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Purpose/Background A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. Methods Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. Findings/Results Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. Implications/Conclusions The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Introduction: Pharmacovigilance studies have definitely established that clozapine can cause myocarditis. Two published reviews suggested that on rare occasions other antipsychotics may induce myocarditis. Areas covered: This review explored myocarditis associated with antipsychotics other than clozapine by conducting a systematic search of the literature and critically analyzing the current data in VigiBase compared to the data on clozapine-associated myocarditis. VigiBase is the World Health Organization’s global pharmacovigilance database that uses a statistical signal for associations with a logarithmic measure of disproportionality called the information component (IC). Expert opinion: For quetiapine, VigiBase provided 106 reports of myocarditis and a significant statistical signal (IC = 1.8; IC025 = 1.5) which was confounded by 48% (51/106) with clozapine co-prescription. Combining the literature and VigiBase cases provided five probable myocarditis cases during quetiapine monotherapy (4 after overdose or rapid titration). For olanzapine, VigiBase provided 107 reports of myocarditis and a significant statistical signal (IC = 2.1; IC025 = 1.8) probably explained by 77% (82/107) using clozapine co-prescription. Combining the literature and VigiBase cases provided one probable myocarditis case during olanzapine monotherapy. Combining the literature and VigiBase provided another three probable cases during therapy with other antipsychotics during overdose or titration with a high dose.

Using Richardson and Davidson’s model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level.

Clozapine was synthesized in 1958. The Food and Drug Administration approved it in 1989 when comprehensive pharmacokinetic studies were not required and it was not known that clozapine was metabolized by the cytochrome P450 1A2 (CYP1A2). Currently it is known that clozapine personalized dosing may be influenced by one’s DNA ancestry (African, European and/or Asian/Indigenous American), sex/smoking subgroup, and the presence/absence of genetic/non-genetic poor metabolizer (PM) status. The literature does not properly reflect the concept of "clozapine-induced inflammation" during rapid titration. Elaborating upon this concept, this historical review discusses: 1) clozapine-induced fever, 2) the effects of inflammation on clozapine metabolism, 3) clozapine-induced myocarditis, 4) other clozapine-induced inflammations, 4) current support for “clozapine-induced inflammation” as a hypersensitivity reaction, 5) the difficulty in addressing such a concept to a readership with diverse beliefs about it and 6) the limitations of this review in convincing skeptics. Clozapine-induced fever in the absence of any concomitant infection was first described in 1972 and is a mild form of "clozapine-induced inflammation" during rapid titration, which also includes myocarditis and other localized inflammations. They may be part of a hypersensitivity reaction that has 3 phases. In the first phase, the titration is too fast for a specific patient; either the psychiatrist was too aggressive in titrating, and/or the patient is a clozapine PM. This situation leads to a release of cytokines. In the second phase, a positive feedback loop develops; the cytokines inhibit CYP1A2, which further increases plasma clozapine concentrations. In the third phase, if the titration continues, the inflammation becomes complicated by the development of an auto-immune phenomenon leading to localized inflammation. Skeptical readers are challenged to try: 1) 6 titrations proposed for stratified dosing and 2) c-reactive protein (CRP) monitoring for personalized dosing in the absence of genetic testing for clozapine PM status.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

In the United States clozapine was approved in 1989 for treatment-refractory schizophrenia (TRS) and in 2002 for reducing suicide risk in schizophrenia [1]. National registry databases and naturali...