Abstract
Perminder Sachdev, School of Psychiatry, University of New South Wales, Sydney, Australia:
The recent changes in the prescription guidelines for thioridazine (Melleril®, Adalzine®) raise issues about the nature of evidence required for such a determination, and the process by which such decisions are made. Whereas it was previously used for a broad range of psychotic and behavioural disorders, thioridazine is now indicated only for the treatment of schizophrenia in patients who have failed treatment with at least two other antipsychotic drugs. This decision was ostensibly prompted by a recent report by Reilly et al. [1] that the risk of QTc-interval prolongation was substantially higher for thioridazine and droperidol. An increase in QTc-interval may be related to polymorphic ventricular arrhythmias, referred to as torsade de pointes, that have been reported in overdoses [2]. Sudden unexplained deaths in psychiatric patients have often been linked to antipsychotic drugs [3], possibly through the causation of arrhythmias[4]. The causal relationship between QTc changes, arrhythmia and sudden death remains speculative, however, and needs to be further examined [3].
Is the evidence against thioridazine damning enough, or is it an over-reaction by the pharmaceutical industry, ever concerned about litigation, that sees little profit in marketing this drug? Thioridazine has previously been reported to cause QTc prolongation at therapeutic doses [5] and has been associated with ventricular arrhythmias [6], but this is a property it shares with many other psychotropic drugs, in particular the tricyclic antidepressants. A Finnish study [7] linked thioridazine to a disproportionate number of sudden deaths. These few reports serve to highlight the scarcity of literature on the topic, and a lack of direct comparison to other drugs in the clinical setting until the Reilly et al. [1] report. The authors of this report acknowledged a number of limitations of their study: i) the possibility of selection bias could not be excluded; ii) many patients were on two or more psychotropics; iii) the numbers were limited for many drugs, thereby reducing the power to detect abnormalities; iv) differential prescribing of certain drugs to patients with baseline QTc abnormalities could not be excluded. The findings therefore need confirmation from further studies. The other drugs implicated in this study were the tricyclic antidepressants and droperidol. No patient in this study had a QTc-interval of more than 500 ms, a threshold below which ventricular arrhythmias are unlikely. The reaction of the regulators in the case of thioridazine has been akin to that for sertindole which was withdrawn from the market because of its propensity for QTc prolongation [8].
The mechanism underlying QTc prolongation by antipsychotic drugs is believed to be the blockade of the delayed rectifier cardiac potassium channel (Ik), coded by the HERG gene [9]. Like thioridazine, these channels are blocked by chlorpromazine, haloperidol and other antipsychotics, as well as tricyclic antidepressants and some other psychotropics [9]. Other factors that are important include drug metabolism [10], plasma binding, serum potassium levels [11], age, cardiac status and the concomitant use of other drugs [12]. The complexity of the determinants warrant a full examination of the risks posed by psychotropic drugs and the context in which these occur.
While caution is necessary, and all physicians must be aware of the cardiac effects of these drugs, the severe restrictions imposed on the use of thioridazine seem to be an over-reaction. The tricyclic antidepressants have not had similar warnings and restrictions attached to them. The impact of this decision on the thousands of patients on maintenance doses of thioridazine has not been fully appreciated. A significant proportion of these patients are intellectually handicapped who have been treated with this drug for behavioural control for decades. This may be unjustified use in many cases, but the emergent need to suddenly stop the drug in so many cases has led to a minor crisis. The lack of specialists in this field has further exacerbated the situation.