Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly

Department of Psychiatry, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia 23238-5414, USA.
Drugs & Aging (Impact Factor: 2.84). 12/2009; 26(12):997-1012. DOI: 10.2165/11318880-000000000-00000
Source: PubMed


The quinidine-like effects of some antidepressant drugs (particularly tricyclic antidepressants) and many antipsychotic drugs (particularly the phenothiazines) confound treatment of psychosis and depression in patients with major mental illness. This is especially true among elderly patients with existing risk factors for corrected QT (QTc) interval prolongation.
We used PubMed, previously reported review articles and the extensive personal files of the authors to identify cases of subjects aged ≥60 years who developed QTc interval prolongation, polymorphic ventricular tachycardia (PVT)/torsade de pointes (TdP) and/or sudden cardiac death while taking antipsychotic or antidepressant drugs or a combination of these medications. We identified 37 patients who had taken, in total, 46 antipsychotic or antidepressant drugs.
Our most striking finding was that almost four-fifths of our cases involved women. When the 14 critically ill subjects receiving haloperidol intravenously were excluded, 91.3% of our subjects were women. Almost three-quarters of our study subjects had cardiovascular disease.
Intravenous administration of haloperidol in the critically ill and profoundly agitated elderly warrants particular comment. Of the 14 subjects in this category identified, six were men and eight were women. In 13 cases, the drug dose far exceeded the 2 mg necessary to produce an antipsychotic effect. These clinicians were using an agent to achieve sedation that usually requires very high doses in the critically ill and profoundly agitated elderly to achieve this effect.
Inclusion criteria for our literature review required antipsychotic and/or antidepressant drug-induced QTc interval prolongation. Even so, our finding that 31 of our 37 subjects developed PVT is sobering. However, the reader should not conclude that drug-induced QTc interval prolongation is highly predictive of PVT or its TdP subtype. All of our study subjects had at least two risk factors for TdP, with age and sex being the most common. We included the rare case of a patient with congenital long QT syndrome who developed further lengthening of the QTc interval and TdP when prescribed an antidepressant drug well known to produce QTc interval prolongation.
We conclude with recommendations for clinicians not expert in the specialty of cardiology to deal with the many questions raised in this review. Specifically, such clinicians treating elderly patients with antipsychotic and antidepressant drugs that may prolong the QTc interval should aggressively obtain a baseline ECG for elderly female patients with additional risk factors such as personal or family history of pre-syncope or syncope, electrolyte disturbances or cardiovascular disease. Elderly male patients are also subject to QTc interval prolongation when such risk factors are present. It is important that the clinicians themselves inspect ECGs. If the QT interval is more than half the RR interval, QTc interval prolongation is likely to be present. In such cases, a cardiology colleague interested in QTc interval issues and TdP should be asked to review the ECG. Finally, nothing in our recommendations replaces meticulous attention to US FDA guidelines in the package insert of each drug.

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Available from: Antony Fernandez, Sep 28, 2015
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    • "This finding needs to be re-examined with a prospective design. Some earlier studies have found a gender difference in QTc prolongation, which could be attributed to different serum testosterone levels (Vieweg et al., 2009; Van Noord et al., 2010), antipsychotic doses (Reilly et al., 2000), antipsychotic dose or polypharmacy (Anil Yagcioglu et al., 2005), and concurrent use of antidepressants (Reilly et al., 2000). Other studies (Anil Yagcioglu et al., 2005; Sumic et al., 2007; "
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    ABSTRACT: Objective Little is known about the pattern of QT interval (QTc) prolongation in Asian patients with schizophrenia. This study examined trends of QTc prolongation in schizophrenia inpatients in six Asian countries and territories between 2004 and 2008/2009 and its independent demographic and clinical correlates.Method Data on 3482 hospitalized schizophrenia patients (2004 = 1826 and 2008/2009 = 1656) in six Asian countries and territories were collected by either chart review or interviews during a 1-month period. Patients' sociodemographic and clinical characteristics, prescriptions of psychotropic drugs, and QTc interval were recorded using a standardized protocol and data collection procedure.ResultsThe frequency of QTc prolongation (>456 ms) was 2.4% in the whole sample, decreasing from 3.1% in 2004 to 1.6% in 2008/2009 (p = 0.004) with wide intercountry variations. However, this decreased trend was driven by decreased QTc prolongation detected in China and Hong Kong (both p-values < 0.05). Multiple logistic regression analysis of the whole sample revealed that patients having more likely to have an illness lasting longer than 5 years and received antipsychotics classified as list-1 drugs according to the Arizona Centre for Education and Research on Therapeutics. Compared with 2004, patients in 2008/2009 were less likely to have QTc prolongation. Thioridazine caused QTc prolongation most frequently (odds ratio (OR) 4.4; 95% confidence interval (CI) 1.2–15.2), followed by sulpiride (OR 2.4; 95% CI 1.3–4.5), clozapine (OR 2.4; 95% CI 1.4–4.2), and chlorpromazine (OR 1.9; 95% CI 1.07–3.5).Conclusions Frequency of QTc prolongation was low in Asian patients with schizophrenia. QTc prolongation in schizophrenia decreased in China and Hong Kong between 2004 and 2008/2009 but increased in Taiwan over the same period, remaining low in the other countries. Copyright © 2015 John Wiley & Sons, Ltd.
    Full-text · Article · Jan 2015 · Human Psychopharmacology Clinical and Experimental
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    • "We advise the reader using drugs that may lengthen the QTc interval to review the paper by Postema et al. (2008) using the tangent method to measure the QT interval. We have discussed this issue in much greater detail elsewhere (Vieweg et al. 2009). Newer surrogate markers for ventricular arrhythmogenesis including TdP Expertise in newer surrogate markers for drug-induced TdP is probably beyond expectations for readers of this journal. "
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    ABSTRACT: A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced IKr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP). The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP. We identify case reports using PubMed, Medline, EMBASE, and Cochrane. 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. 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.
    Full-text · Article · Jun 2013 · Psychopharmacology
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    • "In addition, atypical antipsychotic drugs should not be considered as one class (Heres et al., 2006; NICE, 2009; Lieberman and Stroup, 2011). As a result, greater necessity for tailoring treatments depending on the patient and their characteristics, including current co-morbidities, having considered the safety profile of each drug including its pharmacokinetic profile (NICE, 2009; Poluzzi et al., 2009; Ray et al., 2009; Tiihonen et al., 2009; Vieweg et al., 2009; Lieberman and Stroup, 2011; Meyer-Massetti et al., 2011). In addition, switching patients between treatments should never be considered if they are stable on a particular atypical antipsychotic drug. "
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    ABSTRACT: Introduction: Scrutiny over pharmaceutical expenditure is increasing leading to multiple reforms. This includes Austria with measures to lower generic prices and enhance their utilisation. However the situation for newer antidepressants and atypical antipsychotic drugs (AAPs) is different to PPIs, statins and renin-angiotensin drugs with greater tailoring of therapy and no wish to switch products in stable patients. Authorities welcome generics though given high costs particularly of patented AAPs. Objective: Assess (a) changes in utilisation of venlafaxine versus other newer anti-depressants before and after availability of generics, (b) utilisation of generic versus originator venlafaxine, (c) price reductions of venlafaxine over time and influence on total expenditure, (d) utilisation of risperidone versus other AAPs, (e) suggest potential additional reforms that could be introduced if pertinent. Methodology: A quasi-experimental study design with a segmented time series and an observational study. Utilisation measured in defined daily doses (DDDs) and total expenditure per DDD and over time. Results: No appreciable changes in the utilization patterns of venlafaxine and risperidone after generics. The reduction in expenditure/ DDD for venlafaxine decreased overall expenditure on antidepressants by 5% by the end of the study versus just before generics despite a 37% increase in utilization. Expenditure will further decrease if there was reduced prescribing of duloxetine. Conclusion: Depression, schizophrenia and bipolar diseases are complex diseases. As a result, specific measures are needed to encourage prescribing of generic risperidone and venlafaxine when multiple choices are appropriate, and authorities cannot rely on a ´Hawthorne´ effect between classes to enhance use of generics first line. Measures may include prescribing restrictions for duloxetine. No specific measures planned for AAPs with more generics becoming available.
    Full-text · Article · Jan 2012 · Frontiers in Pharmacology
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