Clozapine was one of these old drugs that has heavily relied on postmarketing surveillance to decrease potentially lethal ADRs. Clozapine was marketed in some European countries in the early 1970s5 but postmarketing surveillance was first used to identify clozapine-induced agranulocytosis. In 1975, agranulocytosis cases were described in Finland6 leading to its withdrawal from some European countries and the cessation of North America studies.5 In 1989, the study by Kane et al.7 led to its approval by the FDA and its marketing in the US with a system requiring weekly white blood cell counts (WBCs). Then clozapine was first introduced or reintroduced in many other countries.

Clozapine-associated myocarditis was also identified by postmarketing surveillance (Supplementary Table S18–23). In 1980, Danish authors8 published in Danish the first case of clozapine-associated myocarditis as an overdose, which can be described as “rapid titration by a patient”. The first overdose case written in English was published in 1992 by US authors.9 The first “rapid titration by a doctor” was described in a German patient in 1995.11 The doctor started with 25mg but increased the dosage very fast, reaching 500mg/day on the 8th day. In 1999 an important article by Killian et al.12 reviewed 23 cases from the Australian drug registry and placed clozapine-associated myocarditis on the radar of the drug agencies. It is unfortunate that the drug agencies did not pay attention to a comment on Killian's cases by Canadian authors: Dejeveran et al.13 stated that “in all cases, daily clozapine doses were increased rapidly” and that the Australian titrations were much faster than their Canadian titrations.

In 2012, two crucial articles defending two extreme positions on clozapine-associated myocarditis were published by Continental Europeans24 and Australians.25 The Continental European position was exemplified by the Dutch group Cohen et al.,24 who brought attention to an incidence rate of 0.7–1.12% in Australia versus 0.07% worldwide. In the Netherlands, they found almost no cases of clozapine-associated myocarditis in spite of extremely wide use of clozapine (approximately 10% of schizophrenia outpatients)26; it is important, however, to emphasize that the Dutch guideline27 proposes very slow clozapine titration, particularly for outpatients.

In a case-control study, Ronaldson et al.25 found that clozapine-associated myocarditis in Australia was significantly associated with rapid titration (rapidity was defined on the basis of each additional 250mg of clozapine administered in the first nine days) with an odds ratio (OR) of 1.26, while valproate co-administration was associated with an OR of 2.59. Since 2012 these two positions may have become further apart. In their 2015 review of the literature, Ronaldson et al.28 proposed that the Australian experience is the correct one since the real incidence of myocarditis is around 3% and “that a similar incidence would be found in other jurisdictions, if a practice of routine monitoring for myocarditis was adopted”. The Continental Europeans responded with a study from the Danish registry; Rohde et al.29 studied all 3262 outpatient starts of clozapine and found 0.03% developed myocarditis in the first 2 months and, more importantly, that none of the 26 deaths in the first 2 months was explained by myocarditis. If the Danish psychiatrists do not identify clozapine-associated myocarditis as Ronaldson et al.28 proposed and continue with clozapine titration in patients with early myocarditis, one should think that many of these patients would die. If one proposes an incidence of 3% of myocarditis in 3262 clozapine initiations, one should expect 97 undiagnosed clozapine-associated myocarditis cases with high risk of death due to lack of identification by their Danish psychiatrists.

In 2020, a meta-analysis30 of clozapine-associated myocarditis found an event rate of 2% in 9 Australian samples and of 0.3% in 15 non-Australian samples. This meta-analysis did not explain this roughly seven-fold difference between Australia and other countries.

Supplementary Table S212,28,31–40 described prior published reviews of clozapine-associated myocarditis found in PubMed. These review articles mainly collected cases from published case reports or ADR reports to drug agencies. The sample size has progressively increased from 23 cases,12 to 24 cases,31 65 cases,33 69 cases,32 88 cases,36 116 cases,34 250 cases,28 or 359 cases.37

VigiBase is the World Health Organization's global ADR database. On January 15, 2021, we completed a search focused on more than 3000 myocarditis cases suspected to be associated with clozapine.

VigiBase, the World Health Organization's global database, is located at the Uppsala Monitoring Centre, Uppsala, Sweden. It currently has >25 million reports of spontaneously reported ADRs from the drug agencies of 145 countries. New reports arrive daily. Clozapine ADRs are classified some times by the reporting clinician but normally those who report would enter free text information and pharmacovigilance staff at a regional or national center or pharmaceutical company would do the encoding using the categories provided by the database. Each patient can be classified in 1 or several clozapine ADR categories. Myocarditis is a well-established clozapine ADR in VigiBase.

From the inception of the database until January 15, 2021, all 3752 reports of myocarditis and clozapine that were reported have been scrutinized by the first and second authors. They represent nearly half the VigiBase reports of myocarditis for all drugs. This is a retrospective review of deidentified cases (see Table 1, footnote a).

VigiBase uses as a standard method a logarithmic measure of disproportionality called the information component (IC).41 The IC measures disproportionality between the expected and the reported rates of myocarditis related to clozapine and is described in detail in footnote e of Table 1. All of these VigiBase standard analyses are contaminated by the possibility of some level of duplicate reports.

All 3572 reports were scrutinized by the first author. He reviewed each case carefully for possible duplicates and for myocarditis unique cases associated with clozapine up through December 31, 2020.

After a careful discussion with the last author, 298 records were eliminated (including 287 duplicate cases, 10 from 2021 and 1 baby) leading to 3274 different patients with myocarditis. They are described in Table 2, which includes the most frequently reported co-medications, fatal outcomes and serious cases. Table 3 described logistic regression models with seriousness (yes/no) or fatal outcomes (yes/no) as dependent variables.

Table 2 describes the clinical characteristics of 3274 cases after eliminating obvious duplications. Pharmacovigilance databases are known for the problems of incomplete information and missing data.42 The percentages of relevant missing data include: 13.5% for age, 52.4% for clozapine dose at the time of diagnosis, and 52.4% for days until myocarditis developed. The prevalences of reported co-medications are included in Table 2 while reported signs and symptoms are reported in Table 4. There is no certainty that these co-medications, symptoms or signs are absent in unreported cases; various reported cases appear to have different levels of completion of information. The 5 most frequently reported symptoms or and signs were tachycardia, pyrexia, troponin increase, CRP increase and chest pain (Table 4). Troponin is a specific marker of myocardial damage but troponin data did not start being reported until 2005.

Less than half of the sample provided data regarding days to diagnosis. Supplementary Fig. S4 shows that 84% (1309/1560) of cases of myocarditis with reported time data were diagnosed in the first 30 days. Supplementary Table S5 presents the same data by month and indicates that another 5% (82/1560) were diagnosed in the second month. Supplementary Table S6 describes the daily frequencies during the first month. Days 12–21 had >50 cases/day. Fatal outcomes are grouped between days 11 and 24; relative lethality was 2% in the first month.

Supplementary Tables S5 and S6 present the clozapine dosage on the last day of treatment. The median dosage during the first week appears definitively inappropriate on some days including 112.5mg/day on days 1 and 2, and 212.5mg/day on day 4. The maximum dose on day 1 of 175mg/day indicated a patient was started on that dose. Other very high maximum daily doses were 300mg/day on days 2, 5 and 7; 400mg/day on day 4; and 500mg/day on day 6. The maximum dosage on some days of weeks 2–3 are also highly inappropriate with values of 600mg/day on days 10 and 20, 650mg/day on day 15, 800mg/day on day 11, and 1600mg/day on day 13 (Supplementary Table S6).

Clozapine appears to definitively have a strong association with myocarditis not present in other antipsychotics (Supplementary Table S3). The first clozapine case was published in 1980 but since 1993 the VigiBase statistical signal of the association between clozapine and myocarditis has become significant and currently is very strong (Supplementary Fig. 1). In pharmacovigilance studies, statistical associations can be explained by confounding factors, but most of the myocarditis cases occurring in clozapine patients happen during titration. This is compatible with what we know about hypersensitivity reactions associated with rapid titration. Furthermore, the strength of the association and robustness42,43 across time and in various countries suggest that clozapine may be a relevant contributing factor or even a causal factor during titration. Myocarditis occurred mostly (84%) in the first month, plus another 5% in the second month. Supplementary Table S7 suggests that the number of cases drops precipitously after 4 months. There are other causes of myocarditis, particularly viral infections44; thus, it is possible that many of the cases not occurring during clozapine titration may be mainly explained by other causes and clozapine may be merely a contributing factor.

To correctly interpret the speed of titration in each patient with myocarditis,45,46 there is need to know information such as ancestry, sex, smoking status, obesity and co-medication47 that is missing. Most psychiatrists looking at Supplementary Table S6 maximum doses would easily agree that 175mg/day of clozapine is not a safe dose for the first day. Similarly, reaching 300mg on day 2, 400mg on day 4 or 500mg on day 6 is not safe. In 2014, Schulte et al.48 emphasized the definitive risk of rapid clozapine titrations for seizures, orthostatic hypotension or even collapse may also be relevant for myocarditis.48

Many of the minimum doses reported in Supplementary Table S6 are very low during the first month. The readers need to understand that this is the last dose that was reported to the national drug agency which sent them to VigiBase. We cannot rule out that patients had much higher doses prior to that, which were first reduced and then finally stopped. Most cases did not have enough detail concerning titration or how doses were discontinued.

Another issue that clinicians need to remember when interpreting these values is that we have found that some clozapine PMs can get therapeutic concentrations with very low doses, even lower than 100mg/day, due to co-medication with inhibitors, the presence of inflammation, obesity or, more rarely, genetic PM status.46,49–52 These patients require much slower titrations and much lower final doses.

A prior VigiBase study53 of all ADRs indicated that a greater proportion of Japanese reports in VigiBase are serious in nature and this is compatible with the small number of myocarditis cases reported from Japan. It appears to us that Japan and other Asian countries may be underreporting cases of myocarditis associated with clozapine. The current limited data suggests that severity (adjusted OR=2.39) and lethality (adjusted OR=4.35) of those currently reported may be greater than in non-Asian countries but these findings will need to be revisited when VigiBase receives many more myocarditis cases from Asian countries.

There are no myocarditis reports in VigiBase from China. Clozapine was introduced in China in 197654 and for many years clozapine was the most frequently prescribed antipsychotic in China.55 However, Chinese psychiatrists have always prescribed approximately half the dosage used in Western countries.56 The first case of myocarditis published in Chinese was in 2001 in the context of an overdose.16 In 2018 an article listed in PubMed reviewed the autopsies of 24 sudden unexpected deaths in psychiatric patients in Shanghai; 2 of them appear to be cases of clozapine-induced myocarditis.21

Clozapine was introduced in Japan in 2009 and restricted to special inpatient institutions. The first published clozapine trial57 used up to 600mg/day, the maximum approved dose in Japan. This is an extremely high dose for an average Japanese patient, who probably metabolizes clozapine like other Asians.58 Japanese titration appears extremely rapid for Japanese patients because the prevalence of fever during titration appears extremely high, as articles describe prevalences of 29%57 or 38%.59

Pharmacovigilance databases are hampered by reporting biases and two of them may be important in this myocarditis study: the effect of the country and of missing data.

VigiBase data supports the idea that Australian physicians are much more aware of clozapine-induced myocarditis than physicians in other countries. They report many more mild cases. After reviewing the clinical diagnosis in one area of Australia, Winckel et al.60 proposed that this diagnosis included cases of inflammation that did not strictly meet the diagnosis of myocarditis and cases with concomitant viral infections. We propose that meeting or not meeting the criteria for a diagnosis of clozapine-induced myocarditis is not important. Any inflammation during clozapine titration is extremely worrisome. It does not matter whether it is secondary to rapid clozapine titration or has another cause; all inflammation releases cytokines that decrease clozapine metabolism.61 As a matter of fact, patients with undiagnosed inflammation cannot tolerate normal titrations and can develop additional clozapine-induced inflammation, making titration very risky.52

VigiBase data also supports the idea that US physicians apparently only report the most severe cases of clozapine-induced myocarditis; US relative lethality was higher than in the rest of the world. The patients with missing data concerning the day of the treatment and the dose were overrepresented among those with serious cases and among fatal cases. The adjustment of US ORs for serious and fatal cases based on the presence of missing data did not appear to explain the high US ORs for seriousness or fatality. Other limitations are described in Supplementary Box S1.50,61–65

Our data from VigiBase suggest an overrepresentation from Australian reports which is compatible with the published meta-analysis describing a seven-fold difference in incidence between Australia and other countries.30Supplementary Box S225,47,51,60,65–84 proposes that this seven-fold difference between Australia and other countries can be understood if clozapine-induced myocarditis is a hypersensitivity reaction. Supplementary Box S313,47,85 discusses the difficulty in exploring the differences in rapid titration although this may be crucial in understanding incidence differences for clozapine-induced myocarditis.

FDA data from 1998 to 2005 indicated that clozapine was associated with 3277 deaths or serious non-fatal outcomes, making it the third most toxic drug in the US.4 In our VigiBase search on July 15, 2019, myocarditis was the fourth leading cause of death in clozapine patients.64 Thus, raising awareness of clozapine-associated myocarditis may be important in reducing clozapine toxicity.