Tardive dyskinesia (TD) is one of the most significant side

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1 Brief Communication Diabetes, Tardive Dyskinesia, Parkinsonism, and Akathisia in Schizophrenia: A Retrospective Study Applying 1998 Diabetes Health Care Guidelines to Antipsychotic Use Emmanuelle Lévy, MD, FRCPC 1, Howard C Margolese, MD, CM, FRCPC 2, Lawrence Annable, BSc, DipStat 3, Guy Chouinard, MD, MSc, FRCPC 4 Background: This study examines the links among diabetes, tardive dyskinesia (TD), and other extrapyramidal symptoms (EPS) in schizophrenia outpatients treated with typical and atypical antipsychotics. Objectives: Using a retrospective chart review, we compared 30 schizophrenia patients with diabetes mellitus (DM) with 30 schizophrenia patients, matched for age and sex, with no DM. We compared prevalence and severity of parkinsonism, akathisia, TD, dystonia, and antipsychotic type (that is, typical vs atypical). Results: We found no statistically significant differences between the DM group and the non-dm group prevalence and severity of EPS, including TD. Conclusion: We did not find DM and TD association to be significant in the era of atypical antipsychotics, possibly because of their antidyskinetic effect. (Can J Psychiatry 2004;49: ) Information on author affiliations appears at the end of the article. Clinical Implications Diabetes mellitus (DM) may no longer be associated with tardive dyskinesia, because extrapyramidal symptoms (EPS) are alleviated by atypical antipsychotics. Because atypical antipsychotics are associated with a higher incidence of DM, psychiatrists should be aware of DM treatment, particularly for schizophrenia patients who are reluctant to consult other physicians. We review the treatment strategies for DM and the use of antipsychotics. Limitations The small sample size may limit the generalization of our results. The precision of our data may have been compromised by the retrospective chart review design. There is a lack of uniformity between the time at which the EPS were evaluated and the latest antipsychotic medication was prescribed. Tardive dyskinesia (TD) is one of the most significant side effects of classical antipsychotics (CAPs). Patient-related factors associated with TD include age, sex, psychiatric diagnosis, extrapyramidal symptoms (EPS), cognitive deficits, and structural brain damage (1,2). Diabetes mellitus (DM) Key Words: antipsychotics, neuroleptics, diabetes mellitus, akathisia, dystonia, tardive dyskinesia, extrapyramidal symptoms may also be a risk factor for TD (1,2). Mukherjee and colleagues suggested a possible association between TD and impaired glucose metabolism (3,4). Other studies report a higher incidence of DM in relatives of patients with TD, suggesting a genetic link between dopamine mechanisms and 398

2 Diabetes, Tardive Dyskinesia, Parkinsonism, and Akathisia in Schizophrenia Table 1 Demographic and clinical characteristics of schizophrenia patients with and without diabetes mellitus glucose regulation (5). Schultz and colleagues suggested that hyperinsulinemia and hyperglycemia associated with insulin resistance contribute to TD pathogenesis (6). In contrast, 2 studies failed to replicate the correlation between TD and DM (7,8). Therefore, the relation between DM and abnormal movements requires further empirical validation. This study hypothesized that antipsychotic (AP)-treated chronic schizophrenia patients with DM are more likely to develop abnormal movements than are patients with no DM. We also expected greater severity of abnormal movements in the DM group. Methods Study Procedure We conducted a retrospective chart review of 60 patients diagnosed with schizophrenia according to DSM-IV criteria. After obtaining approval from the McGill Research Ethics DM+ (n = 30) DM (n = 30) P Age (years) 55.9 (SD 11.6) 55.9 (SD 11.01) 0.99 Men (%) Women (%) Ethnicity (%) White Black Asian History of alcohol abuse (%) History of substance abuse (%) Prolactin level 25.2 (SD 24.5) 20.1 (SD 14.0) 0.30 ECT Number of patients Average number of ECT 4 30 Presence of brain damage (%) Typical AP prescribed (%) Duration of typical AP (months) 70.3 (SD 72.2) 62.2 (SD 69.7) 0.89 CPZ for typical AP (mg daily) (SD 556.3) (SD 462.9) 0.70 AAP prescribed (%) Duration of AAP (months) 27.2 (SD 35.6) 18.7 (SD 28.8) 0.50 CPZ for AAP (mg daily) (SD 495.5) (SD 405.0) Patients using anticholinergics (%) AAP = atypical antipsychotic; AP = Antipsychotic; CPZ = chlorpromazine; DM+ = with diabetes mellitus; DM = with no diabetes mellitus; therapy; ECT = electroconvulsive 0.07 Board, we examined the charts of patients from the outpatient special follow-up (SFU) clinic for schizophrenia, McGill University Health Centre (MUHC). We included patients aged 18 to 65 years who were prescribed APs and who had a DSM-IV diagnosis of schizophrenia and DM, according to 1998 guidelines (9). We identified 35 out of 300 schizophrenia patients attending the SFU clinic with DM type 1 or type 2. To form the control group, we matched for age and sex 30 schizophrenia patients from SFU with DM and 30 schizophrenia patients from SFU with no DM. We excluded the remaining 5 patients because no matched control subjects were found. We obtained the following information from the patients charts: age; sex; ethnicity; DM status, type, and duration; dosage and interval of AP treatment; psychiatric diagnosis; past or present substance use; history of electroconvulsive therapy (ECT); and brain damage. We collected laboratory investigations completed within the last year, including prolactin, random glucose, hemoglobin A 1C, and lipid profile. We also recorded other medication use, including anticholinergics, antiepileptics, antidepressants, benzodiazepines, and oral antihyperglycemics. We evaluated EPS, including parkinsonism, TD, akathisia, and dystonia, using the Extrapyramidal Symptom Rating Scale (ESRS) (10). The ESRS is conducted at least yearly on SFU patients, and results are recorded in their charts. To establish EPS prevalence, a score of 3 or more on at least 1 ESRS item or a score of 2 on 2 items was required. We used the same cut-off scores to define presence or absence of TD, parkinsonism, and dystonia. Akathisia score was derived from the combined subjective and objective akathisia measures, where a total score of 3 or more on the 2 items indicated presence of akathisia. We identified patients as having DM, using 1 of 3 methods: 1) the patient was diagnosed by an endocrinologist in the MUHC metabolic clinic; 2) the patient was currently Can J Psychiatry, Vol 49, No 6, June

3 The Canadian Journal of Psychiatry Brief Communication Table 2 Prevalence of extrapyramidal symptoms as measured by the extraypyramidal symptoms rating scale (ESRS) DM+ (%) DM (%) P Parkinsonism Tardive dyskinesia Dystonia Akathisia EPS total DM+ = with diabetes mellitus; DM = with no diabetes mellitus; EPS = extrapyramidal symptoms Table 3 Severity of extrapyramidal symptoms as measured by the ESRS DM+ Mean (SD) DM Mean (SD) Parkinsonism 7.33 (5.16) 6.60 (5.74) 0.64 Tardive dyskinesia 4.12 (4.41) 5.88 (6.39) 0.11 Dystonia 0.63 (1.61) 0.8 (1.95) 0.74 Akathisia 0.3 (0.6) 0.85 (1.31) 0.06 EPS total (7.47) (11.71) 0.61 receiving hypoglycemics, metformin, and (or) glyburide; or 3) a fasting plasma glucose (FPG) blood test of more than 7 mmol/l was found at the SFU annual laboratory investigations. Statistical Analysis Regarding ESRS severity scores, we used paired t tests to compare DM patients and matched non-dm patients. We used McNemar s chi-square test for matched samples to investigate differences between patients with DM and patients with no DM regarding EPS, parkinsonism, akathisia, TD, and dystonia prevalence. We also compared CAP and atypical antipsychotic use. Results The mean age of our sample was 55.9 years (SD 11.3 years), and 70% were men. DM groups and non-dm groups did not differ significantly (P > 0.05) regarding age, sex, ethnicity, typical and atypical antipsychotic use, mean dosage (that is, chlorpromazine equivalents), treatment duration, anticholinergic use, prolactin level, history of ECT, brain damage, or past or present substance use (see Table 1). There were no statistically significant (P > 0.05) differences between patients with DM and patients with no DM regarding overall prevalence of EPS, parkinsonism, akathisia, TD, or dystonia, as measured on ESRS subscales (Table 2). Further, no statistically significant differences (P > 0.05) were found between patients with DM and patients with no DM in the P severity scores for total EPS, parkinsonism, akathisia, TD, or dystonia (Table 3). Discussion Previous studies report DM as a risk factor for TD. Ganzini and colleagues found 79% TD prevalence in 38 AP-treated patients with DM, compared with 53% in 38 matched control patients with no DM (P < 0.001) (1). Significantly higher TD severity was also found in the DM group (P < 0.001). However, a high prevalence (21%) of spontaneous dyskinesia was found in a DM group not treated with APs, suggesting that dyskinesia linked to DM might be mistaken for TD (1). Among 160 elderly patients beginning APs, Woerner and colleagues reported TD in 54.1% of DM type 2 patients and 25.6% of non-dm patients after 43 weeks of CAP exposure (P = 0.07) (2). After controlling for age and sex, TD risk among patients with DM was stronger (risk ratio 2.38; 95%CI, 1.04 to 5.46) (2). Schultz and others found a significant correlation (P < 0.006) between Abnormal Involuntary Movement Scale severity and baseline glucose measurements when controlling for age in 21 schizophrenia patients (6). These studies suggest higher prevalence and severity of TD in DM patients treated with CAPs. Two studies failed to replicate these findings. In a prospective study, 266 elderly patients were exposed to CAPs for a median 21 days (4). The 41 patients with DM did not display significantly more TD than did 225 patients with no DM, despite the vulnerability of this age group to movement disorders. However, this study did not use atypical antipsychotics. In a retrospective study, Raja and Azzoni compared 34 schiophrenia patients with DM and 34 schizophrenia patients without DM. TD prevalence in DM patients (33.3%) was not significantly different from that in patients with no DM (40%). However, only some patients (that is, 70% of DM patients and 44% of non-dm patients) were treated with APs for more than 3 months. Further, the authors omitted stating whether APs were classical or atypical. Finally, unlike our study, the relation between TD and EPS severity and DM was not explored. Nevertheless, the authors concluded that diabetes was unlikely to play a major role in the pathogenesis of TD (8; p 61). In this study, we did not replicate an association between DM and abnormal movements, which supports the findings of the 2 aforementioned studies (7,8). Contrary to our hypothesis, rates of EPS, including TD in patients with DM, were similar to those in patients with no DM. In our sample, there was a nonsignificant trend toward more patients in the DM (67%) vs non-dm group (53%) being 400

4 Diabetes, Tardive Dyskinesia, Parkinsonism, and Akathisia in Schizophrenia prescribed atypical antipsychotics. This suggests that lower prevalence of TD in the DM group might be explained by the antidyskinetic effect of atypical antipsychotics (11 13). Because prior AP use was not always documented, calculations of cumulative APs are rendered uncertain a consistent limitation in TD studies. Because of known noncompliance in schizophrenia patients, accuracy of assessing cumulative AP exposure, dosage, or concurrent use of other medications, including anticholinergics, which may alter TD rates (14), is limited. This is the case with all studies using cumulative AP exposure. Another limitation is the lack of uniformity between time of ESRS evaluations and the latest medication prescription: some ESRS ratings are dated up to 1 year prior to the latest prescription. The small sample size, yielding low statistical power, may have prevented our finding an association between DM and TD. Given that atypical antipsychotics are also associated with a higher incidence of DM (15 19), it is important for psychiatrists to be aware of DM treatment, particularly for schizophrenia patients who are reluctant to consult other physicians. The 1998 Clinical Practice Guidelines for the Management of Diabetes in Canada (9) recommend measuring FPG annually if DM risk factors are present. Risk factors include family history of DM, ethnicity, obesity, coronary artery disease, hypertension, history of impaired glucose tolerance (that is, FPG < 7 mmol/l), impaired fasting glucose (that is, 6.1 < FPG < 6.9), low high-density lipoprotein cholesterol levels ( 0.9 mmol/l), or high fasting triglycerides levels (> 2.8 mmol/l) (9). Nutritional counselling, diet, exercise, and behavioural modification should first be addressed when patients using atypical anitpsychotics display more than 1 risk factor. If DM type 2 is diagnosed, lifestyle changes and smoking avoidance should be addressed. If adequate glucose levels are not achieved within 2 to 4 months, lifestyle changes should be reviewed and an oral hypoglycemic agent in monotherapy should be added. Sulfonylurea or biguanides are recommended if FPG > 10 mmol/l. Biguanides (metformin) are preferable when used with atypical antipsychotics because biguanides are associated with less weight gain. However, biguanides remain contraindicated with renal or hepatic insufficiency. If adequate glucose levels are not achieved within 2 to 4 months, even after maximizing dosage, combination oral hypoglycemics should be considered. Bedtime insulin with oral agents is reserved for patients not responding to lifestyle modifications and oral combination therapy (9). In conclusion, our results suggest that the association between DM and TD may no longer be significant in the era of atypical antipsychotics. Prospective studies are needed to corroborate these findings. Although the prevention of DM is an important issue with atypical antipsychotics, it does not appear to be a contributing factor of TD. References 1. Ganzini L, Heintz RT, Hoffman WF, Casey DE. The prevalence of tardive dyskinesia in neuroleptic-treated diabetics. A controlled study. Arch Gen Psychiatry 1991;48: Woerner MG, Saltz BL, Kane JM, Lieberman JA, Alvir JM. Diabetes and development of tardive dyskinesia. Am J Psychiatry 1993;150: Mukherjee S, Wisniewski A, Bilder R, Sackeim HA. Possible association between tardive dyskinesia and altered carbohydrate metabolism. Arch Gen Psychiatry 1985;42: Mukherjee S, Roth SD, Sandyk R, Schnur DB. Persistent tardive dyskinesia and neuroleptic effects on glucose tolerance. Psychiatry Res 1989;29: Mukherjee S, Mahadik S. Diabetes mellitus and tardive dyskinesia. In: Yassa R, editor. Neuroleptic-induced movement disorders. New York: Cambridge University Press; Schultz SK, Arndt S, Ho BC, Oliver SE, Andreasen NC. Impaired glucose tolerance and abnormal movements in patients with schizophrenia. Am J Psychiatry 1999;156: Jeste DV, Caligiuri MP, Paulsen JS, Heaton RK, Lacro JP, Harris MJ, and others. Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients. Arch Gen Psychiatry 1995;52: Raja M, Azzoni A. Diabetes is not a risk factor for tardive dyskinesia: a retrospective observational study. Human Psychopharmacol 2002;17: Meltzer S, Leiter L, Daneman D, Gerstein HC, Lau D, Ludwig S, and others clinical practice guidelines for the management of diabetes in Canada. Canadian Diabetes Association. CMAJ 1998;159 (Suppl 8):S1 S Chouinard G, Ross-Chouinard A, Annable L, Jones B. The extrapyramidal symptom rating scale. Can J Neurol Sci 1980;7: Chouinard G. Effects of risperidone in tardive dyskinesia: an analysis of the Canadian multicenter risperidone study. J Clin Psychopharmacol 1995;15:36S 44S. 12. Littrell KH, Johnson CG, Littrell S, Peabody CD. Marked reduction of tardive dyskinesia with olanzapine. Arch Gen Psychiatry 1998;55: Tamminga CA, Thaker GK, Moran M, Kakigi T, Gao XM. Clozapine in tardive dyskinesia: observations from human and animal model studies. J Clin Psychiatry 1994;55(Suppl B): Wszola BA, Newell KM, Sprague RL. Risk factors for tardive dyskinesia in a large population of youths and adults. Exp Clin Psychopharmacol 200;9: Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159: Koller EA, Doraiswamy PM. Olanzapine-associated diabetes mellitus. Pharmacotherapy 2002;22: Koro CE, Fedder DO, L Italien GJ, Weiss S, Magder LS, Kreyenbuhl J, and others. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry 2002;59: Sobel M, Jaggers ED, Franz MA. New-onset diabetes mellitus associated with the initiation of quetiapine treatment. J Clin Psychiatry 1999;60: Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, Goff DC. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 2000;157: Manuscript received June 2003, revised, and accepted December Clinical Research Fellow, Clinical Psychopharmacology Unit, McGill University Health Centre and Department of Psychiatry, McGill University, Montreal, Quebec. 2 Assistant Professor, Clinical Psychopharmacology Unit, McGill University Health Centre and Department of Psychiatry, McGill University, Montreal, Quebec. 3 Professor, Clinical Psychopharmacology Unit, McGill University Health Centre and Department of Psychiatry, McGill University, Montreal, Quebec. 4 Professor, Louis-H Lafontaine Hospital, Fernand-Séguin Research Centre, Department of Psychiatry, University of Montreal, Montreal, Quebec; Director, Clinical Psychopharmacology Unit, McGill University Health Centre and Department of Psychiatry, McGill University, Montreal, Quebec. Address for correspondence: Dr E Lévy, Clinical Psychopharmacology Unit, Allan Memorial Institute, McGill University Health Centre, 1025 Pine Avenue W, Montreal, QC H3A 1A1 psychopharm.unit@mcgill.ca Can J Psychiatry, Vol 49, No 6, June

5 The Canadian Journal of Psychiatry Brief Communication Résumé : Le diabète, la dyskinésie tardive, le parkinsonisme et l acathisie dans la schizophrénie : une étude rétrospective Contexte : Cette étude examine la relation entre le diabète et la dyskinésie tardive (DT) et d autres symptômes extrapyramidaux (SEP) chez les patients schizophrènes externes traités aux antipsychotiques typiques et atypiques. Objectifs : À l aide d un examen rétrospectif des dossiers, nous avons comparé 30 patients schizophrènes souffrant de diabète assortis selon l âge et le sexe avec 30 patients schizophrènes ne souffrant pas de diabète. Nous avons comparé la prévalence et la gravité du parkinsonisme, de l acathisie, de la DT, de la dystonie et du type antipsychotique (soit typique ou atypique). Résultats : Nous n avons constaté aucune différence statistiquement significative entre les groupes diabétique et non diabétique en ce qui concerne la prévalence et la gravité des SEP, y compris la DT. Conclusion : Nous n avons pas trouvé que l association entre le diabète sucré et la DT était significative à l ère des antipsychotiques atypiques, peut-être à cause de leur effet antidyskinétique. 402