Monitoring for myocarditis during treatment initiation with clozapine

Surya, Sandarsh; Bishnoi, Ram J.; Shashank, Reddy Beesam; Miller, Brian J.; Freudenreich, Oliver; McEvoy, Joseph P.

doi:10.1111/acps.13328

Cited by 14 publications

(14 citation statements)

References 19 publications

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“…Thus, the Japanese titration protocol is not safe for Asians, particularly for those with additional risk factors (eg, valproate, obesity, females on contraceptives), which further impair clozapine clearance. Some hospitals in Canada 23 and the USA 24 also report a prevalence of myocarditis around 3%, due to the use of standard titration in Asians, Native Americans, and Europeans with impaired clozapine metabolism.…”

Section: Clozapine-induced Myocarditis Occurring During Titrationmentioning

confidence: 99%

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine

et al. 2022

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White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or pneumonia during clozapine titrations. Prescribers worldwide are largely unaware of that. Meanwhile, as they worry about agranulocytosis, their clozapine-treated patients are at risk of dying from pneumonia or myocarditis. Consequently, an international guideline with 104 authors from 50 countries/regions was recently published to provide personalised clozapine titration schedules for adult inpatients. This forum article reviews pneumonia and myocarditis occurring during clozapine titration, as well as the three most innovative aspects of this new guideline: (1) personalised titration, (2) C reactive protein (CRP) measures, and (3) dose predictions based on blood levels. Clozapine metabolism is influenced by 3 levels of complexity: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer status. These 3 groups of variables should determine the maintenance dose and speed of clozapine titration; they are summarised in a table in the full-text. The international clozapine titration guideline recommends measuring CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, the highest risk period for clozapine-induced myocarditis.

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Section: Clozapine-induced Myocarditis Occurring During Titrationmentioning

confidence: 99%

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine

et al. 2022

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“…The meta-analysis included mainly retrospective studies that used a variety of definitions and markers. Subsequent reports of presumptive myocarditis based on sensitive laboratory tests [ 128 ] or retrospectively identified myocarditis (cases defined as flu-like symptoms plus ≥ 1 symptom/sign of cardiac dysfunction plus ≥ 1 indicative diagnostic abnormality and no evidence of a viral cause) [ 129 ], suggest that the incidence may be higher. The risk of myocarditis is higher among patients commencing clozapine treatment while receiving valproate [ 130 ].…”

Section: Side Effect Monitoring and Managementmentioning

confidence: 99%

A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

et al. 2022

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“…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.…”

Section: High Lethality In Australian Clozapine Patients Associated W...mentioning

confidence: 99%

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

León

2023

Psychiatry Investig

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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.

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Monitoring for myocarditis during treatment initiation with clozapine

Cited by 14 publications

References 19 publications

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine

A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

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

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