Exploration of a causal link between atypical antipsychotic usage and new onset diabetes mellitus: A review of the scientific evidence

22. Drug Side Effects & Tardive Dyskinesia suggest that many patients identified with TED may actually have had pre-existing glycemic abnormalities.

SAFETY AND TOLERABILITY METAANALYSIS OF ARIPIPRAZOLE IN SCHIZOPHRENIA E. Stock,* W. H. Carson, S. B. Kaplita, D. G. Archibald, R. M a r c u s , R. D. M c Q u a d e , T. I w a m o t o

Bristol-Myers Squibb, Wallingford, CT, USA Aripiprazole is an antipsychotic with a unique pharmacologic profile: dopamine D 2 partial agonism, serotonin 5HT1A partial agonism, and 5HT2A antagonism. Meta-analysis results of safety and tolerability are presented. Five 4-6 week, double-blind, multicenter studies were conducted in 1,648 patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder. Patients were randomized to aripiprazole (n=932), placebo (n=416), or active control (haloperidol 10 mg/d (n=201) or risperidone 6 mg/d (n=99)). Aripiprazole did not produce significant dose-dependent changes in Simpson-Angus and Barnes Akathisia scores compared to placebo. Haloperidol l0 mg/d produced significant increases vs. placebo (p<0.01). Afipiprazole was associated with a smaller increase in body weight compared to placebo than haloperidol or risperidone. Aripiprazole did not result in increases in plasma prolactin levels that were different from placebo; however, haloperidol and risperidone both increased protactin levels. Aripiprazote was not associated with QTc prolongation. The incidence of spontaneously reported somnolence with aripiprazole was comparable to placebo. The favorable safety and tolerabitity profile of aripiprazole, including low potential for EPS, weight gain, prolactin elevation, QTc prolongation, and somnolence, suggests that aripiprazole is an important advancement in the antipsychotic armamentarium.

SERTINDOLE TREATMENT DOES NOT INCREASE MORTALITY IN SCHIZOPHRENICSMARKETING SUSPENSION LIFTED M. C. S t u r k e n b o o m , * G. Picelli, N. M o o r e

Epidemiology &Biostatistics and Medical lnformatics, Erasmus MC, Rotterdam, ZH, Netherlands Introduction: The marketing license of sertindole, an a-typical antipsychotic was suspended in Europe in 1998 because of a spontaneous reporting signal that was generated in the ADROIT database. Cardiac mortality was thought to be ten-fold higher during use of sertindole than during use of other a-typical anti-psychotics. In view of the re-assessment of the suspension status in 2001, we conducted a retrospective cohort study that directly compared mortality rates between sertindole use and use of other anti-psychotics. Methods: The source population comprised the 2019 Belgium and Dutch sertindole users who were identified in 1998 for the European Safety and Exposure Study (ESES). All physicians who identified the sertindole users for the ESES study were asked to fill out a CRF on anti-psychotic treatment, patient characteristics and current vital status of the patient. Patient follow-up started at the first prescription for sertindole and ended at the date of last visit+2 months to either the psychiatrist or GP, the date of death, or compilation of the CRF, whichever was earliest. The follow-up period was divided in sertindole and post-sertindole time, based on the date of first and last intake of sertindole. All-cause and canse-specific mortality rates were compared between sertindole exposure and post-sertindole time, while

367 adjusting for year of age, co-morbidity and gender through Coxregression analysis. Results: The final study cohort comprised 1112 patients with a gender and age distribution comparable to that of the source population (50.4% male, mean age males 37.8, females 43.8 years). 53 deaths were reported, 7 during sertindole treatment and 46 after sertindole was stopped. From the 46 post-sertindole deaths, 13 deaths were excluded since they occurred more than 2 months after the last visit to the GP or psychiatrist. The adjusted relative risk of all-cause mortality was 69% lower during sertindole than after stopping sertindole (RR=0.31,0.13-0.70), cardiac mortality was 30% lower during use of sertindole (RR=0.70, 0.17-2.86) and suicides were 87% lower during use of sertindole (RR=0.13, 0.02-1.03) than after stopping use. Current use of other a-typicals was associated with a 90% increase in the risk of death (RR= 1.9, 95%CI:0.7-5.2) as compared to sertindole Conclusion: All-cause and cause-specific mortality rates are not elevated during use of sertindole as compared to the period after stopping sertindote.

OLANZAPINE CAUSES GREATER INCREASES IN SERUM LIPIDS THAN RISPERIDONE T. Tang,* H.Y. Meltzer

Division of Psychopharmacology, Vanderbilt University School of' Medicine, Nashville, TN, USA Differences between antipsychotic drugs for risk of atherosclerotic cardiovascular disease (ACD) and diabetes mellitus are important for the long-term evaluation of risk/benefit ratios for this class of drugs. We are conducting a 1- year multicenter, randomized trial comparing the effect of switching patients with schizophrenia or related disorders from other psychotropic drugs to olanzapine or risperidone. Data were available from 59 subjects at 1 month, 52 at 3 months, and 28 at 6 months. In the olanzapine group, mean serum triglyceride levels increased from 149 mg/dl at baseline to 186, 225, and 211 mg/dl, respectively, at 1, 3, and 6 months, whereas in the risperidone group levels decreased from 143 mg/dl at baseline to 132, 137, and 118 mg/dl at the 3 time points. Mean total cholesterol levels increased from 179--199 mg/dl in the olanzapine group at 3 months and were unchanged (180 mg/dl) in the risperidone group; the mean changes were a 10% increase in the olanzapine group and a 10% decrease in the risperidone group. The increase in low-density lipoprotein levels at 1 month was significant in the olanzapine group but not at later time points. Increases in weight and BMI at 6 months were greater in the olanzapine than the risperidone patients. HBA1c tended to increase in the olanzapine but not the risperidone group. Changes in high-density lipoprotein levels or fasting plasma glucose were not different between groups. These findings suggest differential risk for the development of ACD and possibly type II diabetes in patients receiving risperidone or olanzapine.

EXPLORATION OF A CAUSAL LINK BETWEEN ATYPICAL ANTIPSYCHOTIC USAGE AND NEW ONSET DIABETES MELLITUS: A REVIEW OF THE SCIENTIFIC EVIDENCE R Toalson,* H. McGuire, K. M. Healey, G. Kabinoff, D. H a y

Neuroscience, Eli Lilly and Company, Indianapolis, IN, USA Introduction: Significant attention has been focused on the increased rate of glucose intolerance, hyperglycemia, and new-onset diabetes mellitus among psychiatric patients. Reports have identified cases

International Congress on Schizophrenia Research 2003

368

22. Drug Side Effects & Tardive Dyskinesia

of newly diagnosed diabetes during treatment with all of the atypical antipsychotics. However, the question remains whether an association exists between antipsychotic use and diabetes or whether reports reflect the high risk of diabetes in this population irrespective of medication use. Methods: Most articles on this topic are case reports or small, cross-sectional laboratory studies highlighting the suspected potential for differing rates of new-onset diabetes cases. We conducted a retrospective review of the literature from 19982002, including recent studies presented at major psychiatric meetings, to create a broader perspective on the issue. Results: We identified over 70 abstracts and manuscripts, including case reports; cross-sectional studies; retrospective analyses of controlled clinical studies; pharmacoepidemiology studies; and prospective head-tohead studies. Conclusions: Data from this large body of scientific evidence indicate that the psychiatric patient population is at a higher risk for the development of glucose intolerance, hyperglycemia, and new-onset diabetes mellitus compared to the general population. The available data do not demonstrate a consistent or clinically significant difference in the risk of new-onset diabetes during treatment with the various atypical antipsychotic agents.

THE SAFETY AND TOLERABILITY SERTINDOLE

OF

IN A PATIENT NAME USE

PROGRAM M. T o u m i , * P. Auquier, C. Francois

International Department of Health Economics and Epidemiology, H. Lundbeck SA, Paris, France Background: The antipsychotic drug sertindole prolongs the QT interval on the ECG. This event raised concern for the safety of sertindole and analysis was therefore warranted. In clinical trials, sertindole was not associated with an excess of cardiac or all-cause mortality. Objectives: To assess Serious Adverse Events (SAEs) in a large cohort. Methods: The design was a retrospective survey of patients treated with sertindole under Patient Name Use (PNU) programme. The study period started from the sertindole market suspension (November 1998) and included the most recent information available fur each patient: last visit to tile physician, Council for International Organisations of Medical Sciences (CIOMS), SAE reports. For patients who discontinued sertindole treatment, the observation period ended one month after the date sertindole was stopped. SAEs were recorded according to the ICH GCP definition. ECG monitoring was performed. There was no retrospective drug accountability, and patient compliance was not studied. The survey was performed in 11 European countries. As the dl'ug was dispensed under a PNU program, it was considered exhaustive regarding sertindole. Results: A total of 1,444 patients (55% women, mean age 4i +/- 15) were included in the study. More than 2/3 of the patients received a single antipsychotic therapy. The remaining 1/3 had an association of at least two antipsychotics, mainly a typicai and an atypical one. The main reasons for maintaining sertindole treatment after its market suspension were due to a lack of efficacy (51%), or adverse effccts (24%) from previous antipsychotic treatment(s). The mean sertindole dosage was 13.4 +/- 5.6 mg/24hours. The total exposure was 1,668 PYE. A total of 96 SAEs was reported, eight of which had a fatal outcome. This gave a death rate of 0.48 deaths per 100 PYE, and the 95% Poisson confidence interval was (0.21-0.94). The cause of death was classified according to 4 categories as follows: suicide (3), cardiac death (2), unascertained cause of death (1) and others (2). After psychotic disorders, QTc interval prolongation was the most frequent SAE with 15 occurrences. None of the QTc interval prolnngation cases were associated with clinicai symptoms. No cases

of Torsade de Pointes were recorded. Conclusions: The overall safety results confirmed that sertindole was well tolerated, as the mortality rate in this study was remarkably low.

DIFFERENTIAL VERSUS

EFFECTS

TRANSIENT

RECEPTOR

OCCUPANCY

DEVELOPMENT MOVEMENTS

OF SUSTAINED

DOPAMINE

D2

IN THE

OF VACUOUS

CHEWING

(VCMS) IN RATS

R Turrone,* G. R e m i n g t o n , S. Kapur, J. N o b r e g a

Department of Psychiatry, University ()['Toronto, Toronto, ON, Canada Rationale: Accumulating evidence suggests that antipsychotics (APs) that dissociate rapidly from the dopamine D2 receptor are less likely to induce acute extrapyramidal side effects compared to those that dissociate slowly. It is unclear, however, whether a similar relationship exists in the case of long-term AP-induced motoric side effects like tardive dyskinesia (TD), where systematic kinetics are involved. Objectives: To determine whether transient (via daily subcutaneous injections) versus sustained (via osmotic mini-pumps) AP-induced D2 receptor occupancy differentially effects the development of haloperidol-induced vacuous chewing movements (VCMs) in rats, an animal model of TD. Methods: Six groups of 12 rats received 0.1, 0.25, 1 mg/kg of haloperidol or vehicle via osmotic inini-pump or daily subcutaneous injection for 8 weeks. VCMs were measured on a weekly basis and D2 occupancy levels were measured in vivo using [3H]-raclopride at the end of the experiment. Results: Thirty-nine percent (9/23) of rats given moderate to high (0.25 & 1 mg/kg/day) doses of HAL via mini-pump (achieving mean 82% D2 occupancy) developed high levels of VCMs (13 VCMs/2 min) compared to only 8 percent (2/24) of rats given the same doses via daily subcutaneous injection, despite the fact that they too yielded high (>85%), albeit transient, mean D2 occupancy levels. The 0.1 mg/kg dose did not give rise to any VCMs beyond placebo regardless of the route of administration. Conclusions: Using the VCM model of TD, these findings strongly support the contention that high levels of sustained AP-induced D2 occupancy increase TD risk.

LOW BLOOD

SELENIUM

IN SCHIZOPHRENIC CLOZAPINE: MYOCARDITIS

CONCENTRATIONS

PATIENTS TREATED

A RISK FACTOR

WITH

FOR

AND CARDIOMYOPATHY?

K. Vaddadi,* E. Soosai, G. Vaddadi

Austin and Repatriation Medical Centre, Melbourne, VIC, Australia Introduction: Selenium is an essential trace element that is present as a constituent of selenoproteins(1). It plays an important role in the antioxidant system. Selenium has been implicated in a wide range of human diseases, fi'om cancer to mood disorders(l). Low selenium levels have been causally linked to an endemic form of cardiomyopathy (Kashan disease) found in high prevalence in NE China. Dietary selenium supplementation has greatly reduced the incidence of this fatal condtion(2). Clozapine is an antipsychotic used in treatment non-responsive schizophrenia. Treatment with clozapine has been associated with the development of myocarditis,cardiomyopathy and sudden death(3). We therefore decided to measure the levels of selenium in patients treated with clozapine. Aim: To compare plas-

International Congress on Schizophrenia Research 2003