Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Vickers, Mark L.; Ramineni, Vinay; Malacova, Eva; Eriksson, Lars; McMahon, Kirsten; Moudgil, Vikas; Scott, James G.; Siskind, Dan

doi:10.1111/acps.13398

Cited by 36 publications

(32 citation statements)

References 51 publications

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“…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 ]. In a review of case reports, the success rate of clozapine rechallenge after clozapine-associated myocarditis was 64.7% (11/17) [ 119 ].…”

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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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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“…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][151][152][153][154][155][156][157] Supplementary Table 12 (in the online-only Data Supplement) 28,96,158 details the problem with the official Australian clozapine titration schedules.…”

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

confidence: 99%

“…This is one of the most consistent findings in studies of clozapine-induced myocarditis. 151 • Valproate can behave as an inhibitor during early titration before the inductive effects of valproate on norclozapine predominate. 152 • In 13 patients with clozapine-induced myocarditis from 2 case series with blood levels, 153,154 8 patients took valproate and behaved as clozapine PMs.…”

Section: Supplementary Table 1 the Need For An Open-minded Readermentioning

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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“…Based on its early onset and titration speed dependency, a hypersensitivity reaction is discussed as a likely pathophysiological mechanism of CIM 190,191,[196][197][198][199][200][201] , but current evidence remains inconclusive 176 . Thus far, no reliable predictors for an individual's CIM risk have been established.…”

Section: Cardiac Side Effectsmentioning

confidence: 99%

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

Qubad¹,

Bittner²

2022

Preprint

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Despite its continued relevance as the single most effective and important evidence-based treatment for schizophrenia, the degree of underutilization of clozapine across health systems remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to use clozapine due to its relatively large side-effect burden and its comparatively complex dosing and monitoring requirements. This underscores the necessity for continued education of clinicians in the intricacies of clozapine use and in the still growing case in favor of this vital treatment option. Consequently, this narrative review provides a comprehensive outline of all lines of evidence, which support clozapine’s wide-ranging superior efficacy, and of the current knowledge regarding the prevalence and diagnosis of treatment resistance. The distinct neurobiological and clinical characteristics of this condition makes the swift initiation of clozapine indispensable. Moreover, we review the extensive literature regarding clozapine’s side effect profile and current recommendations for optimal treatment and monitoring algorithms including for particularly vulnerable populations such as elderly patients and pregnant women and for potential re-challenges after myocarditis and neutropenia. We also discuss established approaches to increase treatment response as well as augmentation strategies for patients with partial or full clozapine resistance. We argue for a clear focus on early and consistent detection and management of side effects, which can ensure patient safety and reduce permanent all-cause discontinuation. This strategy needs to be combined with a long-term approach acknowledging the late onset of clozapine’s full advantageous effects, which – in cases like reduced mortality rates – even then may not be easily discernible. Our aim is to encourage a safer, more frequent, and timely use of clozapine to maximize patients’ short- and long-term benefits. Even now, the extent of these benefits as well as patient’s satisfaction with treatment still clearly set clozapine apart from all other available treatment options.

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Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Cited by 36 publications

References 51 publications

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

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

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

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