Abstract
QTc prolongation in the setting of antipsychotic use is well documented in the literature and antipsychotics have been withdrawn from the market due to their association with QTc prolongation and fatal arrhythmias [1]. Normal QTc is approximately 400 ms with upper limits of 440 ms (men), and 470 ms (women). QTc of > 500 ms across both genders is identified as a risk marker for fatal ventricular arrhythmias including Torsade de Pointes (TdP) [1–2]. Genetic, medical and medication-related factors have been implicated in QTc prolongation [2]. We present a rare case of QTc prolongation with clozapine. In the literature, only three case studies document a link between clozapine and QTc prolongation in 2.8 million patient years across 27 years [3].
A 61 year old single woman with a 40 year history of schizoaffective disorder and treatment resistant positive symptoms (hallucinations and delusions) despite several antipsychotic trials. In 1994, she commenced clozapine therapy and remained stable on 400 mg/day combined with sodium valproate 1500 mg/day. QTc on clozapine monotherapy was not known as no ECG reports were available in her community files.
Ms A presented to hospital in November 2010 with agitation and confusion. This was attributed to hyperglycaemic encephalopathy and a urinary tract infection. She had been diagnosed with type-II diabetes mellitus several years previously. An ECG found incidental findings of an inferior segment elevation myocardial infarction (STEMI) and prolonged QTc of 519 ms. Clozapine, together with medical factors aforementioned, was implicated in her QTc prolongation. In consultation with cardiology and psychiatry teams, clozapine and sodium valproate were ceased, and substituted with olanzapine 10 mg. She did not improve and developed clozapine-withdrawal catatonia (a rarely reported side-effect [4]) accompanied by acute positive symptoms.
On olanzapine her QTc fluctuated between 460– 505 ms and then aripiprazole was added along with commencement of ECT, achieving partial response (catatonic component). Olanzapine was later stopped and her QTc normalized on aripiprazole 30 mg, ranging 434–453 ms. Given only partial response to aripiprazole and ECT, clozapine was reconsidered due. At the time of re-challenge, she was medically stable. Clozapine rechallenge, together with aripiprazole 30 mg, resulted in a gradual, dose-dependent increase in QTc. Over 10 days on clozapine 175 mg (50 mg mane, 125 mg nocte), the QT interval reached 488–505 ms. Interestingly, a morning ECG on day 10 showed a 505 ms QTc which decreased to 436 ms later in the day. Clozapine was subsequently ceased because of QTc prolongation and aripiprazole 30 mg monotherapy was continued with QTc ranging between 446–470 ms. However, continued non-improvement in her symptoms warranted cessation of aripiprazole and a switch to olanzapine. During the change-over period to olanzapine, she was on no antipsychotic medication except lorazepam pro re nata. The one ECG done during this time recorded her lowest QTc at 407 ms, essentially our only baseline ECG.
Ms A scored 8 on the Naranjo algorithm [5] which suggests clozapine is a probable cause for QTc prolongation. Clozapine's ability to increase the QTc interval in a dose-dependent fashion has previously been reported in the literature [3]. Antipsychotics are thought to prolong QTc through blocking the human ether-a-go-go-gene (HERG), thus preventing K + influx through IKr channels. The affinity of various antipsychotics for HERG is responsible for their variability and incidence in causing QTc prolongation. Clozapine acts on HERG in vitro, which suggests it has the potential to prolong QTc [6]. However, clinically, the association of clozapine with prolonged QTc is uncommon [3]. Given the rarity of this association, other factors including genetic predisposition and medical comorbidities may have compounded Ms A's risk.
In conclusion, this case suggests that clozapine is an antipsychotic that could increase the QTc interval in a dose-dependent manner. This report also shows a positive association between olanzapine monotherapy and QTc prolongation. Aripiprazole, however, is not implicated. Further research is required to confirm the effects of clozapine on the HERG gene, explore the impact of dual antipsychotic use on QTc prolongation, and assess the effect of medical comorbidities on QTc. The finding of QTc variability on ECGs done within a 24 hour period, on a stable clozapine dose, may also warrant further research to standardize measurements of QTc interval prolongation with ECG timing throughout the day and to correlate this with clozapine serum levels.