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Clinical Experience with Insulin Resistance, Diabetic Ketoacidosis, and Type 2 Diabetes Mellitus in Patients Treated with Atypical Antipsychotic Agents

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Clinical Experience with Insulin Resistance, Diabetic Ketoacidosis, and Type 2 Diabetes Mellitus in Patients Treated with Atypical Antipsychotic Agents David C. Henderson Clinical Experience With Insulin Resistance, Diabetic Ketoacidosis, and Type 2 Diabetes Mellitus in Patients Treated With Atypical Antipsychotic Agents David C. Henderson, M.D. © Copyright 2001 Physicians Postgraduate Press, Inc. Numerous reports have associated atypical antipsychotic agents with hyperglycemia, diabetes mellitus, and diabetic ketoacidosis. Although the mechanisms are poorly understood, clinical experi- ence suggests that these adverse effects are major areas of concern and require attention by the psychi- atric team and primary care clinicians. This article discusses my clinical experience with glucose metabolism impairment related to treatment with antipsychotic medications. (J Clin Psychiatry 2001;62[suppl 27]:10–14) BLOOD GLUCOSE DISORDERS 8 deaths. The majority of DKA episodes occurred in the One personal copy mayfirst be 6 printedmonths of treatment with clozapine. One patient DKA and Type 2 Diabetes Mellitus actually developed diabetes immediately following an Recently, case reports have linked clozapine and olan- accidental 500-mg dose of clozapine. This highlights the zapine to diabetic ketoacidosis (DKA), diabetes mellitus serious potential risk associated with DM and DKA and (DM), and hyperglycemia.1–14 The reports of DKA with clo- should alert clinicians to be proactive in monitoring and zapine and olanzapine and possible increased incidence of preventing medical morbidity associated with psycho- type 2 diabetes mellitus may represent 2 separate popula- tropic medications. tions with varying risks. Several cases of DKA associated A recent case report20 described a 42-year-old, white, with clozapine and olanzapine have been reported, with the human immunodeficiency virus (HIV)-positive man with majority of these cases resulting in partial or complete a history of chronic depression with psychotic features ad- remission when the drug was discontinued.1–3,5,6,8–10,12–18 mitted to the hospital for DKA while taking risperidone, Additionally, several cases of DKA resolved after clozapine fluoxetine, and trazodone. It is unclear whether the patient or olanzapine was discontinued, only to have hyperglyce- received other medications that could impair glucose me- mia return upon reinstitution of the drug. That DKA tabolism. Patients receiving the HIV-1 protease inhibitors patients taken off the drug achieved remission strongly often develop impaired glucose tolerance or diabetes, suggests that insulin secretion is affected in these pa- most likely due to an induction of insulin resistance.21 Ris- tients.1,2,5,6,8,9,12,17 peridone was discontinued, the DKA resolved, and the A group from the U.S. Food and Drug Administration patient was discharged with quetiapine and subcutaneous (FDA) Research program identified 11 reports of exacer- insulin. A recent case report22 described a 42-year-old man bation of existing diabetes and 131 cases of clozapine- with a history of bipolar disorder admitted to the hospital associated new-onset diabetes from the FDA’s Medwatch for new-onset diabetes, requiring insulin, 1 month after surveillance program.19 The Medwatch surveillance pro- beginning treatment with quetiapine. Quetiapine was dis- gram only captures a small percentage of likely cases. continued, and the insulin requirement steadily declined There were 37 cases of probable diabetic ketoacidosis and until it was discontinued 5 months after hospitalization. Additionally, Wilson et al.23 described 14 patients who de- veloped diabetes and DKA (N = 5) while receiving treat- ment with clozapine, olanzapine, or quetiapine. From the Department of Psychiatry and Schizophrenia 15 Program, Massachusetts General Hospital and Harvard We reported a 5-year naturalistic study to examine, in Medical School, Boston, Mass. 101 clozapine patients with schizophrenia, the incidence Presented at the planning teleconference “Metabolic of treatment-emergent DM in relation to other factors in- Disturbances Associated With Antipsychotic Use,” which was held October 20, 2000, and supported by an unrestricted cluding weight gain, lipid abnormalities, age, clozapine educational grant from Janssen Pharmaceutica, L.P. dose, and treatment with valproate. Clozapine dose, use of Reprint requests to: David C. Henderson, M.D., Freedom Trail Clinic, 25 Staniford St., Boston, MA 02114 (e-mail: valproate, and laboratory results were recorded at 6-month [email protected]). intervals. Nineteen patients were eliminated from the 10 J Clin Psychiatry 2001;62 (suppl 27) Diabetic Syndromes and Atypical Antipsychotics study secondary to a history of diabetes preclozapine, or gain and elevated levels of insulin, leptin, and blood lipids the baseline preclozapine glucose values were not avail- as well as insulin resistance, with 3 patients diagnosed as able. Diabetic patients treated with clozapine required having diabetes mellitus. The elevated insulin values nearly a 2-fold increase in insulin requirement or a switch would argue against the role of serotonin antagonism, to insulin from an oral hypoglycemic agent. which theoretically could reduce β cell insulin production. The mean ± SD age at the time of clozapine initiation We presented preliminary results of a cross-sectional of the 82 patients studied was 36.4 ± 7.8 years and 22 study comparing clozapine-, olanzapine-, and risperidone- (27%) were women. During the 60-month study, 43 (52%) treated non-obese body mass index ([BMI] < 30 mg/kg2) of the 82 patients experienced at least 1 elevated fasting schizophrenia subjects who had a frequent-sampled intra- blood glucose (FBG ≥ 140 mg/dL [7.7 mmol/L]) using the venous glucose tolerance test using Bergman’s Minimal “old” American© Copyright Diabetes Association 2001 criteria Physicians24 and 55 Model Postgraduate Analysis.28 There were Press, no differences Inc. between the (67%) of 82 patients experienced at least 1 elevated fast- 3 groups for age, sex, race, family history of diabetes mel- ing blood glucose with the “new” American Diabetes As- litus, BMI, percentage of body fat, and fasting glucose, sociation criteria (FBG ≥ 126 mg/dL [6.9 mmol/L]).25 fasting insulin, cortisol, and leptin levels. Preliminary re- Thirty (37%) of 82 patients were actually diagnosed with sults suggest that there is a significant difference between diabetes during the 5-year follow-up. Weight gain, valpro- the 3 groups for the insulin sensitivity index with cloza- ate, and clozapine total daily dose were not significant risk pine and olanzapine exhibiting significant insulin resis- factors for developing diabetes mellitus. Some patients tance. The acute insulin response to glucose (AIR), a mea- gained weight and developed DM, while others did not gain sure examining the initial response of β cells to a glucose weight but also developed diabetes. Also, several patients load, was not impaired. In fact, subjects treated with cloza- developed a cluster of medical disorders similar to meta- pine and olanzapine had a nonsignificant, but greater, AIR bolic syndrome X, which include centralOne personal obesity, hyper- copy maycompared be printed with risperidone-treated subjects, whose values insulinemia, hypertension, increase in very-low-density were considered within normal limits. Additionally, dif- lipoprotein (VLDL)-triglyceride and LDL-cholesterol, ferences between risperidone and olanzapine and risperi- decrease in high-density lipoprotein cholesterol, athero- done and clozapine were shown for glucose effectiveness, sclerosis, procoagulant state, and hyperglycemia. suggesting potential impairment of glucose utilization. New patients exhibited abnormal fasting glucose val- Glucose effectiveness represents the ability of glucose, in- ues every 6 months, leading to a diagnosis of DM. It ap- dependent of insulin, to increase glucose uptake and sup- pears that the risk for developing diabetes continues as press endogenous glucose production. This function is long as patients receive treatment with clozapine. independent of glucose transporters. It is possible that ad- ministration of clozapine and olanzapine results in insulin Insulin Resistance resistance and impairs glucose effectiveness, thereby plac- There are a number of potential mechanisms for the ing patients at risk for DM. Combined with other risk fac- association of atypical antipsychotic medications with hy- tors, patients may develop DM in weeks to years after ini- perglycemia. Typically, insulin resistance is an early fea- tiating treatment with atypical antipsychotic agents. ture, which is initially compensated in part by increased production of insulin by pancreatic β cells (i.e., hyperinsu- Risk Assessment and Risk Factors linemia).26 Eventually, as β cells become exhausted, the for Diabetes Mellitus combined effects of insulin resistance and decreased insu- Before placing a patient on an atypical antipsychotic lin production reduce insulin-mediated glucose uptake and agent, it is important to perform a risk factor assessment utilization by muscle cells and prevent insulin-mediated for DM and other metabolic disorders. A risk assessment inhibition of hepatic glucose production. should include baseline serum values, weight, BMI, age, Antagonism at serotonin (5-HT)1A receptors by atypical race, family history, level of physical activity, and diet. antipsychotic agents may decrease pancreatic β cell re- There are a number of factors that may place someone at sponsiveness to blood sugar levels, resulting in impair- risk for developing diabetes. Elevated plasma glucose and ment of glucose metabolism.10
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