Considering the impact of viral illness on the aetiology of clozapine myocarditis

To the Editor

In a recent edition of the journal, Siskind et al. (2020) published a meta-analysis of the association between clozapine exposure and myocarditis that found a dramatic and unexplained sevenfold excess of myocarditis among studies emanating from Australia. The authors speculated that this difference might be due to unclear diagnostic criteria and antipodean awareness, leading to higher case ascertainment and/or diagnostic overshadowing of more common causes of heart disease. Kilian et al. (1999) first highlighted clozapine myocarditis by reporting 15 cases among 8000 clozapine-exposed Australians. Of these 15 cases, 6 were described as having flu-like symptoms. In the era of COVID-19, we would like to raise the possibility that viral infections might contribute to clozapine myocarditis by way of institutional or nosocomial infection. During the recent COVID-19 pandemic, the vulnerability of institutional settings has been front-page news, and there have been reports in the peer-reviewed literature of an associated myocarditis (Inciardi et al., 2020) similar to that associated with parvovirus B-19 and influenza.

Australian clinicians are very cautious when initiating clozapine, usually admitting people for titration to acute inpatient hospitals where blood tests, electrocardiograms (ECGs), cardiac echo and other observations can be taken with ease. We hypothesise that higher rates of myocarditis reported in Australia recorded during the early weeks of clozapine treatment might be caused by viral infections contracted in institutional care. The COVID-19 pandemic has focused our attention on protecting the health of people with schizophrenia, who may also be more vulnerable to this infection due to underlying cardiovascular co-morbidities. We advise that clinicians reconsider the need to titrate clozapine in the hospital setting, record episodes of viral infection during clozapine titration and increase infection control measures when coming into contact with patients newly initiated on clozapine. The introduction of hospital-at-home clozapine titration could be one strategy to reduce the burden on inpatient units while protecting patients from viral infections during titration.