Response

First, I want to congratulate Wagner et al^{Reference Wagner, Korman, Solmi, Mortazavi, Aminifarsani and Dubrovin Leão1} for their excellent article on clozapine-associated myocarditis using the Delphi consensus methodology, and the editor for having the courage to publish their article proposing that patients of Asian ancestry need lower clozapine doses. Second, I want to highlight the need for a similar article using the Delphi consensus methodology concerning all clozapine-associated inflammations during rapid titration.

Wagner et al^{Reference Wagner, Korman, Solmi, Mortazavi, Aminifarsani and Dubrovin Leão1} should be congratulated for demonstrating that finally there is international consensus that slower titrations may help reduce the risk of clozapine-induced myocarditis. Reaching wide agreement on such an issue is not a minor task. For many years, views on clozapine-associated myocarditis were strongly coloured by the country in which a psychiatrist was trained, the country’s various titration schedules and the differences in incidence of clozapine-associated myocarditis.^{Reference de Leon2} Danish psychiatrists use very slow titration, many times in an out-patient setting; therefore, they rarely see myocarditis and do not currently see any associated mortality.^{Reference Rohde, Polcwiartek, Kragholm, Ebdrup, Siskind and Nielsen3} In 1980, they published in Danish the first case of clozapine-induced myocarditis and subsequent death of a patient started on 300 mg/day. After that they moved to slow clozapine titrations. Danish psychiatrists do not consider themselves experts on myocarditis as they have almost no cases and were very sceptical of the relevance of myocarditis during clozapine titration.^{Reference Rohde, Polcwiartek, Kragholm, Ebdrup, Siskind and Nielsen3} At the other extreme, Australian psychiatrists as recently as 2024 considered it ‘normal’ to have a 10% rate of clozapine-induced myocarditis.^{Reference Tirupati and Arachchi4} Please make it very clear that I am not blaming the Australian psychiatrists. The marketer introduced clozapine in Australia with two titration schedules that were too aggressive^{Reference de Leon2} for patients of European ancestry if they behave as poor metabolisers within their ancestral group because of the co-prescription of inhibitors, obesity, inflammation before starting clozapine or use of antipsychotics such as olanzapine or quetiapine, which increase the risk of myocarditis.^{Reference de Leon2} The predicament of Japanese psychiatrists has been even worse than that of Australians. The marketer did not complete dosing studies in Japan and introduced clozapine essentially with only US studies. The official titrations were extremely aggressive for Japanese patients; other Asian patients need approximately half of the US-recommended dose. Thus, for Japanese psychiatrists it was normal to frequently see myocarditis; moreover, from the first study, all studies indicated that up to 30% of their patients had fever during clozapine titrations.^{Reference de Leon2} Only recently have the Japanese realised that the official titrations recommended in their package insert are inappropriate for their patients and that fever is not normal. The same realisation has occurred in South Korea where psychiatrists have found that rapid titration leads to too many pneumonia cases, many of them possibly aspiration pneumonia and possibly preventable with slower titration.^{Reference de Leon2} When the Japanese and Korean official titration recommendations in the package insert will be corrected is unknown, as drug agencies move very slowly.

The courageous editor who approved this article by Wagner et al^{Reference Wagner, Korman, Solmi, Mortazavi, Aminifarsani and Dubrovin Leão1} should be complimented for allowing an article that acknowledges that patients of Asian ancestry need slower titrations. This is an implicit acknowledgement that patients of Indian or Pakistani ancestry have, for many years, been overdosed in the UK by almost all UK clozapine prescribers, who were not aware of this difference in clozapine metabolism. ‘Almost all’ is probably correct, as Farooq^{Reference Farooq5} is a Pakistani-born psychiatrist who currently practices psychiatry in the UK, whom we can assume was not overdosing UK patients of Asian ancestry with clozapine. In 1998, when he was working in Pakistan, he published a letter^{Reference Farooq5} in this journal describing that Pakistani psychiatrists have found that Pakistani patients were like the Chinese patients and needed lower clozapine doses. This letter had no impact on clozapine dosing in the UK. The research group headed by Flanagan, who studies clozapine levels in the UK, proposed in 2004 that the minimum therapeutic dose (MTD) to reach the lower end of the therapeutic range (350 ng/ml) is between 265 mg/day for UK female non-smokers and 525 mg/day for male smokers.^{Reference Rostami-Hodjegan, Amin, Spencer, Lennard, Tucker and Flanagan6} This recommended dose range was included in the Maudsley psychopharmacology textbook for many editions. Then in 2024, after re-analysing the UK data, Flanagan and his group^{Reference Reeves, Bertrand, Obee, Hunter, Howard and Flanagan7} exercised great courage in correcting the dosing recommendation and reducing the MTD for Asian patients to a range of 175–250 mg/day. This lower range was introduced in the 15th edition of the Maudsley textbook recently published in June 2025.

In 2022,^{Reference de Leon8} I proposed that a titration that is too rapid for the metabolism of any specific patient can lead to clozapine-induced inflammation, but myocarditis is only one of the multiple forms of clozapine-induced inflammation. It can manifest with fever, c-reactive protein (CRP) elevations, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or multiple other forms of local inflammations besides myocarditis, including pericarditis, pneumonitis, nephritis, colitis and pancreatitis. In many countries, psychiatrists use troponin during titration so clozapine-associated myocarditis is diagnosed early, but other forms of clozapine-associated inflammation are not diagnosed early, nor related to rapid titrations. Finland is probably the top prescriber of clozapine in the world after correcting for population. Moreover, Finnish physicians appear to be very sophisticated in managing clozapine adverse drug reactions (ADRs), as mortality is very low during pneumonia according to a recent large study of 2659 patients.^{Reference Partanen, Häppölä, Kämpe, Ahola-Olli, Hellsten and Rask9} In that study, they described less than 5 cases of myocarditis (<0.2%) but 13 of colitis, 10 of interstitial nephritis, 8 of pancreatitis and less than 5 of pericarditis.^{Reference Partanen, Häppölä, Kämpe, Ahola-Olli, Hellsten and Rask9} Thus, there is need to increase awareness in Finland and many other countries that rapid titrations of clozapine may manifest in inflammations other than myocarditis. Wagner et al^{Reference Wagner, Korman, Solmi, Mortazavi, Aminifarsani and Dubrovin Leão1} may want to consider the challenge of developing a Delphi consensus on the wider concept of clozapine-induced inflammation associated with rapid titration. My hypothesis is that the increased worldwide awareness of clozapine-associated inflammation during titration and, more importantly, the use of CRP and personalised titration based on ancestry, may significantly reduce clozapine-associated myocarditis and the other forms of inflammation.^{Reference de Leon2}