Investigation of the potential of clozapine to cause torsade de pointes

Antipsychotics are frequently associated with QTc interval prolongation, a proposed marker for vulnerability to fatal ventricular arrhythmias, e.g. torsade de pointes (TdP). Little has been published on this topic in relation to clozapine. The objectives of this review were to: (i) calculate the frequency of QTc interval prolongation, T-wave abnormalities, TdP, ventricular tachycardia/fibrillation and sudden unexplained death in patients treated with clozapine and thioridazine from clinical trial and post-marketing reports; (ii) to compare these data with published findings for haloperidol, risperidone, olanzapine, sertindole and ziprasidone; and (iii) to correlate these clinical data with results from preclinical tests presently considered to be of predictive value for a compound's potential to cause QTc interval prolongation and TdP. A review of the global Novartis databases for clozapine and thioridazine and a Medline/Internet search for information on these cardiac events and for preclinical effects on the human ether-a-go-go related gene channels, action potential duration, and QT interval changes produced by the selected antipsychotics were performed. The clozapine database (2.8 million patient-years spanning 27 years) demonstrated that at therapeutic doses all but three reports of QTc interval prolongation and both of TdP were confounded by relevant co-medication/comorbidity. The literature review revealed that all antipsychotics considered except clozapine induced TdP and/or QTc interval prolongation at therapeutic doses. Preclinical in vitro tests appear to overestimate the risk of clozapine, haloperidol and risperidone to prolong QTc interval in patients and underestimate such a risk for sertindole and ziprasidone. Extrapolation of in vitro results to clinical events requires qualified interpretation.     

QTc interval prolongation and antipsychotic drug treatments: focus on sertindole

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.     

Antipsychotic medications and sudden cardiac death

The objectives of this paper are to: 1) discuss practical aspects of antipsychotic induced QT prolongation, torsades de pointes (TdP) and sudden cardiac death, 2) discuss its possible mechanisms, 3) review data for each antipsychotic medication or class of medications and, 4) present recommendations from the literature. We performed computerized searches of the biomedical literature utilizing MEDLINE and PsycINFO computer databases (1966-2001), and by reviewing bibliographies to identify all pertinent case reports, case series, and formal studies using the following search terms: antipsychotics, sudden cardiac death, and QT prolongation. QT prolongation is a dynamic phenomena affected by various factors (mood, disease states, gender, medication, etc.). Sudden cardiac death attributable to antipsychotic medications seems to occurs in a step-wise fashion beginning with QT prolongation, leading to TdP, which can progress to cardiac arrest. Blocking the rapidly-acting potassium rectifier current appears be the primary mechanism of QT prolongation in drugs known to cause TdP and sudden cardiac death. All antipsychotic medications have been shown to cause QT prolongation, however, the degree to which this occurs and the risk of TdP varies. The risk of sudden cardiac death increases with higher doses of medications, use of phenothiazines or intravenous butyrophenones, and in patients with certain medical illnesses, especially cardiac disease. In order to prevent sudden death from antipsychotic medications, we recommend obtaining screening electrocardiograms in all at-risk patients, follow-up electrocardiograms after the initiation of medication, and using the lowest effective dose of medication. If QT prolongation occurs, the risks and benefits of therapy should be considered and medication adjustments made if warranted.     

Psychotropic drugs,cardiac arrhythmia,and sudden death

A variety of drugs targeted towards the central nervous system are associated with cardiac side effects, some of which are linked with reports of arrhythmia and sudden death. Some psychotropic drugs, particularly tricyclic antidepressants (TCAs) and antipsychotic agents, are correlated with iatrogenic prolongation of the QT interval of the electrocardiogram (ECG). In turn, this is associated with the arrhythmia (TdP). This review discusses the association between psychotropic agents, arrhythmia and sudden death and, focusing on TCAs and antipsychotics, considers their range of cellular actions on the heart; potentially pro-arrhythmic interactions between psychotropic and other medications are also considered. At the cellular level TCAs, such as imipramine and amitriptyline, and antipsychotics, such as thioridazine, are associated with inhibition of potassium channels encoded by In many cases this cellular action correlates with ECG changes and a risk of TdP. However, not all psychotropic agents that inhibit HERG at the cellular level are associated equally with QT prolongation in patients, and the potential for QT prolongation is not always equally correlated with TdP. Differences in risk between classes of psychotropic drugs, and between individual drugs within a class, may result from additional cellular effects of particular agents, which may influence the consequent effects of inhibition of repolarizing potassium current.     

Assessing QT interval prolongation and its associated risks with antipsychotics

Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500?ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive.     

A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition

Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.     

Cardiac side effects of psychiatric drugs

This review describes the common effects of psychotropic drugs on the cardiovascular system and offers guidance for practical management. Selected reports from the literature describing common side effects associated with psychotropic drugs are reviewed, and suggestions for further reading are given throughout the text. Orthostatic hypotension is the most common adverse autonomic side effect of antipsychotic drugs. Among the atypical antipsychotics the risk of orthostatic hypotension is highest with clozapine and among the conventional drugs the risk is highest with low potency agents. Rarely, orthostatic hypotension may result in neurocardiogenic syncope. QTc prolongation can occur with all antipsychotics but an increased risk is seen with pimozide, thioridazine, sertindole and zotepine. QTc prolongation is a marker of arrhythmic risk. Torsade de pointe, a specific arrhythmia, may lead to syncope, dizziness or ventricular fibrillation and sudden death. Heart muscle disease presents most commonly in the elderly as chronic heart failure, but myocarditis and cardiomyopathy, although relatively rare, are devastating, but potentially reversible complications of psychotropic drug therapy have been particularly linked to clozapine treatment. Patients with severe mental illness (SMI) are a 'high risk' population with regard to cardiovascular morbidity and mortality. It is probable that many patients accumulate an excess of 'traditional' risk factors for the development of cardiovascular disease, but other mechanisms including psychotropic drugs may also be influential in increasing risk in this vulnerable group. These risks need to be seen in the context of the undoubted therapeutic efficacy of the psychotropic armamentarium and the relief that these drugs bring to those suffering from mental disorder.     

Sudden death in patients receiving drugs tending to prolong the QT interval

AIMS

To examine risks of sudden death in the community associated with drugs grouped by their risk of causing torsades de pointes (TdP) and to explore the risks for individual drugs.

METHODS

Case–control study comparing prior drug intakes and morbidities, using the Arizona classification of drugs causing TdP. Participants included 1010 patients dying suddenly where post-mortem examination did not identify a clear cause of death, and 3030 matched living controls from primary care.

RESULTS

Noncardiac drug risk was posed by antipsychotics and antidepressants. Significantly raised odds ratios (ORs) were found for takers of typical and atypical antipsychotics, ORs [95% confidence interval] 3.94 (2.05, 7.55) and 4.36 (2.54, 7.51), and of selective serotonin reuptake inhibitors [SSRIs] rather than tricyclic antidepressants, ORs 2.21 (1.61, 3.05) and 1.44 (0.96, 2.13). No significant risk was associated with other, noncardiac or psychiatric drugs, OR 1.09 (0.85, 1.41). Arizona classified drugs considered to raise risk of TdP were associated with raised risk of sudden death, as were those only weakly associated with TdP and not considered to pose a risk in normal use, ORs 2.08 (1.45, 3.00) and 1.74 (1.33, 2.28), respectively.

CONCLUSIONS

Atypical and typical antipsychotic drug use were both strongly associated with raised risks, as were SSRIs. Tricyclic antidepressants were not associated with raised risks. The Arizona classification of risk of TdP was a poor predictor of likelihood of noncardiac drug-associated sudden death.     

The use of first generation versus second generation antipsychotics as add-on or as switch treatment and its effect on QTC interval: the Italian experience in a real-world setting

Some psychotropic drugs are connected with prolongation of the QT interval, torsade de pointes and sudden death. Recent data suggest that with regard to this adverse effect, the atypical antipsychotic drugs are no safer than the older drugs. The purpose of this study is to evaluate the different use of first generation versus second generation antipsychotics as add-on (Group I) or switch treatment (Group II) and its effect on QTc interval in a sample of schizophrenic and bipolar inpatients without medical illness. All patients had been evaluated twice by using ECG: on admission and after two weeks of hospitalization. Exclusions criteria were: abnormalities in levels of potassium, magnesium and calcium, cardiovascular and metabolic diseases, alcohol or drug abuse. We found a significant (p < 0.01) greater use of first generation antipsychotic in Group I (73.80%) than in the Group II (33.33%). Also Group I showed a significant increase (p < 0.0001) in total chlorpromazine equivalent (476. 78 ± 448.80 mg/day vs 845.48 ± 491.64 mg/day) and in QTc interval (369.14 ± 33.75 ms vs 387.09 ± 31.97 ms), while we did not find any statistical difference in Group II during hospitalization. Our results, in spite of the small sample size, indicate that antipsychotic add-on can increase QTc interval more than switching to other antipsychotic in psychiatric patients without other risk factors.     

Antipsychotic drugs and QT prolongation

Antipsychotic drugs (AD) are effective and frequently prescribed to more females than males. AD may cause serious cardiovascular side-effects, including prolonged QT interval, eventually leading to torsades de pointes (TdP) and sudden death. Epidemiologic data and case-control studies indicate an increased rate of sudden death in psychiatric patients taking AD. This review summarizes current knowledge about the QT prolonging effects of AD and gives practical suggestions. Amisulpride, clozapine, flupenthixol, fluphenazine, haloperidol, melperone, olanzapine, perphenazine, pimozide, quetiapine, risperidone, sulpiride, thioridazine and ziprasidone cause a QT prolongation ranging from 4 ms for risperidone to 30 ms for thioridazine. Our knowledge about the QT-prolonging effects of many AD is still limited. Females are under-represented in most studies. Many studies were conducted or supported by pharmaceutical companies. To avoid prodysrhythmia caused by QT prolongation, other factors influencing QT interval have to be considered, such as other drugs affecting the same pathway, hypokalemia, hypomagnesemia, bradycardia, increased age, female sex, congestive heart failure and polymorphisms of genes coding ion channels or enzymes involved in drug metabolism. Because the response of a patient to AD is individual, an electrocardiogram recording the QT interval has to be performed at baseline, after AD introduction and after occurrence of any factor that might influence the QT interval.     

QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients

Thioridazine cardiotoxicity has been associated with a prolonged heart-rate corrected QT (QTc) interval. However, no systematic studies have been performed on patients at therapeutic doses. The present study aimed to evaluate the influence of dose and plasma concentration of thioridazine and CYP2D6 enzyme status on the QTc interval in psychiatric patients. Sixty-five Spanish European psychiatric patients receiving thioridazine antipsychotic monotherapy were studied. The plasma levels of thioridazine and its metabolites were determined by high-performance liquid chromatography. All patients were phenotyped for CYP2D6 activity with debrisoquine during treatment. Thirty-five patients (54%) had a QTc interval over 420 ms. The lengthening of QTc interval was correlated with plasma concentration (p < 0.05) and daily dose (p < 0.05) of thioridazine. CYP2D6 enzyme hydroxylation capacity, evaluated by debrisoquine metabolic ratio (MR) (p < 0.05) and thioridazine/mesoridazine ratio (p < 0.05), was also correlated with QTc intervals. The present study shows the relationship between QTc interval lengthening among psychiatric patients treated at therapeutical doses with the dose and the plasma concentration of thioridazine. Since debrisoquine MR has been shown to be correlated with the QTc intervals, CYP2D6 enzyme hydroxylation capacity might be relevant in determining the risk for QTc interval lengthening. Patients with impaired CYP2D6 enzyme activity due to enzyme inhibition by thioridazine might be more prone to increased risk of sudden death due to torsade de pointes type cardiac dysrhythmia.     

QT prolongation and torsades de pointes induced by an antifungal agent, D0870, in conscious dogs.

D0870 ((R)-2-(2,4-difluoro-phenyl)-1-[3-[(E)-4-(2,2,3,3-tetrafluoropropoxy+ ++)-styryl]-1H-1,2,4-triazol-1-yl]-3-(1H-1,2,4-triazole-1-yl) propan-2-ol), a novel bis-triazole antifungal agent, induced sudden deaths at a high dose of 5 mg/kg/day in a 6-month toxicity study in dogs. In the present study, we intended to elucidate the cause of the sudden death in dogs. When used in a single dose, D0870 induced prolongation of QTc intervals in proportion to its plasma concentration, and the threshold plasma concentration of the drug causing 10% QTc prolongation was estimated to be 3.8 microg/ml. Then, we conducted a study to induce sudden death in dogs using loading (50 mg/kg) and maintenance (5 mg/kg/day) doses with long-term ambulatory electrocardiographic monitoring. Marked QTc prolongation (52-96%), ventricular premature contractions, and T-wave alternans were observed in all 10 animals treated with the drug, and seven out 10 animals died of ventricular fibrillation (VF) associated with torsades de pointes (TdP) when the dogs were treated with D0870 for 14 or 16 days. The TdPs were elicited in both tachycardia and bradycardia, and some of them in the former proceeded to VF. Consequently, we clarified that D0870-induced sudden death is primarily attributable to the development of TdP preceding VF and may be enhanced by sympathetic nervous tone produced by emotional or physical stress.     

QT prolongation and safety in the Indian population

The QT interval in electrocardiogram (ECG) reflects the total duration of ventricular myocardial depolarization and repolarization. It has been well recognized that many condition may cause QT interval prolongation. Unfortunately, numbers of cardiac and non-cardiac drug prolong the QT interval and cause a distinctive polymorphic ventricular tachycardia termed torsade de pointes (TdP). TdP can degenerate into ventricular fibrillation, which leads to sudden cardiac death. Recently various regulatory and clinical bodies of Europe, USA, Canada and Australia have made their focus on the drugs that induce prolongation of QT interval. Committee for Proprietary Medicinal Products (CPMP) of the European Agency issued a document entitled 'Points to Consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products' [1, 2]. In addition, USFDA adopted the guideline 'Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-anti arrhythmic drugs' [3]. These documents and guidelines are primarily concern with development of novel agents and the new use or new dose of already approved drugs. The scope of this guideline is to study the effect of drugs on QT prolongation and give idea of evaluation of drug's effects on QT prolongation. Today more than 50 available drugs (both old and new) have been identify, which prolong the QT interval [1]. Several drugs have been withdrawn from many countries on this basis but many of these drugs are still available in Indian market and potentially creating life-threatening arrhythmias. This article will focus on recommendation of study on the normal limits of QT interval in Indian population and preparation of the database, which can be helpful in withdrawal of drugs from the market that produces QT prolongation.     

Sudden cardiac death secondary to antidepressant and antipsychotic drugs

A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use.     

Fluconazole- and levofloxacin-induced torsades de pointes in an intensive care unit patient.

Patients initiated on fluconazole and levofloxacin should be closely monitored for QTc-interval prolongation. While there have been published reports of fluconazole and levofloxacin causing QTc-interval prolongation when given alone, coadministration of these two agents may further increase this risk. This case describes an episode of TdP in which levofloxacin and fluconazole were likely significant factors. QT prolongation was present at baseline prior to drug initiation (QTc = 454-505 ms) and levofloxacin resulted in further prolongation (QTc = 480-536 ms). After two days of therapy with fluconazole, overlapping with levofloxacin, the patient had an episode of PMVT with syncope, and progressive QT prolongation was evident (QTc = 554 ms). Only mild hypokalemia (potassium concentration = 3.6 meq/L) was present, and not additional etiologies for TdP were identified. Levofloxacin and fluconazole were discontinued and no further PMVT was observed, but the QT interval did not return to normal until after an additional 11 days (QTc = 436 ms). As in many cases of TdP, multiple factors were involved. Renal failure, drug dosing, mild hypokalemia, and a baseline abnormal QT interval potentiated the role of levofloxacin and fluconazole in the development of TdP. We recommend that neither drug be used alone or in combination when there is baseline QT prolongation. We also recommend that concomitant use of these agents be avoided when possible. If combination therapy is required, caution is warranted, particularly in patients with risk factors for QT prolongation. Specific attention should be given to drug dosing, interactions, electrolytes, and ECG monitoring.     

Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports

Rationale

A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced I_Kr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP).

Objectives

The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP.

Method

We identify case reports using PubMed, Medline, EMBASE, and Cochrane.

Results

Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, “elderly”, 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n?=?10), older age (n?=?4), heart disease (n?=?3), hypokalemia (n?=?2), bradycardia (n?=?1), liver disease (n?=?1), QTc interval prolonging drugs other than risperidone (n?=?8), and metabolic inhibitors (n?=?2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP.

Conclusion

Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks.     

A Therapeutic Use of the Methadone Fluvoxamine Drug Interaction

ABSTRACT

Methadone is associated with prolongation of the corrected QT interval (QTc) and torsade de pointes in case series, cross sectional studies, a prospective cohort study, and one randomized trial. It has recently been suggested that methadone promoted sudden cardiac death based on the absence of structural heart disease in an autopsy cohort. Given increasing data linking methadone to arrhythmia, clinicians must understand whether the relationship is causal, and if so, anticipate the expected frequency of QTc interval prolongation in their patients. To date has not been well characterized. To assess the impact of methadone on the QTc interval, electrocardiography at baseline and 6 months after methadone induction was evaluated from a previously published prospective cohort study of heroin addicts. Absolute increases above categorical QTc thresholds and the proportion with QTc interval increases exceeding 30 and 60 msec were tabulated. Among 151 subjects, 76% experienced an increase in QTc, whereas 24% had no change or a decrease. The proportion exceeding 450 msec increased from 7% at baseline to 19% at 6 months; those exceeding 500 msec increased from 0% to 2%. Although 18% of subjects had an increase in QTc of 30 msec, only 3% had an increase exceeding 60 msec. Most methadone-treated patients develop QTc prolongation. However, critical QTc prolongation (exceeding 500 msec or increases exceeding 60 msec) occurred infrequently. This highlights the heterogeneity of QTc interval changes and measurement variability but also implies that electrocardiography screening among opioid dependent patients would only occasionally require methadone discontinuation.