetes mellitus, and risk for insulin overdose. Journal of Clinical Psychiatry, 62(12), 993-994 (2001).

Von Hayek, D., Huttl, V., Reiss, J., Schweiger, H. D. and Fuessl, H. S., Hyperglycemia and ketoacidosis associated with olanzapine Nervenarzt, 70(9), 836-837 (1999).

Wehring, H. J., Kelly, D. L., Love, R. C. and Conley, R. R., Deaths from diabetic ketoacidosis after long-term clozapine treatment. American Journal of Psychiatry, 160(12), 2241-2242 (2003).

Westphal, S. A., The occurrence of diabetic ketoacidosis in non-insulin-dependent diabetes and newly diagnosed diabetic adults. American Journal of Medicine, 101(1), 19-24 (1996).

Wetterling, T., Diabetes mellitus type II--induced by "atypical" neuroleptics? Fortschritte Der Neurologie Psychiatrie, 71(6), 312-322 (2003).

Wilson, D. R., D'Souza, L., Sarkar, N., Newton, M. and Hammond, C., New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophrenia Research, 59(1), 1-6 (2003).

Wirshing, D. A., Spellberg, B. J., Erhart, S. M., Marder, S. R. and Wirshing, W. C., Novel antipsychotics and new onset diabetes. Biological Psychiatry, 44(8), 778-783 (1998).

Yazici, K. M., Erbas, T. and Yazici, A. H., The effect of clozapine on glucose metabolism. Experimental and Clinical Endocrinology and Diabetes, 106(6), 475-477 (1998).

Zajecka, J. M., Weisler, R., Sachs, G., Swann, A. C., Wozniak, P. and Sommerville, K. W., A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. Journal of Clinical Psychiatry, 63(12), 1148-1155 (2002).

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