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Patients on Atypical Antipsychotic Drugs Another High-Risk Group for Type 2 Diabetes

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Patients on Atypical Antipsychotic Drugs Another High-Risk Group for Type 2 Diabetes Reviews/Commentaries/Position Statements REVIEW ARTICLE Patients on Atypical Antipsychotic Drugs Another high-risk group for type 2 diabetes 1 MICHAEL E.J. LEAN, MA, MB, BCHIR, MD, FRCP schizophrenia is an expensive medical 2 FRANK-GERALD PAJONK, MD condition to health care systems and to society in general (5,6). The introduction of chlorpromazine after 1956 transformed the lives of many sufferers. Several major chemical classes ABSTRACT — Patients with schizophrenia are more likely than the general population to of antipsychotic drugs were developed, develop diabetes, which contributes to a high risk of cardiovascular complications; individuals with schizophrenia are two to three times more likely to die from cardiovascular disease than the principally the phenothiazines (including general population. The risk of diabetes, and hence cardiovascular disease, is particularly in- chlorpromazine itself), the butyrophe- creased by some of the new atypical antipsychotic drugs. Individuals taking an atypical antipsy- nones (e.g., haloperidol), and the thiox- chotic drug, particularly younger patients under 40 years of age (odds ratio 1.63, 95% CI anthines (e.g., flupenthixol). All these 1.23–2.16), represent an underrecognized group at high risk of type 2 diabetes. The mechanisms “conventional neuroleptics” are effective responsible for antipsychotic-induced diabetes remain unclear. Hypotheses include these drugs’ because they are dopamine D antago- potential to cause weight gain, possibly through antagonism at the H , 5-HT , or 5-HT 2 1 2A 2C nists (7), but they all have major draw- receptors. Other mechanisms independent of weight gain lead to elevation of serum leptin and insulin resistance. Patients with psychoses have difficulties with diet and lifestyle interventions backs and contribute their own stigmata for diabetes and weight management. If hyperglycemia develops, withdrawal from antipsychotic to schizophrenia. These drugs share a set medication will often be inappropriate, and a change to an atypical antipsychotic drug with lower of Parkinsonian-like movement-disorder diabetogenic potential should be considered, especially in younger patients. Management of side effects, the “extrapyramidal side ef- psychoses should routinely include body weight and blood glucose monitoring and steps to fects” (EPSs), resulting from antagonism promote exercise and minimize weight gain. Careful collaboration between the psychiatric and at dopamine D2 receptors in the basal diabetology teams is essential to minimize the risk of diabetes in patients taking atypical anti- ganglia. psychotic medication and for effective management when it develops. This collaboration will also help minimize the already high risk of cardiovascular disease in individuals with Many conventional neuroleptics schizophrenia. cause excessive daytime sedation, and many are muscarinic antagonists, causing Diabetes Care 26:1597–1605, 2003 dry mouth, blurred vision, and constipa- tion, and may precipitate glaucoma in older patients. he number of individuals in the half of these individuals, the illness will be Newer drugs with lower EPS liability, population receiving antipsychotic lifelong, probably requiring long-term the “atypical antipsychotics,” are increas- T drugs is surprisingly high. The most medication. Schizophrenia causes social ingly replacing the conventional neuro- common reason is schizophrenia, al- disability and also carries a high mortali- leptics. The reason why these drugs have though antipsychotic drugs are widely ty—approximately twice as high as in the better efficacy and side-effect profiles is used in other psychiatric conditions (e.g., general population (1). It has a strikingly not fully understood. One suggestion for bipolar disorder and Alzheimer’s disease). high suicide rate of 10% (2,3), but the their lower EPS liability is lower occu- Schizophrenia is far more common than most common cause of death is acceler- pancy of dopamine D2 receptors in the is generally appreciated. For example, as ated heart disease (two to three times that striatum, but the evidence for this is con- many as 1 in 100 individuals in the pop- in the general population) (4). Despite its flicting. However, it is widely accepted ulation will suffer one or more episodes of relatively low prevalence, the early age at that antipsychotic activity depends on an- schizophrenia in a lifetime, and for at least onset and its chronic nature means that tagonism at central D2 receptors and that the threshold for antipsychotic activity is ϳ ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● 65% occupancy of D2 receptors for both conventional neuroleptics and atyp- From the 1Department of Human Nutrition, University of Glasgow, Glasgow, U.K.; and the 2Department of Psychiatry and Psychotherapy, the Saarland University Hospital, Homburg, Germany. ical antipsychotics (8). Address correspondence and reprint requests to Professor M.E.J. Lean, Professor of Human Nutrition, As early as the mid-1960s, associa- University of Glasgow, Glasgow Royal Infirmary, Glasgow G31 2ER, U.K. E-mail: mej.lean@clinmed. tions between diabetes and conventional gla.ac.uk. neuroleptic treatment were reported (9– Received for publication 9 September 2002 and accepted in revised form 12 February 2003. M.E.J.L. has received honoraria for speaking engagements from Roche, Janssen-Cilag, Abbott, and Merck 18), but evidence has accumulated that and research funds from Sanofi-Synthelabo, Roche, Janssen-Cilag, GlaxoSmithKline, and Alizyme Thera- the risk is even higher for some of the peutics. F.-G.P. is employed by Janssen Cilag. atypical antipsychotics. This review sum- Abbreviations: EPS, extrapyramidal side effect; FDA, Food and Drug Administration. marizes the evidence for a causal link, dis- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. cusses some possible mechanisms, and © 2003 by the American Diabetes Association. concludes by reviewing some of the spe- DIABETES CARE, VOLUME 26, NUMBER 5, MAY 2003 1597 Diabetes and antipsychotic drugs Table 1—Diabetogenic potential of atypical antipsychotic drugs during the first year of treatment with clo- zapine are 7.44 (95% CI 1.603–34.751) Reports Diabetes Diabetes compared with patients with psychosis of diabetes Reported resolved when improved when not receiving antipsychotics. In a 5-year Date (by January cases of drug stopped drug stopped naturalistic study of 82 patients being introduced 2002) ketoacidosis or switched or switched‡ treated with clozapine, 52% experienced one or more and 23% two or more epi- Clozapine 1989† 26 10 8‡ 10 (5) sodes of hyperglycemia; 30% were diag- Risperidone 1994 3 1§ 3 — nosed as having type 2 diabetes (46). Olanzapine 1996 21 8 10 7 (3) Koller et al. (43) analyzed the U.S. FDA’s Quetiapine 1998 2 1 1 1 MedWatch surveillance program for the Ziprasidone 2001 0 0 ——period of January 1990–February 2001 Data were compiled from surveys (29–32) plus other case reports found in Medline using the search terms and pooled these data with published “diabetes” and “antipsychotic or clozapine or olanzapine or quetiapine or risperidone or ziprasidone” pub- cases. They found 384 cases of clozapine- lished between January 1999 and January 2002 (33–42). Data in parentheses indicate cases where the dose associated hyperglycemia, with 242 cases of antipsychotic was reduced and/or diabetes was controlled with drugs and/or diet. †Reintroduced with safeguards to detect potential agranulocytosis. ‡In one of these patients, diabetes resolved completely but of confirmed diabetes. Of these, 80 had recurred when clozapine was restarted and did not resolve when clozapine was subsequently.stopped ketosis or acidosis, and 25 patients died §Patient was HIV positive and taking a protease inhibitor concomitantly with risperidone; protease inhibitors during hyperglycemic episodes. On the are known to cause diabetes. other hand, Wang et al. (47) carried out a case-control study in patients taking “psy- cial problems associated with manage- cally relevant hyperglycemia or diabetes chiatric drugs” in the government- ment in this patient population. according to internationally recognized sponsored drug benefit program in New criteria. It is worth noting that in psychi- Jersey (7,227 case subjects with newly IS THERE A LINK BETWEEN atric circles, it is now generally recognized treated diabetes and 6,780 control sub- SCHIZOPHRENIA AND that diabetes is a risk in patients treated jects). They reported that 1.3% of individ- DIABETES? — Even before antipsy- with antipsychotics, particularly cloza- uals who developed diabetes took chotic drugs appeared, there was evi- pine. This means that the number of clozapine versus 1.7% of control subjects. dence that diabetes was more common in published case reports probably under- Considering that the minimum age for in- patients with schizophrenia (17,19–26). represents the true prevalence of antipsy- clusion was Ͼ20 years, the mean age of A more recent study of patients with chotic-associated diabetes. After our individuals in their study was 63.6 years schizophrenia in the U.S. Veterans Ad- survey was completed, other publications for diabetes case subjects and 61.9 years ministration health care system found on the subject have appeared, most nota- for control subjects, marking the popula- that the rate of diabetes was 6.2–8.7% bly those by Koller and her colleagues, tion as highly unusual. Nevertheless, they (27), compared with 1.1% in U.S. men which
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