ArticlesQTc-interval abnormalities and psychotropic drug therapy in psychiatric patients
Introduction
Cardiovascular mortality in psychiatric patients is high.1 Reports of sudden unexplained death in those taking antipsychotic drugs2, 3 have raised the concern that part of this excess may be due to drug-induced arrhythmias, since many of these drugs have cardiac electro-physiological effects similar to those of quinidine.2 The polymorphic ventricular arrhythmia known as torsade de pointes has been recorded in patients with psychotropic drug overdose4 and provides a plausible mechanism for sudden unexplained death associated with drug therapy.5
Several psychotropic drugs are associated with lengthening of the rate-corrected QT interval (QTc) on the electrocardiogram,2 which often precedes torsade.6 There is no direct evidence linking the extent of drug-induced QTc lengthening with the risk of torsade or sudden death. However, QTc-interval lengthening is a predictor of sudden death in patients with cardiac disease7 and the extent of drug-induced QTc-interval lengthening is thought to be an important marker of arrhythmia risk by drug regulatory authorities (see website: www.emeasearch.is.eudra.org/humandocs/PDFs/SWP/098696en.pdf). Risk of arrhythmia with drugs that lengthen ventricular repolarisation may also be indicated by the dispersion of repolarisation, which can be assessed by measuring QT dispersion.8 Abnormal repolarisation may also cause non-specific abnormalities of the T wave, although there is no direct evidence to link such changes with arrhythmia.
Clinical guidelines advise caution in the use of highdose antipsychotic therapy with special reference to the risk of sudden death, as well as regular monitoring of the QTc interval,9 but evidence for this change in practice is small. Only one study has systematically examined QTcinterval abnormalities in psychiatric patients, and found an increased prevalence of abnormalities in a schizophrenic population compared with controls, and an association with high-dose antipsychotic therapy.10 This sample was not large enough to detect differences between drugs, and no relation was found between drug dosage and QTc dispersion.
Therapeutics in mental illness is moving away from high-dose antipsychotic drugs to lower doses and newer drugs; both these strategies have proven benefits, but neither are free of cardiotoxic effects.2, 11 If lengthening of the QTc interval is to be adopted as a marker of arrhythmogenic risk in psychiatric patients, its relation with dose should be clarified and its association with all antipsychotic drugs, antidepressants, and other classes of psychotropics should also be examined.
We measured the frequency of QTc lengthening in a large heterogeneous population of psychiatric patients, and assessed whether QTc lengthening was associated with individual antipsychotic drugs, antipsychotic drug dose, and other risk factors.
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Participants
The study was carried out in six districts in north-east England with the approval of the North Tees Research Ethics Committee. All participants gave their informed written consent. All mental health facilities (including inpatient, day hospital, and outpatient departments) in each district were visited between March, 1994, and July, 1996. All patients aged 18–74 years present on study days were invited to participate. Exclusion criteria were failure to obtain informed written consent or change
Results
495 psychiatric patients were enrolled in the study (297 [60%] men, 198 [40%] women; mean age 45 years, range 18–74). 271 participants were from inpatient wards (55%), 86 from outpatient clinics (17%), 111 from day units (22%), and 27 from nursing homes (5%). 71 (14%) patients had a history of cardiovascular disease. Table 1 shows details of patients' diagnoses. 339 patients were taking antipsychotic drugs (dose range 25–4788 mg chlorpromazine equivalents/day). Of these, 41 (12%) were taking
Discussion
Our study shows an association between QTc lengthening and increasing antipsychotic dose. Use of tricyclic antidepressants, droperidol, and thioridazine were robust predictors of QTc lengthening in a logistic regression model, but there was no relation with any other drugs or risk factors apart from age. Differences between drugs are as important as the link with antipsychotic dose and are not explained by confounding for age or differential prescribing of some drugs in higher doses. Lithium
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