Clozapine rechallenge following QTc prolongation

To the Editor

We read with interest Nielsen’s response (Nielsen, 2012) to our case study published in 2011 regarding QTc prolongation in a patient (Ms A) treated with clozapine (Dhillon et al., 2011). Nielsen raised several issues that need to be factored in before discontinuing clozapine due to prolonged QTc, which included: using Fridericia’s formula rather than Bazett’s formula for calculating the QTc interval (as it better corrects for heart rates greater than 70 beats per minute), using manual readings rather than machine readings and analysing the QT interval in conjunction with clozapine plasma levels.

It was a timely response by Nielsen as Ms A was readmitted in April 2012 owing to physical aggression against residents in her nursing home. Her symptoms had exacerbated following discontinuation of clozapine in February 2011 despite trials of combination anti-psychotics and electroconvulsive therapy. She was clinically stable on clozapine for several years prior to this.

Ms A’s past electrocardiogram (ECG) records were re-examined and it was noted that her heart rate was generally more than 70 beats per minute; thus, utilising the Fridericia formula would be more appropriate than the Bazett formula (Nielsen, 2012). Recalculation of 22 previous QTc values using the Fridericia formula and manual measurements showed adjusted values below 470 ms in all the readings. Whilst using the Bazett formula, however, there were 14 out of 22 readings above 470 ms. Other possible contributing factors to her prolonged QTc, including potential pharmacological causes and interactions (Taylor et al., 2009), were considered and excluded. A repeat echocardiogram revealed improved systolic function since the myocardial infarction in November 2010. Hence, we decided to rechallenge Ms A on clozapine in closely monitored settings with adjusted serial ECG readings.

Ms A had an anti-psychotic-free period and behavioural disturbances were treated solely with benzodiazepines. Her baseline QTc interval was demonstrated to be consistently in the normal range of 400–420 ms. The cardiology team cleared her for clozapine rechallenge. We performed twice-weekly morning ECG readings, weekly clozapine levels and daily physical observations in addition to the requirements stipulated by the local clozapine protocol (Novartis, 2008). At doses of 200 mg daily, Ms A’s highest clozapine level attained was 189. Her physical observations and laboratory investigations were unremarkable.

Apart from one isolated borderline reading of 483 ms, the remaining QTc readings were less than 470 ms after correction with the Fridericia formula. The mean QTc value was 428 ms over 13 readings. There was no linear relationship between plasma clozapine levels and QTc prolongation. The isolated borderline QTc occurred at a dose of 175 mg daily that normalised even when the dose was further increased. Receiving 200 mg of clozapine daily, Ms A showed considerable improvement in her mental state. She returned to her previous residence and has been receiving regular community management.

This case demonstrates a successful rechallenge of clozapine if QTc values are scrutinised within an appropriate theoretical framework. We encourage clinicians to revisit cases where clozapine may have been discontinued due to QTc prolongation. Given that clozapine may be the only choice in the setting of treatment-resistant schizophrenia, issues pertaining to QTc prolongation should promote further rigorous inquiry using the principles outlined by Nielsen rather than immediate cessation of clozapine.