Myocarditis and cardiomyopathy associated with clozapine

doi:10.1016/S0140-6736(99)10385-4

The Lancet

Volume 354, Issue 9193, 27 November 1999, Pages 1841-1845

https://doi.org/10.1016/S0140-6736(99)10385-4 Get rights and content

Summary

Background

Clozapine is effective for resistant schizophrenia. After two sudden deaths in physically well young men soon after starting clozapine, we investigated the cardiovascular complications for this drug.

Methods

From January, 1993, to March, 1999, 8000 patients started clozapine treatment in Australia, and were registered with a mandatory monitoring service. We identified cases of myocarditis and cardiomyopathy from voluntary reports to the Australian Adverse Drug Reaction Committee and sought details of the relevant diagnostic studies, necropsies that had been done in suspicious cases, or both.

Findings

23 cases (20 men, three women, mean age 36 years [SD 9]) were identified: 15 of myocarditis and eight of cardiomyopathy associated with clozapine treatment. Six patients died. All cases of myocarditis (five deaths) occurred within 3 weeks of starting clozapine. Cardiomyopathy (one death) was diagnosed up to 36 months after clozapine was started. Necropsy results showed mainly eosinophilic infiltrates with myocytolysis, consistent with an acute drug reaction.

Interpretation

Clozapine therapy may be associated with potentially fatal myocarditis and cardiomyopathy in physically healthy young adults with schizophrenia.

Introduction

Clozapine is a dibenzodiazepine antipsychotic, distinguished from traditional antipsychotic agents by its weak D2-dopaminergic activity, strong affinity for D4-receptors, potent serotonin and noradrenergic antagonism, and few extrapyramidal symptoms.¹ The drug is generally valuable in the 30% of patients with schizophrenia who do not respond to conventional therapy or who cannot tolerate other agents.² Clozapine has been prescribed for more than 1 million patient-years in more than 60 countries worldwide.

Clozapine-associated agranulocytosis occurs in about 1% of patients in the first year of treatment³ and has received widespread attention. Many countries, including Australia, have therefore introduced mandatory schemes for registering and monitoring patients started on clozapine. Such early monitoring has led to a decrease in the number of deaths from neutropenia or agranulocytosis.⁴ No such deaths were recorded in the first 8000 patients on the Australian registry.

Other less troublesome side-effects have been noted. Orthostatic hypotension and tachycardia are well-recognised cardiovascular effects, occurring in up to 9% and 25% of cases, respectively,⁵ but are rarely clinically important. Two cases of sudden cardiac death and acute myocarditis with an eosinophilic infiltrate at necropsy occurred at our institution soon after the patients had started taking clozapine. These deaths prompted us to investigate the possible relation between clozapine therapy and more serious cardiac complications.

Section snippets

Data collection

We requested from the Adverse Drug Reactions Advisory Committee (ADRAC) of Australia all accumulated data on previous reports of sudden death, myocarditis, or cardiac disease noted in connection with clozapine treatment, from January, 1993, to March, 1999, inclusive (during which time the first 8000 patients were registered in the monitoring system). We identified an additional case at our own institution. Because of the voluntary and confidential nature of the ADRAC reporting system, only

Results

From January, 1993, to March, 1999, 8000 patients started clozapine in Australia (15 520 patient-years of exposure). Of these, 23 patients (20 men, three women, mean age 36 years [SD 9]) had objective evidence of myocarditis or cardiomyopathy (absolute risk 0·29%); six patients died. The clozapine doses at the time of diagnosis of a cardiovascular complication ranged from 100 mg to 725 mg daily.

All 15 cases of myocarditis (table 1) occurred early after the start of clozapine (median 15 days

Discussion

Clozapine is highly effective in the treatment of schizophrenia. The existence of a registry in Australia has permitted assessment of the minimum incidence of clozapine-related cardiac complications, since reporting of adverse events is voluntary, despite user registration being compulsory. Because voluntary reporting schemes such as ADRAC may miss a proportion of adverse events, our results may underestimate the true incidence of these complications.

We found an high incidence of fatal and

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Clozapine metabolism and cardiotoxicity: A prospective longitudinal study
2024, International Journal of Cardiology
Clozapine-induced myocarditis and cardiomyopathy are difficult to detect clinically and may be fatal if not detected early. The current/routine biomarkers for clozapine-induced myocarditis are non-specific indicators of inflammation (C-reactive protein) or cardiomyocyte damage (troponins I and T) that lack sensitivity, and for which changes often arise too late to be clinically useful.
The Clozapine Safety Study was a prospective, longitudinal, observational study to determine what, if any, the plasma concentrations of clozapine, N-desmethylclozapine, and clozapine-N-oxide in patients contribute to cardiotoxicity. Samples were collected and analysed using liquid chromatography mass spectrometry over a 41-month period from patients in the Auckland District Health Board.
Sixty-seven patients were included. Six patients were diagnosed with myocarditis; none were diagnosed with cardiomyopathy in the study period. In patients not undergoing dose titration, clozapine biotransformation may shift to the N-oxide pathway rather than the N-desmethyl pathway with increasing dose. During dose titration, the timeframe in which myocarditis occurs, the rate of increase in the plasma concentration of clozapine-N-oxide, as well as the ratio of N-oxidation relative to N-desmethylation, were significantly higher in patients diagnosed with myocarditis.
The assessment of clozapine-N-oxide formation, and N-oxidation relative to N-desmethylation ratios during treatment, may help identify a biomarker to aid the early detection of patients at risk of developing clozapine-induced cardiotoxicity.
High rates of myocarditis with clozapine in the Hunter region of Australia
2024, Schizophrenia Research
To study the causes of clozapine treatment discontinuation and measure clozapine-induced myocarditis (CIM) rates in an Australian region, to compare the observed rates of CMI with reports from Australia and the world, and discuss factors related to CIM incidence rates in the region.
The study is a retrospective clinical audit of 327 patients prescribed clozapine. All patients were monitored by the mandatory CIM monitoring protocol for the first six weeks of treatment. The validity of a diagnosis of CIM was assessed using six criteria. Socio-demographic and clinical factors and clozapine prescription practices were analysed for their association with CIM. The study could not examine co-existing medical illness, co-prescribed psychotropic medication, genetics, and environmental factors.
CIM occurred in 9.8 % of the cohort after a mean treatment duration of 19.5 days. The diagnosis of CIM was considered valid in all cases. Gender, age at the start of treatment, ethnicity, cumulative clozapine dose, dose titration, and clozapine/norclozapine ratio were unrelated to CIM.
The CIM rate in the Hunter region was higher than in the rest of Australia and the world and increased after adopting the monitoring protocol. Over-diagnosis, patient's age and gender, ethnicity, cumulative clozapine dose, dosing titration, and clozapine metabolism rate were unrelated to the high occurrence rates. The possible role of comorbid illnesses, co-prescribed psychiatric medications, genetic, and environmental factors in the etiology of CIM requires further study. The reasons underlying the high rates of CIM in the Hunter region need further exploration.
The cellular mechanism of antipsychotic-induced myocarditis: A systematic review
2023, Schizophrenia Research
Antipsychotic drug-induced myocarditis is a serious and potentially fatal adverse drug reaction characterized by inflammation of the heart muscle (myocardium) that typically develops within the first month after commencing an antipsychotic drug. Although the precise mechanism of this severe adverse drug reaction is unknown, multiple theories have been proposed with varying levels of support from cellular or animal studies. We conducted a systematic review, in accordance with PRISMA guidelines, of published preclinical and clinical studies investigating the cellular mechanism by which antipsychotic drugs induce myocarditis. A literature search including all studies available before December 10, 2022, yielded 15 studies that met our inclusion criteria. Antipsychotics examined in the included studies included clozapine (n = 13), ziprasidone (n = 1), amisulpride (n = 1), haloperidol (n = 1), levomepromazine (n = 1), olanzapine (n = 1), and sertindole (n = 1). The evidence suggests several overlapping mechanistic cascades involving: (1) increased levels of catecholamines, (2) increased proinflammatory cytokines, (3) increased reactive oxygen species (ROS), (4) reduced antioxidant levels and activity, and (5) mitochondrial damage. Notable limitations such as, a focus on clozapine, sample heterogeneity, and use of supratherapeutic doses will need to be addressed in future studies. Discovery of the mechanism by which antipsychotic drugs induce myocarditis will allow the development of clinically-useful biomarkers to identify those patients at increased risk prior to drug exposure. The development or repurposing of therapeutics to prevent or treat drug-induced myocarditis will also be possible and this will enable increased and safe use of antipsychotics for those patients in need.
The association between exposure to clozapine, olanzapine, and quetiapine and the outcomes perimyocarditis and heart failure: A population-based cohort study
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The risk of cardiac adverse events following clozapine use is debated and is unknown for the chemically related and widely used antipsychotics olanzapine and quetiapine. National Swedish registers were used to identify all patients 16–75 years old with antipsychotic dispensations between 2005 and 2018. The short-term outcome was a diagnosis of perimyocarditis (pericarditis and/or myocarditis) within two months of first dispensation, and the long-term outcome was heart failure (including cardiomyopathy) within three years. Cox regressions with time varying exposure were used to estimate hazard rates (HR) and their 95% confidence intervals (CI). A total of 201,045 individuals were included in the cohort. The risk of developing perimyocarditis during clozapine treatment tripled compared to no antipsychotic treatment (HR 3.4, CI 1.6–7.3), although the absolute rate remained comparably low. The long-term risk of heart failure during clozapine treatment was also elevated (HR 1.3, CI 1.1–1.7). Treatment with either or both olanzapine or quetiapine was not associated with an increased relative risk of perimyocarditis, or heart failure compared to no antipsychotic treatment. Clozapine use is therefore associated with a substantially elevated short-term risk of perimyocarditis and an increased risk of heart failure within three years.
Myocarditis in patients on long-term antipsychotics –mechanism, management and recent updates
2023, Heliyon
Clozapine is the first atypical antipsychotic drug and was frequently cited as the most effective antipsychotic for treatment-resistant schizophrenia, but it is associated with a concert of significant cardiotoxic side effects. Clozapine-induced Myocarditis (CIM) is diagnosed based on the combination of clinical symptoms, laboratory investigations, radiological findings, and sometimes biopsy. The literature on CIM management and clinical consensus on the best course of action is mixed.
An all-language literature search on Medline, Cochrane, Embase, and Google Scholar until April 2022. The following search strings and Medical Subject Heading (MeSH) terms were used: “CIM,” “clozapine,” “cardiotoxicity,” and “myocarditis.” We explored the literature on CIM for its pathophysiology, diagnosis, monitoring, and management.
The clinical features of CIM may be highly variable, ranging from asymptomatic disease to fulminant heart failure, and cessation of medication was the mainstay treatment of CIM, followed by supportive therapy. Other antipsychotics have also been linked with cardiotoxic side effects.
Despite being the most effective antipsychotic, clozapine is associated with a cardiotoxic side effect. Current literature suggests that these antipsychotic-related cardiotoxic events impact the treatment selection for schizophrenia and other psychotic disorders, and they must be kept in mind while designing new treatment protocols in the future.
Effect of antipsychotic use by patients with schizophrenia on deceleration capacity and its relation to the corrected QT interval
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Schizophrenia patients treated with antipsychotics are at higher risk of sudden cardiac death. Decreased deceleration capacity (DC) of the heart rate is an accurate predictor of cardiac mortality. We evaluated the risk of sudden cardiac death due to antipsychotic use by assessing DC and examining the association between DC and the corrected QT interval (QTc) in schizophrenia patients.
We measured the DC and QTc of 138 schizophrenia patients. We then compared the DC of 86 age- and sex-matched healthy controls with that of 86 schizophrenia patients. We investigated the correlation of DC of approximately 138 schizophrenia patients with prescribed doses of antipsychotics using linear regression analysis. We compared the DC of schizophrenia patients with and without prolonged QT intervals.
We found DC significantly differed between schizophrenia patients on antipsychotic medication and healthy controls. Additionally, DC was negatively correlated with antipsychotic use, especially chlorpromazine, zotepine, olanzapine and clozapine, in a dose-dependent manner. There was no significant association between DC and the QTc.
Assessing DC could facilitate monitoring and identification of increased risk of cardiac mortality in patients with schizophrenia that take antipsychotics. Assessing both DC and the QTc may enhance the accuracy of predicting sudden cardiac death.

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ArticlesMyocarditis and cardiomyopathy associated with clozapine

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Data collection

Results

Discussion

Am J Cardiol

Lancet

Forensic Sci Int

Schizophr Res

Adverse effects of antipsychotic agents: do newer agents offer advantages?

Drugs

Optimizing treatment with clozapine

J Clin Psychiatry

Clozapine induced agranulocytosis: incidence and risk factors in the United States

N Engl J Med

Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry

J Clin Psychiatry

Management of adverse effects of clozapine

Schizophr Bull

Immunologic drug reactions

Sudden cardiac death in Air Force recruits

JAMA

Global health statistics: a compendium of incidence, prevalence, and mortality estimates for over 200 conditions

Incidence of 3 presentations of acute myocarditis in young men in military service: a 20 year experience

Eur Heart J

The epidemiology of infectious myocarditis, lymphocytic myocarditis and dilated cardiomyopathy

Eur Heart J

Articles
Myocarditis and cardiomyopathy associated with clozapine