pi :: Psychiatry Investigation

de Leon: Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

Review Article

Psychiatry Investigation 2023;20(3):183-195.

Published online: February 28, 2023

DOI: https://doi.org/10.30773/pi.2022.0293

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

Jose de Leon^1,²

¹Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA

²Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain

Correspondence: Jose de Leon, MD Mental Health Research Center at Eastern State Hospital, 1350 Bull Lea Road, Lexington, KY 40511, USA Tel: +1-859-846-8440, Fax: +1-859-846-8446, E-mail: jdeleon@uky.edu

Received October 8, 2022 Revised December 17, 2022 Accepted December 26, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This review article argues against trusting standard clozapine references, including the US package insert, because they do not include advances in the sciences of pharmacokinetics and pharmacovigilance and ignore the effects of ethnic ancestry on therapeutic dosing. The minimum therapeutic dose leading to the minimum therapeutic concentration of 350 ng/mL in serum/plasma can be used to compare individuals/groups with treatment-resistant schizophrenia. The US clozapine package insert recommends targeting doses of 300–450 mg/day and, subsequently, increments of up to 100 mg with a maximum dose of 900 mg/day. Ethnic ancestry is defined by DNA ancestry group. Asians (people with ancestry ranging from Pakistan to Japan) and Indigenous Americans are similar in clozapine dosing; their average clozapine minimum therapeutic dose ranged from 166 mg/day (female non-smokers) to 270 mg/day (male smokers). For those with European ancestry, average clozapine minimum therapeutic doses ranged from 236 mg/day (female non-smokers) to 368 mg/day (male smokers). Based on limited studies, Black (African sub-Saharan ancestry) patients may be treated with typical US doses (300–600 mg/day), assuming no poor metabolism (PM) status. Ancestry’s impact on clozapine lethality in four countries is discussed (two countries with highly homogenous populations, Denmark and Japan, and two countries with increasingly heterogenous populations due to immigration, Australia and the UK). An international guideline with 104 authors from 50 countries/regions was recently published, providing 6 personalized clozapine titration schedules for adult inpatients (3 ancestry groups and PM/non-PM schedules) and recommending c-reactive protein monitoring at baseline and weekly for 4 weeks.

Keywords: Asian continental ancestry group, Clozapine/adverse effects, Clozapine/therapeutic use, CYP1A2, Myocarditis/chemically induced, Mortality/drug effects

INTRODUCTION

This reflection challenges the reader not to trust standard clozapine references including package inserts since they do not include advances in the sciences of pharmacokinetics and pharmacovigilance.

A paradoxical hypothesis: major standard clozapine references should not be trusted

In this first quarter of the 21st century, most psychiatrists worldwide refer to US psychiatry and psychopharmacology to provide guidance. This author cannot deny that there are strong historical reasons to acknowledge the contributions of US psychiatry in the late 20th century [1], but he proposes that following US recommendations for clozapine dosing around the world is a mistake. Similarly, most national drug agencies would probably acknowledge that the US drug agency, the Food and Drug Administration (FDA) plays a leading role for orienting their package inserts [2], but following the US clozapine package insert in all countries is a huge mistake.

The author cannot deny that a reasonable argument in favor of trusting the US recommendations for clozapine use is that the US is responsible for the resurrection of clozapine. Clozapine was introduced in German-speaking countries [3] and was almost “killed” by a letter to the editor [4] from Finland describing 8 patients who died from clozapine-induced agranulocytosis. Then, clozapine was resuscitated for a restricted use in treatment-resistant schizophrenia (TRS) by a US multicenter randomized clinical trial (RCT) published in 1988 [5] that led to approval by the FDA in 1989 and the generalized worldwide use of clozapine for TRS. Moreover, the birth of the concept of TRS [5] can be traced back to that US study. That US RCT recruited 309 patients including 208 (65%) of European ancestry and 111 (35%) of other ancestries. There were 74 (23%) patients of African ancestry, 31 (10%) of Hispanic ethnicity which may include patients with Indigenous American ancestry, 2 (1%) patients of East Asian ancestry and 4 (1%) others [5]. There was no attempt to consider the effects of ancestry on clozapine dosing or response.

In summary, the author acknowledges the leading role of the US in 1) psychiatry, 2) psychopharmacology, 3) drug approval, and 4) resurrection of clozapine use for TRS, but in spite of this he is going to try to convince the skeptical reader that the information provided by the FDA in the US clozapine package insert [6], US chapters on clozapine psychopharmacology [7], US textbooks on clozapine [8], and US clozapine review articles [9] cannot be trusted. He dares to propose that trusting these sources may have deleterious effects in the use of clozapine around the world. If the reader is profoundly shocked by this statement and wants to stop reading, he/she needs to read Supplementary Table 1 (in the online-only Data Supplement) [6-15] that explains that for understanding these or any new ideas the reader needs to be open-minded. As most psychiatrists are not well versed in pharmacokinetics, there is another Supplementary Table 2 (in the online-only Data Supplement) [14,16-21] explaining some basic pharmacokinetic concepts such as poor metabolizers (PMs), who tend to have adverse drug reactions (ADRs) with average doses, while ultrarapid metabolizers (UMs) need high doses for efficacy. These concepts were originally developed for genetic cases but Supplementary Table 3 (in the online-only Data Supplement) [22-54] explains how there are genetic and nongenetic PMs and UMs in terms of clozapine dosing. Clozapine PMs and UMs are defined based on the key idea that for comparing clozapine dosing across individuals or groups it is important to know the minimum therapeutic dose which leads to the minimum therapeutic concentration in serum/plasma of 350 ng/mL for TRS. Standard US sources reviewing clozapine use and dosing [6-9] do not mention these concepts.

Clozapine and development of pharmacokinetic science

In 1989 when clozapine was approved by the FDA, we did not know how clozapine was metabolized. Then in 1994, Karolinska researchers proposed that clozapine is mainly metabolized by a pharmacokinetic protein, a liver enzyme, called cytochrome P450 (CYP) 1A2 [55]. Moreover, these researchers also figured out that inducers such as carbamazepine and powerful inhibitors such as fluvoxamine modified the relationship between clozapine dose and serum concentrations [56]. Based on that study one can propose that in the average clozapine patient, once carbamazepine is added and has acquired its maximum inductive effects, there is need to multiply the dose approximately by 2 to maintain its efficacy. Once fluvoxamine is added, there is need to reduce the dose to 1/10 or 1/5 to maintain its safety, which is a very risky proposition unless blood levels are available. This is why 27 years later the author continues to provide similar recommendations on clozapine dosing [27,28]. Currently, it is evident that co-medications influence clozapine personalized dosing from high to low: 1) potent inducers, such as rifampicin; 2) potent to moderate inducers, such as carbamazepine or phenytoin; 3) mild inducers, such as omeprazole; 4) moderate inhibitors, such oral contraceptives or high intake of caffeine; and 5) potent inhibitors, such as fluvoxamine, amiodarone and ciprofloxacin [27,28]. As tobacco smoking is a mild inducer of CYP1A2 and estrogens are moderate CYP1A2 inhibitors, in the absence of other inducers/inhibitors, clozapine personalized dosing goes from high to low in: 1) male smokers, 2) female smokers, 3) male non-smokers, and 4) female non-smokers [27,28].

Advances in pharmacokinetic science and the FDA

Psychiatrists are not familiar with the fact that in 1996 FDA experts were faced with an earthquake delivered in the form of the drug lethality associated with terfenadine, a second-generation antihistaminic [57]. In 1985 the FDA had approved terfenadine, which behaved very safely in RCTs. In 1996, the FDA realized terfenadine was associated with 125 deaths [57]. Moreover, since its approval, pharmacokinetic science had developed and explained that terfenadine was mainly metabolized by the CYP3A4. The problem was that powerful CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, and grapefruit juice) were frequently used in the US general population at that time. These powerful inhibitors inhibited the metabolism of terfenadine which led to torsades de pointes [57]. Many of the other drugs have also been withdrawn from the US market since their pharmacokinetic properties contributed to their potential lethality [58]. Since 1996, the FDA has progressively increased the requirements of pharmacokinetic studies [59]; thus any new antipsychotic approved in 2022 would have to be thoroughly studied from the pharmacokinetic point of view and it is very unlikely that it would be withdrawn from the market. FDA regulations do not require old drugs to be restudied following current pharmacokinetic requirements [60]. Thus, clozapine has never been well studied. This is not unique for clozapine; other antipsychotics, including haloperidol [61] or risperidone [62], approved before 1996, have the same problem. Once a drug becomes generic there is no incentive for the pharmaceutical company to economically support the huge effort needed to complete comprehensive studies and update the package insert [63].

Advances in pharmacokinetic science had little impact on the clozapine package insert

Therefore, the US clozapine package insert has not been updated to reflect our current pharmacokinetic knowledge [64]. The US insert and other package inserts should report that CYP1A2 activity varies across: 1) deoxyribo nucleic acid (DNA) ancestry groups, 2) 4 sex/smoking subgroups, and 3) the presence or absence of PM status. Supplementary Table 3 (in the online-only Data Supplement) explains that clozapine PM status can be explained by genetic cases (<10% of patients) and nongenetic cases associated with coprescription of inhibitors, obesity and/or inflammation.

Clozapine is mainly metabolized by CYP1A2 and there is general agreement that CYP2D6 plays a very small role, so it is not clear why the FDA decided to recommend lower doses of clozapine for CYP2D6 PMs [6]. This mistake has never been removed from the US package insert despite pharmacogenetic experts’ [64] agreement that CYP2D6 PM status is not relevant in clozapine dosing.

Advances in pharmacovigilance science very slowly impacted the US clozapine package insert

After-marketing reports of ADRs during the period called post-marketing surveillance [65] led to the development of a new science called pharmacoepidemiology, which includes the concept of pharmacovigilance [66]. Supplementary Table 4 (in the online-only Data Supplement) [66-68] explains that pharmacovigilance considers the published reports of ADRs and the reports of the national drug agencies which are sent to the World Health Organization’s pharmacovigilance database called VigiBase [67].

The first pharmacovigilance finding of clozapine-induced agranulocytosis [4] led to the cessation of US clozapine studies that had been started in 1974 [69]. Other pharmacovigilance data led the FDA to modify the US clozapine package insert to include warnings for myocarditis in 2002, and severe clozapine-induced gastrointestinal hypomotility (CIGH) in 2020 [70].

The FDA has been “obsessed” with clozapine-induced agranulocytosis since its marketing [70]. In a review of the FDA data from 1998–2005, Moore et al. [71] found that clozapine was associated with 3,277 deaths or serious nonfatal outcomes, making it the third most toxic US drug. That article [71] did not explain how clozapine patients died, but the FDA continued to focus on clozapine-induced agranulocytosis. By studying the deaths of clozapine patients from 2000 to 2019 found in VigiBase [72], it is obvious that prescribers worldwide know about clozapine-induced agranulocytosis since they reported 29,586 cases of potential agranulocytosis. These cases led to 433 deaths with a relative lethality of 1%. In the same period of 2000 to 2019, pneumonia and myocarditis caused more deaths. There were 1,922 deaths due to pneumonia (30% relative lethality; 1,922/6,506) and 484 deaths due to myocarditis (11% relative lethality; 484/4,536) [72].

Most clozapine-induced pneumonia does not occur during agranulocytosis and its pathophysiology is complex [73]. TRS may explain 2/3 of the risk of pneumonia [74]. Clozapine can contribute to community-acquired pneumonia by decreasing antibodies and to aspiration pneumonia by causing swallowing disturbances, sedation, hypersalivation and/or other possible ADRs, such as CIGH. Once pneumonia develops, the systemic inflammation releases cytokines that inhibit CYP1A2 and other CYPs can cause clozapine intoxication [73]. The combination of severe pneumonia and clozapine intoxication appears to be particularly lethal when compared with other antipsychotics [75].

Lack of attention to the concept of clozapine-induced inflammation

The literature does not properly reflect the concept that “clozapine-induced inflammation” can happen during rapid titrations. A PubMed search on May 1, 2022, provided no article with “clozapine-induced inflammation” in the title or the abstract [76]. In 2012, Røge et al. [77] describe clozapine “pro-inflammatory” activity during early titration bud did not comment on the role of rapid clozapine titration.

On the other hand, the concept of “clozapine-induced inflammation” included two concepts described in the literature: clozapine-induced fever reviewed in Supplementary Table 5 (in the online-only Data Supplement) [78-84] and clozapine-induced myocarditis reviewed in Supplementary Table 6 (in the online-only Data Supplement) [85-102]. Both of them have been proposed to be a hypersensitivity reaction probably explained by rapid clozapine titrations. Supplementary Table 7 (in the online-only Data Supplement) [27,28,76,103,104] summarizes the model of clozapine-induced inflammation.

THE MAIN OVERSIGHT: CLOZAPINE DOSING SHOULD CONSIDER ETHNIC ANCESTRY

The main oversight of worldwide clozapine package inserts is that they do not consider the effects of ethnic ancestry on clozapine dosing. Ethnic ancestry is defined as one’s DNA ancestry group.

DNA ancestry

The model of human evolutionary history [105] suggests that there are 5 ancestry groups (each group progressively branched out and separated from the original African population): 1) Blacks with ancestry from Sub-Saharan Africa, 2) Europeans (and Western Asians), 3) Asians, 4) Oceanians, and 5) the original inhabitants of the Americas or Indigenous Americans. Different CYPs have different profiles for PMs and UMs, probably based on the complex interactions between human migrations and exposure to a diet containing variable compositions of harmful xenobiotics [106]. These 6 ancestry groups are not particularly relevant for understanding CYP2D6 activity but may be for CYP1A2 activity. Unfortunately, these 6 DNA ancestry groups are not geographic groups. The FDA defines the Asian phenotype [107] as including those people with ancestry ranging from Pakistan to Japan. The Indigenous Americans are descendants of East Asians, so it is not surprising that for clozapine dosing, they behave as Asians [108].

Clozapine dosing in the US

The US clozapine package insert [6] recommends targeting doses of 300 to 450 mg/day; subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg with a maximum dose of 900 mg/day. US textbooks and articles [7-9] follow these recommendations.

The long and complicated history of the need for lower clozapine doses for Asians

Since 1997 [109,110] indirect and circumstantial evidence suggests Asians should be treated with lower clozapine doses than US-recommended doses; this has never led to a modification of the US package insert or received attention from US clozapine experts. Supplementary Table 8 (in the online-only Data Supplement) reviews this limited evidence, which includes studies on clozapine concentrations [109-111] and the experience of clinicians in Asian countries regarding clozapine dosing [112-121]. Supplementary Table 8 (in the online-only Data Supplement) also describes a 2007 study, in which Ghotbi et al. [122] demonstrated that, in effect, Koreans (with Asian ancestry) have lower CYP1A2 activity than Swedes (with European ancestry) after controlling for smoking, oral contraceptives and known CYP1A2 alleles.

This group of studies led to a systematic review where the average clozapine minimum therapeutic dose was 223 mg/day in 876 East Asians versus 327 mg/day in 1,147 Western patients, mostly of European ancestry [29]. This comparison between East Asian and Western patients is limited by the lack of control for sex and smoking and the exclusion of an Indian sample [123]. After accessing 4 additional Asian samples and stratifying by sex-smoking subgroups, it was clear Indians have a clozapine metabolism similar to East Asians [33]. Furthermore, after accessing a Mexican study [124], Indigenous Americans were found to be similar to Asians [125]. Thus, when combining all of these Asian and Indigenous American samples, the average clozapine minimum therapeutic dose ranged from 166 mg/day (in 252 female non-smokers) to 270 mg/day (in 137 male smokers) [29].

The clinical relevance of overdosing patients of Asian ancestry by using doses recommended for patients of European ancestry is finally reaching the literature. Recently in India, Chichra et al. [126] completed a retrospective review of a cohort of 288 patients initiated on clozapine of which 38 (17%) had new-onset seizures during clozapine treatment. These patients had significantly higher mean clozapine doses at 1 year of follow-up (373±120 vs. 319±120 mg/day) and this remained significant after adjusting for age and sex. This article suggest that the traditional practice of Indian psychiatrists trained in India of not going above 300 mg/day [115] may be a good idea, particularly when clozapine serum concentrations are not available.

Clozapine dose and European ancestry

In 6 samples of patients of European ancestry, the average clozapine minimum therapeutic dose ranged from 236 mg/day (in 218 female non-smokers) to 368 mg/day (in 546 male smokers) [127]. This range for a clozapine minimum therapeutic dose of 236 to 368 mg/day appears higher than the Asian range of 166 to 270 mg/day, but lower than the typical doses of 300 to 600 mg/day recommended in the US package insert. Since early times, Europeans [128,129] have been aware that US psychiatrists prescribed 1.5 to 2-fold higher clozapine doses than in Europe.

A hypothesis for explaining the high doses of clozapine in the US

When developing an international titration schedule [29], for political reasons, the author initially decided to keep the highest US dose. In the end, the US dosage appeared to be the right one for African-Americans in the absence of risk factors for PM status based on a US clozapine RCT [130] and olanzapine data. Olanzapine is mainly metabolized by CYP1A2 and behaves pharmacokinetically in a way similar to clozapine [131] and, based on a US population pharmacokinetic model [132], it can be estimated that average olanzapine doses should be 1.25 times higher in African-Americans than in patients of European ancestry.

More recently, Flanagan et al. [133] explored the plasma clozapine concentrations of patients from the UK and Ireland with ethnicity data (763 Afro-Caribbean, 536 Asian, and 7,940 Caucasian patients). After adjusting for confounders, the predicted dose to reach 350 ng/mL was 33% higher in Afro-Caribbean and 20% lower in Asian patients when compared with Caucasians.

CLOZAPINE LETHALITY AND DOSING ACROSS VARIOUS COUNTRIES

This section proposes the controversial hypothesis that ancestry may impact clozapine lethality in various countries around the world. This relationship is very complex since it impacts clozapine clinical practice in each country. The discussion focuses on four countries: two countries with highly homogenous populations, Denmark and Japan, and two countries with increasingly heterogenous populations due to immigration, Australia and the UK.

Denmark: a country of homogenous ancestry with extremely low lethality associated with clozapine

Denmark has less than 6 million people of European ancestry and only recently has immigration increased, but they tend to be immigrants with European or Western Asian ancestry that may be similar regarding clozapine dosing. Danish physicians should be considered the leaders in the identification of clozapine-induced myocarditis (Supplementary Table 9 [in the online-only Data Supplement], first panel [67,77,85-87,134-136]). Approximately 40% of the Danish clozapine titrations are given in an outpatient setting [99] and are very gradual; the others are started as inpatients but coordinated with outpatient psychiatrists. Thus, it is not surprising that clozapine-induced myocarditis is rare, according to the Danish registry (Supplementary Table 9 [in the online-only Data Supplement], second panel [99]) or VigiBase reports (Supplementary Table 9 [in the online-only Data Supplement], third panel [67]). The last panel of Supplementary Table 9 (in the online-only Data Supplement) [74,99,137] propose that paying attention to pneumonia may decrease clozapine mortality in Denmark, particularly during the first year.

Japan: probable high lethality in clozapine patients in a country with homogenous ancestry

Japan has around 126 million people, a very homogenous population of Asian ancestry. Japan has a large system of hospitals for long-term psychiatric inpatients, many with TRS [138]. The Japanese national drug agency has complicated bureaucratic procedures highly influenced by university professors working as advisors in their spare time [139], which led to the delay in clozapine approval (first panel of Supplementary Table 10 [in the online-only Data Supplement] [140,141]). Clozapine was therefore approved without studies based in Japan, but rather on US data and recommending US dosing. The Japanese drug agency was quite fearful of agranulocytosis [142] and developed a Clozapine Patient Monitoring Service following the US example. Moreover, clozapine was restricted so that it can only be started in some hospitals and prescribed by some physicians. The official Japanese titrations have led to approximately 1/3 of the patients developing clozapine-induced fever (second panel of Supplementary Table 10 [in the online-only Data Supplement] [142,143]) due to intolerance of the titration. Other forms of clozapine-induced inflammation are also frequent in Japan (third panel of Supplementary Table 10 [in the online-only Data Supplement] [67,104,142-145]). Therefore, Japanese psychiatrists had no experience with slower titration and were not aware that their titration is too rapid for their patients until a 2022 article identified [146] much slower titration during rechallenge as a method for avoiding a clozapine-induced eosinophilic pneumonia (fourth panel of Supplementary Table 10 [in the online-only Data Supplement]).

High lethality in Australian clozapine patients associated with myocarditis

Australia may be the mirror-image of Denmark [76]. Danish psychiatrists have no expertise in clozapine-induced myocarditis because they have been pioneers in identifying it and use very slow clozapine titration. Australian psychiatrists have extensive experience with clozapine-induced myocarditis. According to VigiBase, until 2021 [67] Australia, a country with less than 26 million people, accounted for half of the worldwide clozapine-induced myocarditis (50%, 1,621/3,274) cases and 1/3 of the mortality (32%, 50/158).

Many of the articles on clozapine-induced myocarditis have been published by Australian authors and this may have some negative consequences. First, the author’s clozapine articles are frequently rejected by Australian clozapine experts, who think they are being unfairly attacked, so an editorial [63] written in 2019 was rejected by 9 journals before being published in 2020. Second, in an Australian review article, Ronaldson et al. [98] proposed that an incidence rate of 3% for clozapine-induced myocarditis is normal, which led authors in several countries to use this reference and justify as normal this incidence rate of 3% in their settings. Rates around 3% have been described in some hospitals in Canada [147], the US [148], and New Zealand [149].

Supplementary Table 11 (in the online-only Data Supplement) provides a summary of the very important contribution of Australian authors, which has led this author to understand the crucial role of rapid titration in the development of clozapine-induced myocarditis [46,67,90,96,150-157]. Supplementary Table 12 (in the online-only Data Supplement) [28,96,158] details the problem with the official Australian clozapine titration schedules.

High lethality in UK clozapine patients is puzzling

The first 4 panels of Supplementary Table 13 (in the onlineonly Data Supplement) provide information that the author has gathered on the use of clozapine in the UK; the emphases are on guidelines [39,127,159,160], the contribution of clozapine-induced agranulocytosis [70,161-163], what is known of UK fatal outcomes of clozapine-induced myocarditis [67,104,164], clozapine-induced CIGH [165], and clozapine-associated pneumonia [166].

Two months ago, the author’s understanding of clozapine use in the UK was completely shaken by discovering a VigiBase pharmacovigilance study focused on ADRs with fatal outcomes reported by physicians. Over a 10-year period (2010-2019), Montastruc et al. [167] found 1,761 fatal outcomes associated with clozapine. Clozapine was the third most lethal drug in the world overall, but was the most lethal drug among nongeriatric adults worldwide. The distribution was uneven since UK physicians reported 968 fatal outcomes versus 892 in the rest of the world (a country with 67 million people had more fatal outcomes in clozapine patients than the entire rest of the world), including only 105 fatal outcomes reported by physicians in the other European countries [68] The major ADRs associated with worldwide fatal outcomes in VigiBase until 2019 have been described [168] and necessarily include these 986 fatal outcomes reported by UK physicians. After the generalized use of weekly hematological monitoring and during 2000–2019 [72], the four major causes of worldwide fatal outcomes in order were: pneumonia with 1,922 (29.5%, 1,922/6,506), sudden deaths/cardiac arrest with 1,221 (90.5%, 1,221/1,349), myocarditis with 484 (11.1%, 484/4,356) and agranulocytosis with 433 (1.5%, 433/29,586) [168]. UK clozapine experts need to explore how these 4 major causes may explain that UK physicians reported 968 UK fatal outcomes in clozapine patients over 10 years, around 97 patients/year. Based on what we know from VigiBase and UK studies (Supplementary Table 13 in the online-only Data Supplement), it is possible to speculate that pneumonia and sudden death may be the major causes of death among clozapine patients in the UK [68].

The extremely high number of fatal outcomes reported by UK physicians to their drug agency and then to VigiBase appeared hard to believe to the author; unfortunately, a later independent verification indicates the problem is even worse. In an article focused on CIGH, Handley et al. [165] found 4,547 UK fatal outcomes from reports of physicians and nonphysicians from 1992 to 2017. If the last 10 years are selected, this provides 3,828 deaths, 383 deaths/year and a range from 209 deaths in 2008 and 629 deaths in 2011. Thus, it is possible that since 2017, every year 383 clozapine patients may have died due to ADRs in the UK. To compare this number, one needs to remember that 8 deaths associated with agranulocytosis in Finland led to the cessation of US clozapine studies, as well as clozapine restrictions around the world.

If we assume that the data from Handley et al. [165] and Montastruc et al. [167] are correct, this may indicate that of 383 deaths in the UK annually on average, approximately 97 are reported by physicians and another 286 (383-97=286) are reported by nonphysicians. One can argue that the UK system led the pharmaceutical company which controls the hematological database to overreport all deaths in clozapine patients even if they are not really explained by clozapine, which may contribute to 286 deaths annually on average, but this overreport by the drug company could not justify the 97 deaths reported annually by physicians who appear to believe they were possibly caused by clozapine.

The high number of fatal outcomes in clozapine patients in the UK cannot be explained away as a very high number of patients taking clozapine in the UK compared with other countries (see the fifth panel of Supplementary Table 13 [in the online-only Data Supplement] [169]), since UK clozapine prescription is intermediate among European countries.

UK clozapine patients include those of African, European and Asian ancestries (see the sixth panel of Supplementary Table 13 [in the online-only Data Supplement] [170-172]). There is urgent need to explore whether or not patients of Asian ancestry, who need lower clozapine doses, have greater fatal outcomes in the UK.

FOR SAFER CLOZAPINE USE ALL OVER THE WORLD

A new international titration guideline

An international guideline with 104 authors from 50 countries/regions was recently published to provide personalized clozapine titration schedules for adult inpatients [28]. The two most innovative aspects of this new guideline are: 1) 6 different titration schedules proposed for stratified dosing and 2) c-reactive protein (CRP) monitoring at baseline and weekly for 4 weeks at the same time as the white blood cell count. CRP offers protection for identifying clozapine genetic PMs. If the genetic PM cannot tolerate the prescribed titration, CRP would become abnormal. Thus, CRP is a form of personalized titration, as is using clozapine levels to determine minimum therapeutic dosing.

Update of the international titration guideline

The clozapine titration guideline [28] is based on pharmacokinetic predictions and limited data, so it is a document in progress. Even before it was published, it required 2 major modifications [173]. Writing the first draft and recruiting co-authors worldwide took one year to complete; the modifications could not be included in the published version. The first modification is that the recommended dosage of 300 to 600 mg/day for average patients in the US (who are not Asians or Indigenous Americans) has become the recommended titration for Black patients with ancestry from sub-Saharan Africa. Second, the titrations for PM patients within each ancestry group should be used for patients in whom clozapine is added to olanzapine or quetiapine. The co-prescription of these two antipsychotics may increase the risk of clozapine-induced myocarditis [67,157]. The author is used to adding clozapine to other antipsychotics and does not stop the others until a possible clozapine therapeutic dose has been reached. Clarifications for patients of mixed ancestry have also been suggested [31].

The international guideline is being translated into Chinese, Croatian, Korean, Japanese, Russian, and Spanish and being disseminated in summary articles in psychiatric journals of national distribution across multiple countries/regions [3,21,31,70,76,100,141,173-175].

Limitations of the international titration guideline

Clozapine is a generic drug so no company will support new prospective studies of the 6 proposed titration schedules and the author does not know how to obtain funding for such ambitious studies. The proposal of the international guideline that CRP elevations are better and earlier markers than troponin for clozapine-induced myocarditis is supported by an old Australian abstract [176] reanalyzing data from the Ronaldson et al. [96] study. In 105 cases of clozapine-induced myocarditis, CRP could rise up to 5 days before troponin [176].

A philosopher of science named Karl Popper [177,178] proposed that science advances by falsifying a hypothesis, so the author recommends that the reader try to demonstrate that the author’s theory is wrong by using the titration guideline in the care of his/her patients. However, by using the international clozapine titration guideline, the author thinks that readers may find out on their own that diagnosing all types of inflammation [76] may be relevant in decreasing clozapine-related lethality during titration.

FURTHER REFLECTIONS ON ETHNOPSYCHOPHARMACOLOGY RELEVANT FOR EAST ASIANS

Ethnopsychopharmacology refers to the need to consider both cultural and biological diversity and tailor treatment to individual characteristics rather than relying on global guidelines [179]. Thus, this article stresses that the biological diversity seen around the world has not been correctly considered when dosing clozapine. Unfortunately, biological diversity has not received enough attention in psychopharmacology practice, in general, and in patients of East Asian ancestry, specifically. Supplementary Table 14 (in the online-only Data Supplement) uses as examples four other psychiatric drugs (diazepam [52,180-184], carbamazepine [185-187], olanzapine [21,25,131,157,188], and haloperidol [24,61,64,189-191]) in which paying attention to East Asian ancestry may be important. The literature provides reasonable information concerning lower diazepam dosing in East Asians and for genotyping human leukocyte antigen-B*15:02 before starting carbamazepine in East Asian countries, except Japan [185,186]. On the other hand, it is likely that patients of East Asian ancestry may need lower doses of olanzapine [131] and haloperidol [191] and this appears to have been ignored by Western textbooks and articles.

CONCLUSION

Regarding clozapine, there is need for studies of 1) clozapine blood levels in patients with sub-Saharan African, Western Asian, and Oceanian ancestries; 2) the influence of clozapine titration on clozapine-induced inflammations in various countries; and 3) clozapine-induced myocarditis including blood levels [192] in countries such as China [44,67] or Russia [193], with frequent clozapine use, but limited awareness of this diagnosis. Concerning ethnopsychopharmacology, more attention is needed to personalize antipsychotic dosing and more definitive studies are required for patients of East Asian ancestry, who may need lower doses not only of clozapine, but of olanzapine and haloperidol than those of European ancestry.

Albert Magnus (1200–1280 AD) was known during his lifetime as “Doctor universalis” and “Doctor expertus” because of his encyclopedic knowledge. His knowledge not only included philosophy and theology, but he wrote on different sciences, such as botany, geography, astronomy, mineralogy, alchemy, zoology, and physiology [194]. One of his most important quotes in the development of the scientific method is “The aim of natural science is not simply to accept the statements of others, but to investigate the causes that are at work in nature.” To conclude, the author wants to pay tribute to the Asian clozapine prescribers and researchers who did not accept the clozapine doses promoted in the US, but observed that Asians may need lower doses. Among clozapine prescribers, he wants to emphasize 1) Farooq, a Pakistani psychiatrist who in 1998 [112] proposed in the British Journal of Psychiatry that Pakistani patients may need lower clozapine doses similar to Chinese patients; 2) the Indian psychiatrists trained in India who have figured out that most Indian patients can be treated with up to 300 mg/day of clozapine [115]; and 3) Kikuchi et al. [146] the first Japanese psychiatrists who dared to describe how the titrations proposed by the Japanese package inserts may cause clozapine-induced inflammations in some patients. Two groups of clozapine researchers, in Taiwan Chang et al. [109] and in Singapore Chong et al. [110], in 1997 published serum clozapine concentrations definitively indicative that patients of Chinese ancestry need approximately half the clozapine dosage used in the US. After 25 years, the clozapine package inserts from the US and other Western countries do not reflect the need for lower doses in Asians and their descendants, the Indigenous peoples of the Americas. It is not known how many lives could have been saved in these 25 years if lower doses had been used, but cases of patients of Asian ancestry who developed clozapine-induced inflammation and tolerate much slower titrations keep getting published [146,195].

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.30773/pi.2022.0293.

Supplementary Table 1.

The need for an open-minded reader

pi-2022-0293-Supplementary-Table-1.pdf

Supplementary Table 2.

Basic concepts in pharmacokinetics

pi-2022-0293-Supplementary-Table-2.pdf

Supplementary Table 3.

Basic concepts in pharmacokinetics applied to clozapine

pi-2022-0293-Supplementary-Table-3.pdf

Supplementary Table 4.

Basic concepts of pharmacovigilance

pi-2022-0293-Supplementary-Table-4.pdf

Supplementary Table 5.

Clozapine-induced fever

pi-2022-0293-Supplementary-Table-5.pdf

Supplementary Table 6.

Clozapine-induced myocarditis

pi-2022-0293-Supplementary-Table-6.pdf

Supplementary Table 7.

Clozapine-induced inflammation

pi-2022-0293-Supplementary-Table-7.pdf

Supplementary Table 8.

Clozapine dosing in Asians

pi-2022-0293-Supplementary-Table-8.pdf

Supplementary Table 9.

Clozapine in Denmark

pi-2022-0293-Supplementary-Table-9.pdf

Supplementary Table 10.

Clozapine in Japan

pi-2022-0293-Supplementary-Table-10.pdf

Supplementary Table 11.

Contribution of Australians to the field of clozapine-induced myocarditis

pi-2022-0293-Supplementary-Table-11.pdf

Supplementary Table 12.

Detailed analysis of accumulated clozapine dosage in Australian protocols

pi-2022-0293-Supplementary-Table-12.pdf

Supplementary Table 13.

Clozapine in the UK

pi-2022-0293-Supplementary-Table-13.pdf

Supplementary Table 14.

Ethnopsychopharmacology relevant for patients of East Asian ancestry

pi-2022-0293-Supplementary-Table-14.pdf

Notes

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.

Conflicts of Interest

The author has no potential conflicts of interest to disclose.

Funding Statement

None

ACKNOWLEDGEMENTS

The author thanks Lorraine Maw, M.A., at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA, for editorial assistance. In November and December 2022, when the second version of this article was being updated, the author, with the help of his international collaborators, was attempting to introduce the need for recommending lower clozapine doses in Asians in worldwide clozapine package inserts; the initial steps focused on the package inserts in the United States and Japan. Thus, the author is extremely grateful to multiple people who helped him with this article, which may become an important part of convincing drug agencies to include lower doses for Asians in clozapine package inserts. Among these people, the author wants to acknowledge: Se Hyun Kim M.D., Ph.D., the editor of the journal and the three reviewers of this article who helped him improve the second version.

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