Antipsychotic Drugs: Prolonged QTc Interval, Torsade de Pointes, and Sudden Death

Glassman, Alexander H.; Bigger, J. Thomas

doi:10.1176/appi.ajp.158.11.1774

Cited by 745 publications

(456 citation statements)

References 63 publications

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“…Subject recruitment and screening were as above, except that additional screening was performed using an electrocardiogram (exclusion if QT(ms)/RR(s) 0.5 4440, or QT4450 ms for males and 4470 ms for females) and plasma electrolytes (exclusion if K þ o3.5 mmol/l or Mg 2 þ o0.70 mmol/l or corrected Ca 2 þ o2.15 mmol/l), given the potential for ziprasidone to prolong the ECG QT interval (Glassman and Bigger, 2001).…”

Section: Estimation Of Ziprasidone Occupancy In Man Using [ 11 C]way-mentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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Section: Estimation Of Ziprasidone Occupancy In Man Using [ 11 C]way-mentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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“…2 While it is not known how much of this excess risk can be attributed to antipsychotic-induced cardiotoxicity, it is clear that many antipsychotics are arrhythmogenic. 3 Among the antipsychotic drugs, haloperidol remains one of the most widely used worldwide. Haloperidol-induced ventricular arrhythmias of the torsades de pointes (TdP) type have been reported with a range of doses starting as low as 4 mg 4 administered over a 24 h period and as high as 825 mg 5 over a 24-h period.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Desai

Tanus‐Santos

et al. 2003

Pharmacogenomics J

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We studied the pharmacokinetics and QT interval pharmacodynamics of a single 10 mg dose of oral haloperidol in a randomized, double-blind, placebo-controlled, crossover trial of healthy poor (PMs) and extensive (EMs) metabolizers of CYP2D6. There was a statistically significant greater mean QT c on haloperidol (421.6720.1 ms) than on placebo (408.4718.5 ms, P ¼ 0.0053) occurring 10 h post haloperidol/placebo administration. Men and women had similar ranges of QT c changes from placebo. Despite a statistically significant greater mean elimination half-life (19.173.6 vs 12.974.0 h, P ¼ 0.04) and lower mean apparent oral clearance (12.874.1 vs 27.0711.3 ml/min/kg, P ¼ 0.02) of haloperidol in CYP2D6 PMs than in EMs, this exposure change did not translate into marked QT c changes from baseline that could be considered clinically important. Although the magnitude of the mean QT c prolongation on haloperidol relative to placebo is relatively small, it may assume significance in the presence of other risk factors for QT prolongation. The Pharmacogenomics Journal (2003) 3, 105-113. doi:10.1038/sj.tpj.6500160Keywords: haloperidol; CYP2D6 genotype; QT INTRODUCTION Schizophrenia is a common psychiatric disease with a lifetime prevalence of nearly 1% of the general population 1 that is associated with an increased risk of premature death. A recent meta-analysis revealed that schizophrenic patients are 1.5 times more likely of dying from all causes compared to an age-and gendermatched cohort of the general population. 2 While it is not known how much of this excess risk can be attributed to antipsychotic-induced cardiotoxicity, it is clear that many antipsychotics are arrhythmogenic. 3 Among the antipsychotic drugs, haloperidol remains one of the most widely used worldwide. Haloperidol-induced ventricular arrhythmias of the torsades de pointes (TdP) type have been reported with a range of doses starting as low as 4 mg 4 administered over a 24 h period and as high as 825 mg 5 over a 24-h period. Cardiac side effects at high doses likely involve excessive exposure to haloperidol. However, the extent to which low doses of haloperidol contribute to QT interval prolongation in the absence of risk factors 6 such as age, concomitant medications, electrolyte imbalances, ischemic heart disease, or congenitally prolonged QT intervals is less well characterized. Prolongation of the QT interval is a biomarker for the malignant ventricular arrhythmia of TdP.In vitro cardiac electrophysiology studies that we have conducted demonstrate that supratherapeutic concentrations of haloperidol prolong the heart rate corrected QT interval (QT c ) by approximately 26% in an isolated perfused feline heart model. 7 The mechanism of haloperidol-mediated QT prolongation

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“…Prolongation of the QTc interval of the electrocardiogram (ECG) may be associated with the development of torsade de pointes, a ventricular arrhythmia that can cause syncope and may progress to ventricular fibrillation and sudden death (26). The average QTc interval in healthy adults is approximately 400 msec.…”

Section: Prolongation Of Qtc Intervalmentioning

confidence: 99%

“…Sertindole in the amount usually administered in a clinical dose was found to increase the QTc interval by 22 msec, and the increase was dose dependent. There was evidence of increased risk of arrhythmias and unexpected deaths with this drug (26). On the other hand, Wilton et al (27) investigated mortality rates and cardiac dysrythmias in prescription-event monitoring studies of sertindole and two other drugs (risperidone and olanzapine) for comparative purposes.…”

Section: Prolongation Of Qtc Intervalmentioning

confidence: 99%

Side effects of atypical antipsychotics: a brief overview

2008

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Patients with schizophrenia suffer from increased rates of multiple medical problems, due to their lifestyle (high smoking prevalence, high-fat diet), inherent neglect of personal care, and barriers to treatment of physical illness (1). A further important contributor to adverse health outcomes is the side effect profile of antipsychotic medications. Since the introduction of the second generation or atypical antipsychotics (AAP), these agents have been widely prescribed for the management of patients with schizophrenia, bipolar disorders, other psychotic disorders or conditions with severe behavioral disturbance. The increasing use of AAP is in part due to their lower propensity to induce extrapyramidal symptoms and tardive dyskinesia compared to typical antipsychotics. Now, more than 15 years after the first atypical antipsychotic entered the market, psychiatrists have gradually come to realize that while extrapyramidal symptoms and tardive dyskinesia occur less frequently with atypical agents, these medications may present a different set of adverse effects. The quality of available evidence for the association of specific antipsychotics with particular side effects varies considerably. In this article, we review the recent findings concerning weight gain, diabetes mellitus (DM), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataract in patients receiving AAP. WEIGHT GAINForty to sixty-two percent of people with schizophrenia are overweight or obese. Obesity increases these patients' risk for cardiovascular morbidity and mortality. In addition, excessive weight and obesity can have important effects on an individual's adjustment in the community, adherence to prescribed medication, ability to participate in rehabilitation efforts, and self-image (2).Treatment with first-and second-generation antipsychotics can contribute to weight gain (3-5). A meta-analysis by Allison and Casey (4) provided an estimate of the mean weight gain in patients receiving standard doses of antipsychotics over a 10-week period: the mean increases were 4.45 kg with clozapine, 4.15 kg with olanzapine, 2.92 kg with sertindole, 2.10 kg with risperidone, and 0.04 kg with ziprasidone. Data on quetiapine have been variable, but it seems that the weight gain liability on this drug may be similar to that of risperidone (6). Weight gain with olanzapine at the commonly used dose of 15mg/day may exceed 10 kg during the first year of treatment (7). On the other hand, weight gain seems to be dose-dependent: Rondanelli et al (8) reported no change in weight in elderly patients who received 1.4 mg/day risperidone or 4.4 mg/day olanzapine or 75 mg/day quetiapine over a 12-month period.Marder et al (9) recommended that the patient's body mass index (BMI) should be recorded before medication initiation or change and at every visit for the first 6 months. The patient should be weighed (and the BMI recorded) at least quarterly when he stabilizes, and more often if he is overweight. BMI monito...

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Antipsychotic Drugs: Prolonged QTc Interval, Torsade de Pointes, and Sudden Death

Cited by 745 publications

References 63 publications

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Side effects of atypical antipsychotics: a brief overview

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