QTc prolongation and clozapine: Fact or artefact?

To the Editor

Clozapine offers essential help to patients with treatment-resistant schizophrenia, and the disruption or discontinuation of treatment may have severely detrimental effects (Nielsen et al., 2011a). It is, however, a potent blocker of the Ikr potassium channel (hERG), the main mechanism for myocardial repolarization alterations, so clozapine also has the potential to prolong the QTc interval (Hoffmann and Warner, 2006).

In a recent letter, an Australian team reported 61-year-old Ms A’s case of QTc prolongation during treatment with clozapine (Dhillon et al., 2011). Although we acknowledge the listed explanations, such as genetic predisposition and medical comorbidities, a number of issues remain unresolved. As clozapine is known to increase the heart rate substantially (Nielsen et al., 2011), corrections are commonly erroneously made using Bazett’s formula. Assuming machine reading of the QTc, overcorrection is likely to have occurred because most machines use this correction formula regardless of heart rate, but this question is not clarified by the team.

When the heart rate exceeds 70 beats per minute (bpm), the Fridericia formula offers more reliable corrections (Nielsen et al., 2011b). Two sets of scores show the widening gap between the two correction formulas with increased heart rates: corrected QT intervals of 454 ms and 442 ms are elicited for a QT interval of 420 ms with heart rate of 70 bpm, after Bazett and Fridericia correction, respectively. At the elevated rate of 90 bpm, the figures are 514 ms and 481 ms.

Another issue is morphological T-wave alterations that occur during treatment with clozapine (Lieberman and Safferman, 1992). A flattening of the T-wave complicates the determination of the T-wave end, in both machine and manual readings, and this may result in artificially prolonged QT intervals (Nielsen et al., 2011b). Ms A had exhibited great variation in QTc interval length in the course of the same day, which may lead us to suspect that the findings in fact reflect difficulties in QT interval measurement. Moreover, clozapine patients display significant variations in dose–plasma concentration and one could speculate that QTc prolongation may only be attributed to high plasma levels. Variation up to 45 times after single-dose administration has been recorded, with elderly non-smoking women having the highest plasma concentration. In addition, Ms A was reported to have an infection, which is known to increase plasma levels (Nielsen et al., 2011a).

Whether clozapine actually does prolong the QTc interval is an unresolved question. If the reporting of QTc prolongation during treatment with clozapine is to be useful in elucidating the problem, then it should include data on heart rate, the correction formula, the clozapine plasma levels and whether the reading was done manually or by a machine. Psychiatrists should be extremely cautious of discontinuing clozapine treatment because doing so may increase the risk for psychotic relapse and suicidal behaviour. Large-scale studies for further investigation of electrocardiographic changes during clozapine treatment are warranted.