This editorial proposes some new ideas about clozapine. Clozapine’s history explains why new ideas are needed. For approval of a new antipsychotic drug in the United States (US), the Food and Drug Administration (FDA) requires (1) comprehensive pharmacokinetic studies in order to consider the drug’s influence on dosing due to pharmacogenetic variables, environmental variables such as drug–drug interactions (DDIs), or personal variables, such as sex, age or medical comorbidity; (2) randomized clinical trials (RCTs) of hundreds or a few thousand patients; and (3) open trials with longer follow-up to monitor for adverse drug reactions (ADRs).
Clozapine was synthesized in 1958. It was rejected by several of the first clinicians who tested it and after some RCTs in German-speaking countries encouraged by Hippius, it was approved in some European countries in the 1970s. In 1974, the first US study was published and the marketer (Sandoz) started the initial regulatory studies. Then after the first reports of 18 cases of agranulocytosis in Finland, which caused nine deaths, were published, Hippius and his German-speaking colleagues were barely able to keep clozapine available. The marketer, Sandoz, decided to focus on patients with treatment-resistant schizophrenia (TRS) in order to obtain approval by the FDA; in 1984, an RCT was started at 16 US sites and was published in 1988. In 1989, the FDA approved clozapine with the requirement that weekly white blood cell counts (WBCs) be administered. This led to the resurrection of clozapine use all over the world.
A RETROSPECTIVE REASSESSMENT OF THE DEFICIENCIES OF CLOZAPINE STUDIES
That year of approval, 1989, explains the current problems regarding clozapine usage. After clozapine became generic in the US, there have been no incentives or monetary support for conducting further studies that would improve clozapine’s package insert. It is not possible to provide a comprehensive review of the problems found in clozapine’s package insert, but the three major deficiencies are related to (1) metabolism, (2) the relative relevance of ADRs, and (3) ignorance of clozapine-induced inflammation associated with rapid titrations.
Lack of studies of clozapine metabolism
In 1989, it was unknown which enzyme metabolized clozapine and that DDIs could be significantly associated with lethality. The FDA focused on DDIs after 1996, when a new antihistamine that was safe in the RCTs killed 125 patients when prescribed to the US general population, some of whom were taking multiple medications. In 1994, Bertilsson et al. first reported that clozapine was mainly metabolized by the cytochrome P450 1A2 (CYP1A2) and that fluvoxamine was a powerful inhibitor and carbamazepine an inducer. The polycyclic aromatic hydrocarbons (PAHs) of tobacco smoking stimulate the aryl receptor and induce CYP1A2. The estrogens are CYP1A2 inhibitors so females on average have lower CYP1A2 activity and metabolize clozapine less efficiently than males. Thus, in the late 1990s it was clear that clozapine dosing should consider sex-smoking subgroups; female non-smokers need the lowest clozapine dose and male smokers the highest.
No US or British textbook or article review by clozapine experts reflects the next important step. In 1997, studies from Taiwan and Singapore independently described how Chinese patients were receiving half the dosage used in Western countries but had approximately the same clozapine plasma concentrations. In 1998 a comment from a Pakistani psychiatrist suggesting that Pakistani patients may be similar to Chinese patients regarding clozapine dosing was published in the British Journal of Psychiatry, but was forgotten or ignored. The reader would need to decide whether or not it was reasonable for Western psychiatrists to use their typical dosages and probably overdose their patients of Asian ancestry despite these studies and one more small comparative study that followed in 2005. By the way, this Asian phenotype does not correspond to geography; it corresponds to DNA ancestry and the complicated history of human evolution. This definition of Asian ancestry includes people whose ancestry can be traced to countries ranging from Pakistan to Japan. Moreover, the original people of the Americas (Indigenous Americans) are descendants of East Asians and also need lower clozapine doses.
After a visit to the Beijing Anding Hospital in 2015 and discussing their dosing, the first author became convinced that East Asians (Chinese, Koreans and Japanese) may need lower clozapine doses than patients of European ancestry. There is general agreement in the literature that 350 ng/ml may be the minimum therapeutic plasma concentration for TRS, which can allow us to calculate the minimum therapeutic dose to reach that concentration, as seen in various studies. In a systematic review with his Chinese colleagues, the first author found that the average minimum therapeutic dose was 223 mg/day in 876 East Asians versus 327 m/day in 1147 Western patients mostly of European ancestry. This systematic review is limited by the lack of control for sex and smoking in the comparison between East Asian and Western patients and by excluding an Indian sample from the calculations. The next step required obtaining additional data from the authors of four published studies from Asia, and this led to the finding that, after sex-smoking stratification, Indians had clozapine metabolism similar to East Asians. Finally, after adding data from Mexican patients (Indigenous Americans) who had similar metabolism, the average minimum therapeutic dose for 252 female non-smokers of Asian or Indigenous American ancestry was 166 mg/day while for 137 male smokers it was 270 mg/day. The US package insert and many US textbooks recommend 300 to 600 mg/day of clozapine.
Within each ancestry group and sex-smoking subgroup, there may be some patients called poor metabolizers (PMs) who, with lower dosages (approximately half), can reach minimum therapeutic concentrations. In 573 Asian patients, the causes of PM status included 7% possibly genetic, 2% inhibitor co-prescription, 2% inflammation, and 1% obesity. There are no published studies of clozapine genetic PMs in Asia but in Japan it has been described that four different CYP1A2 alleles can result in lower metabolic activity (CYP1A2*8, CYP1A2*11, CYP1A2*15 and CYP1A2*16) and each of them is present in less than 1% of the population. The most important inhibitors that cause PM status (this phenomenon is called phenoconversion by pharmacologists) are fluvoxamine, oral contraceptives and high intake of caffeine. Clozapine binds to fat tissue and that leads to decreased clozapine metabolism and in some patients this may lead to clozapine PM status.
The cytokines released during any systemic inflammation, whether caused by infection or not, inhibit clozapine metabolism by inhibiting CYP1A2 and other CYPs. This systemic inflammation can be identified by C-reactive protein (CRP) elevations. A retrospective review of 131 clozapine inpatients at Beijing Anding Hospital found that infections and inflammations were frequent in clozapine patients; 18 episodes in 16 patients contaminated 2% (482/24,789) of the days of clozapine treatment. Moreover, these episodes had clinical relevance for dosing; the review found (1) no clinically relevant effects on the plasma clozapine concentrations in the 11% of infectious episodes which presented with no leukocytosis or CRP elevations, (2) effects indicating that halving the clozapine dose would be advisable in 61% of infectious episodes, and (3) effects indicating that reducing the clozapine dose to one-third would be advisable in 28% of infectious episodes. The determining effect is not the presence or absence of infection, but the systemic severity of the inflammation.
Lack of good studies on more lethal clozapine ADRs
In a review of the FDA data from 1998 to 2005, Moore et al. found that clozapine was associated with 3,277 deaths or serious, non-fatal outcomes, making it the third most toxic US drug. The article did not explain how clozapine patients died, but from the moment clozapine was approved, the FDA has obsessed about clozapine-induced agranulocytosis. By studying the deaths of clozapine patients from 2000 to 2019 found in the ADR database of the World Health Organization (WHO), 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, pneumonia and myocarditis caused more deaths. There were 1922 deaths due to pneumonia (30% relative lethality; 1922/6506) and 484 deaths due to myocarditis (11% relative lethality; 484/4536).
Most clozapine-induced pneumonia does not occur during agranulocytosis and its pathophysiology is complex. TRS may explain 2/3 of the risk of pneumonia. Clozapine can contribute to community-acquired pneumonia by decreasing antibodies and to aspiration pneumonia by causing swallowing disturbances, sedation, hypersalivation and/or possible other ADRs, such as clozapine-induced gastrointestinal hypomotility (CIGH). Once pneumonia develops, the systemic inflammation releases cytokines that inhibit CYP1A2, and other CYPs can cause clozapine intoxication. The combination of severe pneumonia and clozapine intoxication appears to be particularly lethal.
On the other hand, the development of clozapine-induced myocarditis may be mainly explained by iatrogenic factors, using too rapid titrations. A rapid titration in Western countries may occur when the standard titration for patients of European ancestry is prescribed to patients of Asian ancestry or a European clozapine PM. In Asian countries, particularly in China, clozapine-induced myocarditis may be problematic in its lack of diagnosis since clinicians may not be aware of its existence. Anyway, this can be better understood under the concept of clozapine-induced inflammation.
The neglected issue of clozapine-induced inflammation during rapid titration
In 1972, German-speaking psychiatrists described clozapine-induced fever during early titration in the absence of any concomitant infection. They then found that it was associated with signs of inflammation and happened in approximately 5% of their patients. In the US, it was called benign hyperthermia. This is a mild form of clozapine-induced inflammation during rapid titration, which also includes CRP elevations, myocarditis and other localized inflammations. All of these manifestations may be 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 could not 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 autoimmune phenomenon leading to localized inflammation.
In a literature review, Verdoux et al. proposed that manifestations of clozapine-induced inflammation due to rapid titration may include a wide variety of presentations including (1) systemic inflammatory processes, namely, fever, fever with isolated CRP elevation, or lupus; or (2) localized signs of inflammation, namely, myocarditis, serositis, pneumonitis/alveolitis, hepatitis, pancreatitis, nephritis, colitis or dermatological disorders. This classification is somewhat arbitrary since these presentations may lie on a continuum with no clear-cut boundary between them, and several conditions may co-occur. Moreover, it overlaps with manifestations associated with eosinophilia; the typical clozapine-induced myocarditis is associated with eosinophilic infiltrations. A recent review from a European pharmacovigilance database identified 47 new cases of clozapine-related drug reactions with eosinophilia and systemic symptoms (DRESS) syndrome. These 47 cases appeared similar to the >3000 cases of clozapine-induced myocarditis from the worldwide pharmacovigilance database. The respective lethalities were 3.9% versus 3.1%, diagnosis during the first month, 64% vs 84%, and valproate co-prescription 10% vs 9%. Valproate can be an inhibitor of clozapine metabolism during titrations; over time, its inductive effects may predominate over its inhibitor effects.
MAKING CLOZAPINE USE SAFER IN INDIA AND AROUND THE WORLD
Published clozapine inpatient titration guideline for TRS
An international guideline with 104 authors from 50 countries or regions was recently published to provide personalized clozapine titration schedules for adult inpatients. The two most innovative aspects of this new guideline are the following: (1) Six different titration schedules proposed for stratified dosing; and 2) CRP monitoring at baseline and weekly for four weeks at the same time as the WBC. CRP offers protection for identifying clozapine genetic PMs. If the genetic PM cannot tolerate the prescribed titration, the CRP would become abnormal. This is a form of personalized titration, as is using clozapine levels to determine minimum therapeutic dosing, but clozapine levels are not widely available in India.
The clozapine titration guideline is based on pharmacokinetic predictions and limited data, so it is a document in progress. One year after its first draft was completed—so that co-authors worldwide could be recruited—but before it was finally published, it required two major modifications. First, the recommended dosage of 300–600 mg/day for average patients in the US who are not Asians or Indigenous Americans has become the recommended titration for Black patients, those whose ancestry is from sub-Saharan Africa. There is almost no published data on them but this is compatible with the author’s unpublished data and clinical experience. 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. 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.
Future updates and other guidelines
Other guideline updates will need to be developed as new information becomes available. The first version focused on adult inpatients with TRS since many countries use inpatient titration and the author is used to inpatient titration. Future TRS guidelines for children or with adult outpatient titration need to be developed. Outpatient titration should be slower than inpatient titration and weekly CRP monitoring should be used as long as is reasonable but at least for four weeks, the highest risk period. Patients with off-label clozapine indications, such as bipolar disorder, polydipsia or intellectual disability, may need lower clozapine dosing, but this has not been well studied. There is also a need for clozapine maintenance guidelines to prevent deaths associated with maintenance treatment including pneumonia and other clozapine ADRs that may be dose-dependent, such as constipation, seizures or arrythmia.
The author thanks Lorraine Maw, M.A., for editorial assistance. He is grateful to George M. Simpson, M.D., who published the first clozapine study in the United States (US) in 1974 and who introduced him to the safe use of clozapine. For five years, the author supervised Dr. Simpson’s double-blind clozapine study that used three clozapine dosages (100, 300 and 600 mg/day). This study has given him access to a unique database of 50 patients with multiple clozapine levels under well-controlled conditions that still is giving him new insights into clozapine pharmacokinetics. The author is grateful to multiple collaborators around the world: (1) two young collaborators (Can-Jun Ruan, Ph.D., and Georgios Schoretsanitis, M.D.) who have had enough courage to collaborate with him in his unrealistic enterprise of changing the US clozapine package insert; (2) Carlos De las Cuevas, M.D., and Emilio J Sanz, M.D., Ph.D., who helped him verify in VigiBase that his intuitions about clozapine’s association with pneumonia and myocarditis were right; and 3) multiple clozapine researchers from three continents who were willing to collaborate with him by giving him access to their results on clozapine levels and cases of myocarditis. It is not easy to trust one’s data to an expert who writes an email from the US proposing a possible collaboration. The trust of these multiple clozapine researchers has allowed the author to verify the relevance of DNA ancestry on clozapine metabolism without having any research funding.
1. de Leon J The history of clozapine in clinical practice:From its introduction to a guideline proposing personalized titrations J Psychopharmacol 2022 36 657–60
2. de Leon J The future (or lack of future) of personalized prescription in psychiatry Pharmacol Res 2009 59 81–9
3. de Leon J, Ruan CJ, Schoretsanitis G, De Las Cuevas C A rational use of clozapine based on adverse drug reactions, pharmacokinetics, and clinical pharmacopsychology Psychother Psychosom 2020 89 200–14
4. Bertilsson L, Carrillo JA, Dahl ML, Llerena A, Alm C, Bondesson U, et al Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test Br J Clin Pharmacol 1994 38 471–3
5. Jerling M, Lindström L, Bondesson U, Bertilsson L Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine:Evidence from a therapeutic drug monitoring service Ther Drug Monit 1994 16 368–74
6. Perry PJ, Bever KA, Arndt S, Combs MD Relationship between patient variables and plasma clozapine concentrations:A dosing nomogram Biol Psychiatry 1998 44 733–8
7. de Leon J, Rajkumar AP, Kaithi AR, Schoretsanitis G, Kane JM, Wang CY, et al Do Asian patients require only half of the clozapine dose prescribed for Caucasians?A critical overview Indian J Psychol Med 2020 42 4–10
8. Chang WH, Lin SK, Lane HY, Hu WH, Jann MW, Lin HN Clozapine dosages and plasma drug concentrations J Formos Med Assoc 1997 96 599–605
9. Chong SA, Tan CH, Khoo YM, Lee HS, Wong KE, Ngui F, et al Clinical evaluation and plasma clozapine concentrations in Chinese patients with schizophrenia Ther Drug Monit 1997 192 19–23
10. Farooq S Ethnicity and clozapine metabolism Br J Psychiatry 1998 173 87
11. Ng CH, Chong SA, Lambert T, Fan A, Hackett LP, Mahendran R, et al An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels Int Clin Psychopharmacol 2005 20 163–8
12. González-Esquivel DF, Jung-Cook H, Baptista T, de Leon J Amerindians may need clozapine dosing similar to that of Asians Rev Psiquiatr Salud Ment (Engl Ed) 2021 14 177–9
13. Spina E, de Leon J Clinical applications of CYP genotyping in psychiatry J Neural Transm (Vienna) 2015 122 5–28
14. Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology:Update 2017 Pharmacopsychiatry. Pharmacopsychiatry 2018 51 9–62
15. Ruan CJ, Zang YN, Wang CY, Cheng YH, Sun C, Spina E, et al Clozapine metabolism in East Asians and Caucasians:A pilot exploration of the prevalence of poor metabolizers and a systematic review J Clin Psychopharmacol 2019 39 135–44
16. Rajkumar AP, Poonkuzhali B, Kuruvilla A, Jacob M, Jacob KS Clinical predictors of serum clozapine levels in patients with treatment-resistant schizophrenia Int Clin Psychopharmacol 2013 28 50–6
17. Ruan CJ, Wang CY, Tang YL, Lin SK, Lee ST, Hong KS, et al Exploring the prevalence of clozapine phenotypic poor metabolizers in 4 Asian samples:They ranged between 2% and 13 J Clin Psychopharmacol 2019 39 644–8
18. de Leon J, Schoretsanitis G, Smith RL, Molden E, Solismaa A, Seppälä N, et al An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels Pharmacopsychiatry 2022 55 73–86
19. de Leon J, Schoretsanitis G, Kane JM, Ruan CJ Using therapeutic drug monitoring to personalize clozapine dosing in Asians Asia Pac Psychiatry 2020 12 e12384
20. Ruan CJ, de Leon J Is there a future for CYP1A2 pharmacogenetics in the optimal dosing of clozapine? Pharmacogenomics 2020 21 369–73
21. Diaz FJ, Josiassen RC, de Leon J The effect of body weight changes on total plasma clozapine concentrations determined by applying a statistical model to the data from a double-blind trial J Clin Psychopharmacol 2018 38 442–6
22. Ruan CJ, Zang YN, Cheng YH, Wang CY, de Leon J Around 3% of 1,300 levels were elevated during infections in a retrospective review of 131 inpatients in a Beijing Hospital with more than 24,000 clozapine days Psychother Psychosom 2020 89 255–7
23. Moore TJ, Cohen MR, Furberg CD Serious adverse drug events reported to the Food and Drug Administration, 1998-2005 Arch Intern Med 2007 167 1752–9
24. de Leon J, De las Cuevas C, Sanz EJ, Ruan C-J, Correll CU Clozapine and the risk of haematological malignancies Lancet Psychiatry 2002 9 537–8
25. Schoretsanitis G, Ruan CJ, Rohde C, Verdoux H, De Las Cuevas C, Spina E, et al An update on the complex relationship between clozapine and pneumonia Expert Rev Clin Pharmacol 2021 14 145–9
26. Villasante-Tezanos AG, Rohde C, Nielsen J, de Leon J Pneumonia risk:Approximately one-third is due to clozapine and two-thirds is due to treatment-resistant schizophrenia Acta Psychiatr Scand 2020 142 66–7
27. De Las Cuevas C, Sanz EJ, Ruan CJ, de Leon J Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database:Focus on reports from various countries Rev Psiquiatr Salud Ment (Engl Ed) 2021 S1888-9891(21)00070-7 doi:10.1016/j.rpsm.2021.07.004
28. de Leon J Reflections on the complex history of the concept of clozapine-induced inflammation during titration Psychiatr Danub 2022 in press
29. Verdoux H, Quiles C, de Leon J Clinical determinants of fever in clozapine users and implications for treatment management:A narrative review Schizophr Res 2019 211 1–9
30. Schoretsanitis G, de Leon J Best practices for starting clozapine in patients with schizophrenia:How to switch from the prior antipsychotic(s) J Clin Psychiatry 2022 83 22ac1450
31. De Las Cuevas C, Sanz EJ, Rohde C, de Leon J Association between myocarditis and antipsychotics other than clozapine:A systematic literature review and a pharmacovigilance study using VigiBase Expert Rev Clin Pharmacol 2022 15 65–78