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Safety and tolerability of high-dose quetiapine in treatment refactory schizophrenia: Preliminary results from an open-label trial
22. Drug Side Effects & Tardive Dyskinesia age group. Results: Use of the TdP drug list resulted in the following prevalence rates: 7.3% for contrainidcation A; 14% for contraindication B; 1.8% for both contraindications A and B; and 19.6% for either contraindication A or B. Use of the QT drug list provided the following prevalence rates: 16.8% for A; 14.1% for contraindication B; 3.4% for both A and B; and 27.6% for either contraindication A or B. Conclusions: In this large sample, the prescription of a QTc prolonging antipsychotic drug may be contraindicated for about 20-28% of the patients. Further study will be required to address the potential impact of prescribing practices on the risk of drug-induced TdR
SAFETY AND TOLERABILITY OF HIGH-DOSE QUETIAPINE IN TREATMENT REFACTORY SCHIZOPHRENIA: PRELIMINARY RESULTS FROM AN OPEN-LABEL TRIAL M. W. Nelson,* R. L. Reynolds, D. L. Kelly, C. M. Richards, R. R. Conley
Maryland Psychiatric Research Center, University of Maryland, Baltimore, Baltimore, MD, USA The second generation antipsychotic quetiapine is thought to have a favorable side effect profile when compared to traditional antipsychotics and possibly other second generation antipsychotics. This favorable side effect profile is predominantly based on the use of quetiapine in the recommended dosage range of 150 to 750 mg/day in patients with schizophrenia. We examined the safety and side effect profile of quetiapine using a target dose of 1200mg/day (range 1000 to 1400 rag/day) to treat patients with documented treatment refractory schizophrenia. Patients were titrated to 1200rag/day during the first three weeks of this 12 week open-label trial. The mean daily dose was 1266.7 rag/day (SD +/- 84.3 rag/day) at endpoint. Data on the occurrence of side effects and extrapyramidal symptoms (EPS) was collected and evaluated. Changes in weight, glucose, cholesterol, prolactin, thyroid function and QTc interval were also assessed. Quetiapine at high doses in patients with treatment refractory schizophrenia was not associated with increased EPS compared to baseline and was generally well tolerated.
FASTING PLASMA LIPIDS, GLUCOSE AND INSULIN, AND C-REACTIVE PROTEIN ARE RELATED TO ADIPOSITY IN SCHIZOPHRENIA J. W. Newcomer,* D. W. Haupt, A. K. Melson, J. A. Schweiger, A. Luber, J. Maeda, R Fahenstock, M. C h a r e p o o
Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA Increased adiposity induced by treatment with antipsychotic medications can disturb glucose and lipid metabolism. Increased adiposity, plasma glucose and lipids are independent multivariate risk factors for cardiovascular disease (e.g., myocardial infarction and stroke), and individuals with schizophrenia experience increased cardiovascular mortality in comparison to the general population. High sensitivity C reactive protein (hs-CRP) is an acute phase reactant produced by the liver and secreted in response to increased circulating levels of factors such as proinflammatory cytokines (i.e., interleukin 6), secreted in turn by adipose tissue. Elevated fasting plasma lipids and hs-CRP are used clinically as predictors of future cardiovascular events. Recent reports have suggested that disturbances in
363 glucose and lipid metabolism can occur during treatment with specific antipsychotic medications, both as a function of adiposity as well as independent of differences in adiposity. We measured fasting plasma lipids, glucose, insulin, hs-CRR and body mass index (BMI) in healthy controls (n=69) and non-diabetic schizophrenia or schizoaffective patients treated with typical antipsychotics (n=21), risperidone (n=22) and olanzapine (n=26). BMI significantly predicted fasting plasma triglycerides, glucose and hs-CRP in patients and controls, with no significant difference in the effect of BMI across subject or treatment conditions. In contrast, a significant difference in the effect of BMI across subject and treatment conditions was observed for fasting plasma insulin and homeostasis model assessment (HOMA) insulin resistance, suggesting that insulin resistance may increase with adiposity to a greater extent for patients taking certain medications. Increased adiposity, independent of treatment conditions tested, is associated with dyslipidemia and inflammatory products that predict CV risk. MH01510, MH53363, MH63985, NARSAD, USPHS 5MO1 RR00036, P30 DK56341 and P60-DK20579.
ZIPRASIDONE METABOLISM AND ITS CLINICAL IMPLICATIONS: AN UPDATED REVIEW R. O b a c h , * C. B e e d h a m , J. Miceli
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton, CT, USA Ziprasidone, an atypical antipsychotic distinguished by weight neutrality and favorable effects on serum lipids and glycemic metabolism, is highly metabolized in humans. Metabolism is mediated via 2 enzymes: reduction by aldehyde oxidase, and 2 oxidative pathways involving CYP3A4. These pathways ultimately result in 4 major metabolites in circulation: BITP-sulfoxide, BITP-sulfone, ziprasidone sulfoxide, and S-methyldihydroziprasidone. CYP3A metabolism is well-established as a cause of drug-drug interactions, but this pathway accounts for only one third of ziprasidone metabolism, so compounds that affect CYP3A activity will not cause clinically meaningful drug interactions with ziprasidone. Aldehyde oxidase, which accounts for the remainder, appears to be less important than cytochrome 17450 enzymes in drug metabolism. Furthermore, in vitro inhibitors of this enzyme have not been associated with clinical interactions, nor has aldehyde oxidase induction been reported. Aldehyde oxidase should not be confused with the unrelated enzyme aldehyde dehydrogenase, which is responsible for oxidation of acetaldehyde, the initial product of ethanol oxidation, to acetic acid. Aldehyde oxidase is not important in this reaction, so there is no basis for a pharmacokinetic interaction between ethanol and ziprasidone. Consistent with the estimated minor contribution of CYP3A4 to ziprasidone metabolism, clinical interaction studies show only a 35-40% increase in ziprasidone exposure with concomitant ketoconazole, a potent inhibitor of CYP3A4, and a 35% decrease with concomitant carbamazepine, a CYP3A inducer. Co-administration of cimetidine, a weak inhibitor of human aldehyde oxidase in vitro, causes only a 6% increase in ziprasidone exposure. In contrast to some P450 enzymes, genetic polymorphisms with functional consequences have not been demonstrated for human aldehyde oxidase, and ziprasidone exposure demonstrates unimodality in humans, with exposures in healthy subjects and patients ranging about 3- to 7-fold. In conclusion, ziprasidone is metabolized through dual pathways. The limited role of CYP3A4 in ziprasidone metabolism and lack of evidence of alteration of aldehyde oxidase activity by coadministration of other drugs diminish concerns about possible pharmacokinetic drug
International Congress on Schizophrenia Research 2003
SAFETY AND TOLERABILITY OF HIGH-DOSE QUETIAPINE IN TREATMENT REFACTORY SCHIZOPHRENIA: PRELIMINARY RESULTS FROM AN OPEN-LABEL TRIAL M. W. Nelson,* R. L. Reynolds, D. L. Kelly, C. M. Richards, R. R. Conley
Maryland Psychiatric Research Center, University of Maryland, Baltimore, Baltimore, MD, USA The second generation antipsychotic quetiapine is thought to have a favorable side effect profile when compared to traditional antipsychotics and possibly other second generation antipsychotics. This favorable side effect profile is predominantly based on the use of quetiapine in the recommended dosage range of 150 to 750 mg/day in patients with schizophrenia. We examined the safety and side effect profile of quetiapine using a target dose of 1200mg/day (range 1000 to 1400 rag/day) to treat patients with documented treatment refractory schizophrenia. Patients were titrated to 1200rag/day during the first three weeks of this 12 week open-label trial. The mean daily dose was 1266.7 rag/day (SD +/- 84.3 rag/day) at endpoint. Data on the occurrence of side effects and extrapyramidal symptoms (EPS) was collected and evaluated. Changes in weight, glucose, cholesterol, prolactin, thyroid function and QTc interval were also assessed. Quetiapine at high doses in patients with treatment refractory schizophrenia was not associated with increased EPS compared to baseline and was generally well tolerated.
FASTING PLASMA LIPIDS, GLUCOSE AND INSULIN, AND C-REACTIVE PROTEIN ARE RELATED TO ADIPOSITY IN SCHIZOPHRENIA J. W. Newcomer,* D. W. Haupt, A. K. Melson, J. A. Schweiger, A. Luber, J. Maeda, R Fahenstock, M. C h a r e p o o
Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA Increased adiposity induced by treatment with antipsychotic medications can disturb glucose and lipid metabolism. Increased adiposity, plasma glucose and lipids are independent multivariate risk factors for cardiovascular disease (e.g., myocardial infarction and stroke), and individuals with schizophrenia experience increased cardiovascular mortality in comparison to the general population. High sensitivity C reactive protein (hs-CRP) is an acute phase reactant produced by the liver and secreted in response to increased circulating levels of factors such as proinflammatory cytokines (i.e., interleukin 6), secreted in turn by adipose tissue. Elevated fasting plasma lipids and hs-CRP are used clinically as predictors of future cardiovascular events. Recent reports have suggested that disturbances in
363 glucose and lipid metabolism can occur during treatment with specific antipsychotic medications, both as a function of adiposity as well as independent of differences in adiposity. We measured fasting plasma lipids, glucose, insulin, hs-CRR and body mass index (BMI) in healthy controls (n=69) and non-diabetic schizophrenia or schizoaffective patients treated with typical antipsychotics (n=21), risperidone (n=22) and olanzapine (n=26). BMI significantly predicted fasting plasma triglycerides, glucose and hs-CRP in patients and controls, with no significant difference in the effect of BMI across subject or treatment conditions. In contrast, a significant difference in the effect of BMI across subject and treatment conditions was observed for fasting plasma insulin and homeostasis model assessment (HOMA) insulin resistance, suggesting that insulin resistance may increase with adiposity to a greater extent for patients taking certain medications. Increased adiposity, independent of treatment conditions tested, is associated with dyslipidemia and inflammatory products that predict CV risk. MH01510, MH53363, MH63985, NARSAD, USPHS 5MO1 RR00036, P30 DK56341 and P60-DK20579.
ZIPRASIDONE METABOLISM AND ITS CLINICAL IMPLICATIONS: AN UPDATED REVIEW R. O b a c h , * C. B e e d h a m , J. Miceli
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton, CT, USA Ziprasidone, an atypical antipsychotic distinguished by weight neutrality and favorable effects on serum lipids and glycemic metabolism, is highly metabolized in humans. Metabolism is mediated via 2 enzymes: reduction by aldehyde oxidase, and 2 oxidative pathways involving CYP3A4. These pathways ultimately result in 4 major metabolites in circulation: BITP-sulfoxide, BITP-sulfone, ziprasidone sulfoxide, and S-methyldihydroziprasidone. CYP3A metabolism is well-established as a cause of drug-drug interactions, but this pathway accounts for only one third of ziprasidone metabolism, so compounds that affect CYP3A activity will not cause clinically meaningful drug interactions with ziprasidone. Aldehyde oxidase, which accounts for the remainder, appears to be less important than cytochrome 17450 enzymes in drug metabolism. Furthermore, in vitro inhibitors of this enzyme have not been associated with clinical interactions, nor has aldehyde oxidase induction been reported. Aldehyde oxidase should not be confused with the unrelated enzyme aldehyde dehydrogenase, which is responsible for oxidation of acetaldehyde, the initial product of ethanol oxidation, to acetic acid. Aldehyde oxidase is not important in this reaction, so there is no basis for a pharmacokinetic interaction between ethanol and ziprasidone. Consistent with the estimated minor contribution of CYP3A4 to ziprasidone metabolism, clinical interaction studies show only a 35-40% increase in ziprasidone exposure with concomitant ketoconazole, a potent inhibitor of CYP3A4, and a 35% decrease with concomitant carbamazepine, a CYP3A inducer. Co-administration of cimetidine, a weak inhibitor of human aldehyde oxidase in vitro, causes only a 6% increase in ziprasidone exposure. In contrast to some P450 enzymes, genetic polymorphisms with functional consequences have not been demonstrated for human aldehyde oxidase, and ziprasidone exposure demonstrates unimodality in humans, with exposures in healthy subjects and patients ranging about 3- to 7-fold. In conclusion, ziprasidone is metabolized through dual pathways. The limited role of CYP3A4 in ziprasidone metabolism and lack of evidence of alteration of aldehyde oxidase activity by coadministration of other drugs diminish concerns about possible pharmacokinetic drug
International Congress on Schizophrenia Research 2003