Clozapine, a highly effective antipsychotic medication, is widely recommended in guidelines as a therapeutic option for treatment-resistant schizophrenia [1-3]. A meta-analysis of randomized controlled trials showed superior improvement in psychiatric symptoms with clozapine compared to other antipsychotics [4]. Similarly, a meta-analysis of cohort studies showed reduced hospitalization and all-cause discontinuation risk [5]. However, despite the high-quality evidence reported on its efficacy, clozapine remains underutilized worldwide [6,7]. One reason for this is safety concerns.

Clozapine has the third highest number of adverse events related to death outcomes reported to the United States Food and Drug Administration (US FDA) following opioid analgesics [8]. Although agranulocytosis and myocarditis have traditionally been the focus of particular attention [9-11], an analysis of VigiBase, the pharmacovigilance database of the World Health Organization, suggests that pneumonia is the most common adverse event causing death outcomes [12]. Other pharmacovigilance databases reported that clozapine may have a higher risk of seizure than other antipsychotics [13,14]. Several adverse events associated with clozapine are considered dose-dependent (strictly concentration-dependent), suggesting that factors influencing pharmacokinetics may play a role in their occurrence [15]. Regarding drug-drug interactions, fluvoxamine is a cytochrome P450 1A2 inhibitor, and its concomitant use increases the serum concentration of clozapine [16].

The basal factor to consider in preventing the adverse events associated with clozapine is probably genetic ancestry. For example, Asians have lower clozapine metabolism than Caucasians and reach therapeutic reference ranges at lower doses [17,18]. Recently, guidelines for clozapine titration personalized based on ancestry have been published [11]. The guidelines recommend six titration schedules for low and average metabolism for each of the three ancestry groups (Asia or the original people from the Americas, European/Western Asian, and the US with ancestries other than from Asia or the original people from the Americas). Although good therapeutic drug monitoring (TDM) studies of clozapine have been conducted, studies directly evaluating the association between genetic ancestry and adverse events are limited. Besides the underutilization of clozapine, the lack of sufficient information on race in many clinical studies and medical databases makes evaluation difficult. Therefore, we considered using the region as an alternative indicator of genetic ancestry. This study evaluated the differences in clozapine-related adverse events by reporting regions using the pharmacovigilance database of the FDA.

Data Source

This pharmacovigilance study used the FDA Adverse Event Reporting System (FAERS) database. We used the Japan Pharmaceutical Information Center (JAPIC) AERS, the FAERS database preprocessed by the JAPIC. The JAPIC AERS was processed as follows: 1) removing duplicate cases; 2) cleaning drug names based on the WHO drug dictionary and Drugs@FDA (https://www.accessdata.fda.gov); 3) assigning the Medical Dictionary for Regulatory Activities/Japanese (MedDRA/J) to adverse events; and 4) unifying units. We built a relational database according to PRIMARYID using four data tables: patient demographic information (DEMO), drug information (DRUG), adverse event information (REAC), and adverse event outcomes (OUTC). This study analyzed cases reported to the FDA from the fourth quarter of 1997 to the first quarter of 2022. The DRUG table was classified into four categories according to the relevance of the adverse event: “primary suspect drug,” “secondary suspect drug,” “concomitant,” and “interacting.” We included all the categories in our analysis.

Ethics approval and consent to participate were not required as this study was performed using an open-access database.

Definition of Reporting Regions

We categorized each case into five regions based on the reporting country information in the FAERS database, following ancestry-based clozapine titration guidelines: America, Europe/West Asia, Oceania, Asia, and Africa [11]. Asia was defined as Pakistan to Japan according to racial categories by the FDA [19]. The classification of the countries registered in the FAERS database into regions is shown in Supplementary Table 1.

Definition of Adverse Events

Adverse events were coded using the preferred term (PT) in the MedDRA/J version 25.0 [20]. We aggregated the number of reports by region for individual PTs and for the narrow scope of the Standardized MedDRA Query (SMQ), which groups related PTs. Agranulocytosis (SMQ20000023, 15 PTs), cardiomyopathy (SMQ20000150, 42 PTs), infective pneumonia (SMQ20000231, 83 PTs), convulsions (SMQ20000079, 101 PTs), extrapyramidal syndrome (SMQ20000095, 48 PTs), neuroleptic malignant syndrome (SMQ20000044, 3 PTs), gastrointestinal obstruction (SMQ20000105, 81 PTs), and hyperglycemia/new onset diabetes mellitus (SMQ20000041, 57 PTs) were analyzed in this study. The PTs included in each SMQ are presented in Supplementary Table 2.

Data Analysis

We aggregated the PTs in all clozapine cases according to the geographic regions and evaluated the relative reporting rates. The robustness of the results was tested in an analysis limited to cases from the country with the highest number of reports in each region. The relative reporting rate was calculated by dividing the number of reported cases for each PT by the total number of clozapine cases in each region. We also calculated regional relative reporting rates by sex and for cases limited to death outcomes. SMQs were similarly aggregated by geographic region, and reporting odds ratios (RORs) and 95% confidence intervals (CIs) were further calculated using multivariate logistic regression analysis to evaluate the relative reporting rates with consideration of the background factors in each region. In the multivariate logistic model, the regional reference level was America, with the highest number of reported cases, and the covariates were age, sex, reporting year, reporter’s type of occupation, patient outcome, and concomitant medications. Cases for which information on these covariates was unknown in the FAERS database were excluded from the analysis. The concomitant medications included antipsychotics (except clozapine), fluvoxamine, valproate, carbamazepine, phenytoin, and phenobarbital. These medications were included because their concomitant use increases the risk of adverse effects and affects the pharmacokinetics of clozapine in the treatment of schizophrenia. Antipsychotics, except clozapine, were defined as 21 FDA-approved antipsychotics (Anatomical Therapeutic Chemical N05A*, excluding lithium; Supplementary Table 3). Statistical significance was set at p < 0.05. All statistical analyses were performed using R 4.3.1 (The R Foundation for Statistical Computing).

Reported Cases of Clozapine-related Adverse Events

A total of 15,808,026 cases were registered in the FAERS database, with 101,872 cases of clozapine-related adverse events. The most frequently reported regions were America (n = 46,053), followed by Europe (n = 33,143), Oceania (n = 7,250), Asia (n = 1,502), and Africa (n = 65). Within each region, the most frequently reported countries were the US in America (n = 35,860, 77.9%), the United Kingdom in Europe (n = 20,164, 60.8%), Australia in Oceania (n = 5,654, 78.0%), Japan in Asia (n = 664, 44.2%), and South Africa in Africa (n = 36, 55.4%). The 13,859 cases for which the reporting country was unknown were excluded. Additionally, reports from Africa were very few compared to other regions and were similarly excluded from the analysis, and only population characteristics were shown.

Population characteristics varied based on the reporting region. The cases were younger in Asia and Africa than in America. Physicians reported most cases; however, the percentages varied from 23.9% to 47.4%. Oceania had fewer reports from physicians than other regions and relatively more reports from pharmacists (19.3%) and other health-professionals (33.3%). Death in patient outcomes was highest in America (22.1%) and lowest in Asia (8.7%). The concomitant use of antipsychotics, except clozapine, was markedly different, at approximately 20% in America, Europe, and Oceania compared to 46.1% in Asia. Olanzapine, quetiapine, risperidone, and aripiprazole, in that order, were the most common antipsychotics concomitantly used with clozapine. Concomitant use of olanzapine or risperidone was particularly common (> 15%) in Asia. The population characteristics of the clozapine cases are summarized in Table 1.

Relative Reporting Rates of PT

The top 10 PTs reported in each region are listed in Table 2. In America and Europe, leukocyte or neutrophil count abnormalities accounted for half of the top 10 PTs. Neutropenia in America had a high relative reporting rate of 19.51%. In Oceania, leukocyte or neutrophil count abnormalities also ranked high; however, the relative reporting rate of myocarditis was higher than that in other regions (6.48%). In Asia, pyrexia had the highest relative reporting rate at 13.91%. Only two of the top 10 PTs had leukocyte count abnormalities, whereas PTs related to extrapyramidal symptoms had higher relative reporting rates, with salivary hypersecretion at 10.85% and tremor at 5.13%. The analysis limited to cases from the country with the highest number of reports in each region showed slight differences in rank, although the overall trend was similar (Supplementary Table 4). No major sex differences were observed. In Asia, however, extrapyramidal symptoms (salivary hypersecretion and tremor) and somnolence were ranked higher among women, with higher relative reporting rates (Supplementary Table 5). For cases limited to death outcomes, pneumonia ranked high in all regions (Supplementary Table 6).

Relative Reporting Rates of SMQ

The relative reporting rates for each SMQ by region are listed in Table 3. The relative reporting rates of agranulocytosis differed only slightly between regions, ranging from 1.92% to 3.40%. Oceania exhibited a notably high relative reporting rate for cardiomyopathy at 4.25%. The relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, gastrointestinal obstruction, and hyperglycaemia/new onset diabetes mellitus were higher in Asia than in the other regions (5.26%, 9.72%, 12.65%, 5.13%, and 8.26%, respectively).

The results of the multivariate logistic regression analysis with reference to America for each SMQ, adjusted for background factors, are shown in Figure 1. Agranulocytosis had significantly lower relative reporting rates in Europe (ROR, 0.72; 95% CI, 0.65–0.80) and Oceania (ROR, 0.70; 95% CI, 0.57–0.87). Cardiomyopathy had significantly higher relative reporting rates in Europe (ROR, 2.17; 95% CI, 1.77–2.66) and Oceania (ROR, 7.64; 95% CI, 6.09–9.57), with a particularly marked difference in Oceania. Asia had a significantly higher relative reporting rate in five of eight SMQs: infective pneumonia (ROR, 1.73; 95% CI, 1.33–2.27), convulsions (ROR, 3.86; 95% CI, 3.11–4.79), extrapyramidal syndrome (ROR, 2.76; 95% CI, 2.27–3.35), gastrointestinal obstruction (ROR, 5.12; 95% CI, 3.90–6.72), and hyperglycaemia/new onset diabetes mellitus (ROR, 1.48; 95% CI, 1.18–1.86). Neuroleptic malignant syndrome had significantly higher relative reporting rates only in Europe; however, the effect size was small (ROR, 1.21; 95% CI, 1.04–1.40).

This is the first study to evaluate the regional differences in the relative reporting rates of clozapine-related adverse events using a spontaneous reporting system (SRS). The relative reporting rates of clozapine-related adverse events were inconsistent across regions. For example, neutro-penia is the most indicative and concerning adverse event associated with clozapine [9]; however, our results showed the highest relative reporting rate of approximately 20% in America, whereas the rate was only approximately 5% in Europe and Oceania. Furthermore, the relative reporting rate of neutropenia did not necessarily rank as high in all regions worldwide.

Asia, in particular, had a different reporting profile for adverse events than other regions. Neutropenia was ranked alongside pyrexia, extrapyramidal syndrome symptoms like salivary hypersecretion and tremor, constipation, somnolence, and seizures in the top 10 PTs based on relative reporting rates in Asia. Similarly, in the SMQ, Asia had higher relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, and gastrointestinal obstruction than other regions, even after adjusting for confounding factors. These results may be explained by the differences in genetic ancestry in the reporting region. Previous TDM studies have suggested that these adverse events are dose- or concentration-related [15]. Asians are more likely to have higher serum concentrations of clozapine due to its lower clearance than Caucasians, as a result of which dose-dependent adverse events occur even at low doses [17,18]. Thus, Asia exhibited a bias toward reporting dose-dependent adverse events in clozapine to FAERS compared to other regions. Moreover, the titration schedule of clozapine may have affected the relative reporting rates of concentration-dependent adverse reactions. The official titration schedule for clozapine in Japan is slower than that in the US, but faster than the international guidelines for Asians recommended by Yasui-Furukori et al. [21]. A retrospective chart review by Kikuchi et al. [22] reported that nearly half of the patients in the Japanese population are titrated faster than recommended by the international guidelines, leading to an increase in inflammatory adverse events. In Korea, 22.1% patients developed fever within 8 weeks of initiation of clozapine, which is associated with a higher concentration-to-dose ratio [23]. Regarding concomitant medications, a greater number of concomitant antipsychotics at baseline is associated with an increased risk of pneumonia during initial clozapine titration [24]. A systematic review and a Japanese pharmacovigilance study suggested that antipsychotic polypharmacy increases the risk of extrapyramidal symptoms [25] and convulsions [26]. The concomitant use of other antipsychotics is markedly higher in Asia, and these differences in regional prescribing patterns may have raised the relative reporting rate of these adverse events in clozapine. The relative reported rates of hyperglycaemia/new onset diabetes are also higher in Asia, probably because Asians are at a higher risk of developing Type 2 diabetes than Caucasians [27].

Oceania was the only region where myocarditis ranked in the top 10 PTs among all, and cardiomyopathy had a markedly higher relative reporting rate in the SMQ. Similar results were obtained in VigiBase, where this pharmacovigilance study showed that approximately half of the reports of myocarditis came from Australia [28]. A previous study indicated that 65% of cases deemed as clozapine-induced myocarditis in Australia did not meet the criteria, implying potential overdiagnosis [29]. Therefore, the findings of this study may be influenced, in part, by overreporting to FAERS. Conversely, although underreporting is a concern because of the very small number of cases of myocarditis in Asia in SRS [28], the incidence of myocarditis appeared to be low (0.1%, 2/1,408 cases) in an intensive retrospective study in which all the registered diagnoses, imaging findings, laboratory findings, and consultation notes were examined [23].

This study has several limitations. First, the reporting country may not accurately reflect genetic ancestry. In particular, despite having a predominantly Caucasian population, the US is characterized by a diverse range of ethnicities, including Hispanics, Asians, Africans, and other groups. Considering the population distribution, the majority of America in this study probably comprised “the United States with ancestries other than from Asia or the original people from the Americas,” as defined by the international guidelines of de Leon et al. [11] However, this is only an inference and does not guarantee results. Second, we adjusted for confounding factors using concomitant medications that affect pharmacokinetics; however, we could not consider smoking [30], caffeine [31], and more directly related clozapine doses and serum concentrations due to a lack of information. Third, a general limitation of SRS is the lack of denominator information, as only adverse event cases are registered [32]. Therefore, the relative reporting rates and RORs used as the index in this study cannot directly indicate the magnitude of the risk, and caution should be exercised in interpreting the results. Furthermore, SRS may have different reporting methods and criteria for adverse events in each country, raising concerns about over- or under-reporting of each adverse event (e.g., myocarditis in Oceania and Asia) [33]. The distribution of patient outcomes and reporter’s type of occupations differs by region in the FAERS database in this study, and this problem is difficult to solve in pharmacovigilance studies.

In conclusion, our results reveal that the spontaneous reporting of adverse events associated with clozapine is inconsistent across regions, with a higher proportion of concentration-dependent adverse events reported in Asia than in other regions. This observation may be related to the lower clozapine metabolism and faster titration in Asians, supporting previous findings. Therefore, adhering to international guidelines for proper titration schedules is crucial to enhance clozapine safety. However, SRS has several limitations, necessitating further research to validate this hypothesis.

The authors have no competing interests to declare. The interests from the past three years are as follows. Masakazu Hatano received honoraria from Ishiyaku Publishers, Inc., Meiji Seika Pharma Co., Ltd., Medical Friend. Co., Ltd., Nanzando Co., Ltd., Sumitomo Pharma Co., Ltd., and WELCIA Holdings Co., Ltd. Takeo Saito received honoraria from Meiji Seika Pharma Co., Ltd. and Kyowa Pharmaceutical Industry Co., Ltd. Shigeki Yamada received honoraria from AstraZeneca K.K., Daiichi Sankyo Co., Ltd., EA Pharma Co., Ltd., Eisai Co., Ltd., Meiji Seika Pharma Co., Ltd., Nippon Shinyaku Co., Ltd., Nipro Corporation, Otsuka Pharmaceutical Factory, Pfizer Japan Inc., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Toa Eiyo Ltd., and Towa Pharmaceutical Co., Ltd. And funding from EA Pharma Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., SUGI Holdings Co., Ltd., and Otsuka Pharmaceutical Factory.

Conceptualization: Masakazu Hatano. Data acquisition: Masakazu Hatano, Haruna Araki. Formal analysis: Masakazu Hatano, Haruna Araki. Funding: Masakazu Hatano. Supervision: Shigeki Yamada. Writing–original draft: Masakazu Hatano. Writing–review & editing: Takeo Saito, Shigeki Yamada.