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The safety and tolerability of sertindole in a patient name use program
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
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