Kikuchi et al. published an extremely illustrative clozapine case.1 A 43-year-old nonsmoking male Japanese patient was started on 12.5 mg/day of clozapine and up-titrated to 150 mg/day on day 15. A fever on day 17 led to suspicion of pneumonia and antibiotic treatment. On day 22, clinicians wisely diagnosed clozapine-induced acute eosinophilic pneumonia. After clozapine discontinuation, they waited until there were no signs of inflammation, including a normal C-reactive protein (CRP) level, and used a much slower titration than the titration recommended by the Japanese package insert. Moreover, Kikuchi et al.1 kindly reference our adult inpatient clozapine titration guideline,2 which has now been translated into Japanese (http://www.jscnp.org/clozapine/index.html). The guideline describes (1) six different titration schedules proposed for stratified clozapine dosing and (2) CRP monitoring at baseline and weekly for 4 weeks simultaneous with the white blood cell count. To achieve the minimum therapeutic concentration of 350 ng/ml, the clozapine dosage needs to be adjusted based on ancestry: from Asians (lowest) to Europeans and to sub-Saharan Africans (highest). Thus, Asians need the slowest titration and the lowest maintenance dose for average patients, ranging from 175 to 300 mg/day (175 mg/day for female nonsmokers and 300 mg/day for male smokers). Clozapine poor metabolizers (PMs) need slower titration and maintenance doses ranging from 75 to 150 mg/day in Asians (Table 1). Nongenetic clozapine PMs include those with (1) obesity, which decreases clozapine metabolism, (2) co-prescription of inhibitors, such as oral contraceptives, or (3) the presence of inflammation that, by releasing cytokines, inhibits the main clozapine metabolic enzyme, the cytochrome P450 1A2 (CYP1A2). Genetic PMs may account for <10% of Japanese patients, as in other Asian countries.5 Baseline CRP offers protection from unawareness that a systemic inflammation is impairing clozapine metabolism. Weekly CRP may help to identify unknown clozapine genetic PMs who may develop increased CRP during non-PM-level titrations.6 The international clozapine titration guideline is a document in progress, already modified3 to recommend PM titrations for patients on olanzapine or quetiapine (Table 1), who are at greater myocarditis risk.4 The patient described by Kikuchi et al. developed a "clozapine-induced inflammation"6 due to his lack of tolerance of the standard Japanese titration. Lack of tolerance of clozapine titration can manifest through CRP elevations, eosinophilic myocarditis, and other localized inflammations. All of these manifestations are part of a hypersensitivity reaction that has three 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 cannot tolerate it due to PM status. 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.6 This hypersensitivity reaction can manifest with eosinophilia too,7 including a clozapine-related drug reaction with eosinophilia and systemic symptoms syndrome. The Japanese clozapine titration and dosing schedule is much slower than the US protocol but it may be too fast for Japanese PMs. A presumably Chinese genetic PM only needed 90 mg/day to reach the minimum therapeutic concentration of 350 ng/ml (Supporting Information Figure S1 of the clozapine international guideline2). The international titration recommends very slow titration for Asian PMs, but the titrations are designed to provide approximately the same serum clozapine concentration as for non-PMs. Unfortunately, Japanese prescribers have never been warned that the official Japanese titration schedule is associated with an extremely high incidence of clozapine-induced inflammation. Due to lack of space, only three proofs are provided. First, the first published Japanese clozapine study had a 29% (11/38) incidence of clozapine-induced fever,8 which is not considered normal in other countries. Second, myocarditis9 in Japan is frequent and explained 73% (30/41) of Asian reports of clozapine-induced myocarditis included in the global pharmacovigilance database. Asian countries had the highest risk of serious (odds ratio = 2.39, P = 0.02) and fatal (odds ratio = 4.35, P = 0.02) outcomes during clozapine-induced myocarditis.4 Third, a Japanese hospital,10 following the official Japanese titration schedule, was not aware that other countries do not have and do not consider normal their high incidences of fever (38%, 57/152), pleuritis (13%, 20/152), myocarditis (5%, 7/152), and interstitial nephritis (1%, 2/152). We hope this letter contributes to the dissemination of our guideline (Table 1) and its Japanese translation. Using slower and personalized titrations in Japan may resolve the high rates of fever, eosinophilia, myocarditis, and all types of clozapine-induced inflammation during titrations. Norio Yasui-Furukori helped with the dissemination of the Japanese translation of the international clozapine titration guideline. Yuji Otsuka is a co-author in the international clozapine titration guideline described in this article and completed the Japanese translation which is available at the web page of the Japanese Society of Clinical Neuropsychopharmacology (http://www.jscnp.org/clozapine/index.html). Jose de Leon wrote the first draft of this article. All authors reviewed, provided comments and approved the final version. Lorraine Maw, MA, at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA helped with editing. The authors are grateful to the reviewers who provided suggestions for improving the article and to Hiroyoshi Takeuchi, MD, who provided suggestions for improving the table. This article was completed without any external funding. No commercial organizations had any role in the writing of this paper for publication. In the last 3 years, the authors had no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analyzed for the present study. N/A N/A N/A Data sharing is not applicable to this article as no datasets were generated or analyzed for the present study.