Arrhythmias and sudden death in patients taking antipsychotic drugs

The first report that patients with schizophrenia might be at special risk of arrhythmia and sudden death appeared in the early 1960s, when thioridazine was found to prolong the QT interval, an electrocardiographic abnormality that could lead to torsades de pointes and sudden death.^1–4 This same problem arose with sertindole—lengthening of the QTc interval and an apparent excess of sudden deaths in clinical trials—and led the US Food and Drug Administration to refuse it a licence.⁵ Nevertheless, whether cardiac deaths are related to the illness itself or to the drugs used to treat it has remained unclear. Data from a very large American cohort of almost 100 000 outpatients with schizophrenia who were treated with antipsychotics were published recently and begin to suggest an answer: the drugs play a major part, although a risk factor conferred by the disease or associated with it may contribute (for example, smoking).⁶ The study originated from unpublished preclinical work comparing ziprasidone, a new atypical antipsychotic drug that Pfizer had developed, with established antipsychotics. Ziprasidone caused notable QTc prolongation, and the FDA had concerns about licensing it mainly because of this abnormality.

The study examined administrative records (including all prescriptions) from three regions in the United States, comparing the incidence of cardiac arrest and ventricular arrhythmias and all cause mortality in patients with schizophrenia treated with an antipsychotic with that in two other cohorts, one with patients of glaucoma and one with patients of psoriasis. Both these conditions require long term medication, and neither is associated with cardiac risks. Of the patients with schizophrenia about 41 000 had received haloperidol, 24 000 thioridazine, 22 000 risperidone, and 8000 clozapine. With haloperidol, thioridazine, and risperidone the rate of cardiac arrest and ventricular arrhythmias and all cause mortality was two to five times higher than in the comparison groups. The findings confirm that all cause mortality in schizophrenia is relatively high. A dose-response relation could be identified only for thioridazine: the risk ratio for cardiac arrest and ventricular arrhythmias between the highest and the lowest doses was 2.5. In other words, the risk is greater with doses of thioridazine above 100 mg per day than with equivalent doses of haloperidol (3 mg or more).⁷

In practice it would be prudent to avoid doses of thioridazine over 100 mg per day and not to use the drug concurrently with any other that can lengthen the QT interval, such as erythromycin, azithromycin, and amitriptyline and other antidepressants—whether tricyclics or selective serotonin reuptake inhibitors.⁸ The findings also call for a reassessment of the place of thioridazine in the management of schizophrenia. The relation of prolonged QT intervals to adverse outcomes remains uncertain. It seems certain, however, that adverse cardiac effects occur and can be mediated through cardiomyopathies, myocarditis, and other pathophysiological effects that might be expected to impair cardiovascular function.⁹ Since at least some of these effects are likely to be dose related, it may be asking for trouble to use high doses—or different antipsychotics in combination. In the latest issue of Current Problems in Pharmacovigilance the Committee on Safety of Medicines emphasises the hazards of clozapine.¹⁰ It recommends an electrocardiogram before treatment and close observation of all patients who develop persistent tachycardia during the first two months after starting treatment with the drug.

It is sobering to find that life expectancy for patients with schizophrenia may have fallen in recent years.¹¹ All these findings point to a need to pay more attention to the cardiac status of psychotic patients.