Clozapine-related Myocarditis Research Articles

Profound Shock after Initiation of Clozapine Therapy

Clozapine, a tricyclic dibenzodiazepine, is an atypical antipsychotic with dopaminergic, muscarinic, histaminic and serotonergic activity that has been used in the treatment of schizophrenia [1]. Although prescribers commonly recognize the hematologic adverse effect agranulocytosis its cardiac side effects, such as myocarditits, are less often considered [2]. A retrospective analysis of an Australian reporting system of patients with recent initiation of clozapine found an incidence of myocarditis about 1 in 500 young adults [3]. Studies since this publication have demonstrated incidences ranging from 0.015% to 8.5%. This compares to an estimated incidence of clozapine-induced agranulocytosis of between 3.8% and 8% [4]. A case definition for clozapine-related myocarditis used by Ronaldson et al described the syndrome as “any new symptoms of myocarditis within 45 days of commencing clozapine with histologic or clinical signs of cardiac dysfunction with either laboratory or radiographic evidence of myocardial pathology or congestive heart failure in the absence of alternative plausible schizophrenia” [5].

A New Monitoring Protocol for Clozapine-Induced Myocarditis Based on an Analysis of 75 Cases and 94 Controls

To develop an evidence-based monitoring protocol for clozapine-induced myocarditis. Potential cases of clozapine-related myocarditis occurring between January 1994 and January 2009 and a comparative group of patients taking clozapine for at least 45 days without cardiac disease were documented from the patients' medical records. A total of 75 cases and 94 controls were included. Nine cases died. The time to onset was 10-33 days with 83% of cases developing between days 14 and 21 inclusive. At least twice the upper limit of normal troponin was found in 90% of cases, but 5 cases had C-reactive protein more than 100 mg/L and left ventricular impairment by echocardiography without a clinically significant rise in troponin. The proposed monitoring protocol recommends obtaining baseline troponin I/T, C-reactive protein and echocardiography, and monitoring troponin and C-reactive protein on days 7, 14, 21 and 28. Mild elevation in troponin or C-reactive protein, persistent abnormally high heart rate or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein investigation until features resolve. Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is over 100 mg/L. Combining these two parameters has an estimated sensitivity for symptomatic clozapine-induced myocarditis of 100%. The sensitivity for asymptomatic disease is unknown. This protocol recommends active monitoring for 4 weeks, relying predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness, but defines a threshold for cessation.

Diagnostic Characteristics of Clozapine-Induced Myocarditis Identified by an Analysis of 38 Cases and 47 Controls

To analyze cases of clozapine-induced myocarditis for clinical and diagnostic trends. A case definition was developed by a multidisciplinary group using reports of myocarditis with clozapine submitted to the Australian Therapeutic Goods Administration. The definition uses for diagnosis either histology or the combination of new signs of cardiac dysfunction combined with a cardiac-specific diagnostic parameter occurring within 45 days of starting clozapine. Potential cases of clozapine-related myocarditis occurring between January 1993 and September 2008 and a comparative group of long-term clozapine users were documented from the patients' medical records. Thirty-eight of 59 reviewed cases met the case definition. Three patients died, and the diagnosis for these was confirmed on cardiac histology. Nearly all of the remaining patients had persistent tachycardia and elevated troponin level. The time to onset was 14-22 days in all except 2 patients. Of the patients who survived, 66% (23 cases) had eosinophilia occurring 0-7 days (mean, 4.0) after the peak in troponin. C-reactive protein (CRP) level was elevated to above 100 mg/L (952 nmol/L) in 79% (23 cases), and some had elevated levels of CRP when troponin level was still normal. None of the control group (47 patients) met the case definition. Eosinophil counts should not be relied on for diagnosis of clozapine-related myocarditis, but elevated CRP may be an early indicator of developing myocarditis. Patients starting clozapine should be actively monitored for myocarditis during the first 4 weeks, with extra care taken during week 3.

CRP levels predict clozapine-related myocarditis

CRP levels predict clozapine-related myocarditis

Clozapine‐induced cardiotoxicity: a clinical update

Clozapine is a valuable drug for patients with treatment-resistant schizophrenia. Myocarditis is the most publicised cardiac complication of clozapine treatment, but cardiomyopathy and pericarditis have also been reported. Myocarditis has heterogeneous and non-specific presenting features, making it difficult to identify patients with clozapine-related myocarditis clinically. A high index of suspicion is required. The gold standard for diagnosis of myocarditis is an endomyocardial biopsy, but this is not a practical initial approach. Transthoracic echocardiography is a valuable, reproducible and widely available tool to assist in diagnosis of clozapine-induced cardiotoxicity. The level of B-type natriuretic peptide, a hormone secreted in response to ventricular wall stress, may be useful for evaluating patients with clozapine-induced cardiac dysfunction and may in the future be useful for screening asymptomatic patients. The mainstay of treatment of clozapine-induced cardiotoxicity is cessation of clozapine and provision of supportive care.

Clozapine-Related Myocarditis and Cardiomyopathy in an Australian Metropolitan Psychiatric Service

Myocarditis and cardiomyopathy are rarely reported complications of clozapine treatment. The incidence of clozapine-related myocarditis has been variably reported at between 0.03% and 0.19% of initiations and cardiomyopathy has been reported even less commonly. In our Brisbane-based service, nine of 94 patients initiated on clozapine over the previous 3 years appeared to have experienced myocarditis or cardiomyopathy. The unique co-location of our service with a major cardiothoracic hospital facilitated a review of identified cases to inform decisions regarding clozapine treatment and rechallenge in this service. Cases were identified by survey of psychiatric and cardiac medical staff at The Prince Charles Hospital and subjected to re-evaluation by a multidiscipline consensus panel. The panel compared cases to international reports and identified the clinical features that supported a diagnosis of clozapine-related myocarditis or cardiomyopathy. This process resulted in the stratification of the nine cases into the following categories of diagnostic likelihood: three highly probable, three probable, and two possible cases of clozapine-related myocarditis, and one possible case of clozapine-related cardiomyopathy. Successful clozapine rechallenge/continuation was undertaken in two patients and the panel agreed that this was a viable future option for several other patients. Findings of the panel review supported the initial clinical diagnoses. This confirmed that there was an apparent high incidence of clozapine-related myocarditis within this service, for which there was no clear reason. Mechanisms underlying clozapine-related myocarditis and cardiomyopathy, as well as successful clozapine continuation and rechallenge were considered, but definitive explanations remain unknown. This review highlighted the clinician's role in post-marketing drug surveillance to guide rational management of suspected adverse drug effects.

Clozapine-related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service

Myocarditis and cardiomyopathy are rarely reported complications of clozapine treatment. The incidence of clozapine-related myocarditis has been variably reported at between 0.03% and 0.19% of initiations and cardiomyopathy has been reported even less commonly. In our Brisbane-based service, nine of 94 patients initiated on clozapine over the previous 3 years appeared to have experienced myocarditis or cardiomyopathy. The unique co-location of our service with a major cardiothoracic hospital facilitated a review of identified cases to inform decisions regarding clozapine treatment and rechallenge in this service.Cases were identified by survey of psychiatric and cardiac medical staff at The Prince Charles Hospital and subjected to re-evaluation by a multidiscipline consensus panel. The panel compared cases to international reports and identified the clinical features that supported a diagnosis of clozapine-related myocarditis or cardiomyopathy.This process resulted in the stratification of the nine cases into the following categories of diagnostic likelihood: three highly probable, three probable, and two possible cases of clozapine-related myocarditis, and one possible case of clozapine-related cardiomyopathy. Successful clozapine rechallenge/continuation was undertaken in two patients and the panel agreed that this was a viable future option for several other patients.Findings of the panel review supported the initial clinical diagnoses. This confirmed that there was an apparent high incidence of clozapine-related myocarditis within this service, for which there was no clear reason. Mechanisms underlying clozapine-related myocarditis and cardiomyopathy, as well as successful clozapine continuation and rechallenge were considered, but definitive explanations remain unknown. This review highlighted the clinician's role in post-marketing drug surveillance to guide rational management of suspected adverse drug effects.

Clozaril Labels to Add New Heart-Related Warning

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessClozaril Labels to Add New Heart-Related WarningJim RosackJim RosackSearch for more papers by this authorPublished Online:15 Mar 2002https://doi.org/10.1176/pn.37.6.0025The Food and Drug Administration (FDA) announced in late February that Novartis Pharmaceuticals Corp. had agreed to add a new section to the boxed warnings in the labeling of its atypical antipsychotic, Clozaril (clozapine). In addition, the entire boxed-warnings section has been moved to the front of the labeling insert in an effort to emphasize the relative dangers of prescribing the drug.The new section warns prescribers of the increased risk of patients on clozapine developing a potentially fatal myocarditis, most commonly in the initial three to six weeks of drug therapy. FDA officials said that the added warning further strengthens the recommendation that clozapine therapy be reserved for those patients whose schizophrenia has proven refractory to other approved treatments.Overall, according to postmarketing surveillance data from four countries, 82 cases of myocarditis have been reported in patients receiving clozapine. They have resulted in 31 deaths—a 38 percent mortality rate.The established incidence of myocarditis, according to the data, is 0.3 cases per 100,000 patient years of exposure to clozapine, with a fatality rate of 0.2 cases for 100,000 patient years. Although the incidence of myocarditis varies greatly between subgroups of the general population—for example, between children and the elderly—these rates represent an incidence among those taking clozapine of at least 17 times greater than the average of the overall general population and a mortality rate of at least 14 times greater than the general population.According to cardiologists consulted by Psychiatric News, the development of myocarditis may be difficult to diagnose in patients with schizophrenia who are being treated with clozapine.First of all, myocarditis in general presents with variable and usually vague symptoms. Most commonly patients have tachycardia, which has also been associated with patients on the drug who have no signs of myocarditis. Patients may experience palpitations. In patients whose heart muscle is inflamed, corresponding fatigue that is otherwise unexplained and shortness of breath are also common. Some patients may experience an atypical, hard-to-describe chest pain that could be referred to as dull, constant, or heavy. Fever, usually low grade, is often present, but may be entirely absent.In addition, cardiologists told Psychiatric News that patients with myocarditis may have an elevated white blood count and/or elevated erythrocyte sedimentation rate (ESR) and often show an enlarged cardiac silhouette on a chest X-ray. Some patients’ electrocardiograms may show nonspecific ST-T wave abnormalities.According to the new labeling, because tachycardia is the most common presenting symptom of myocarditis, patients who develop increased heart rates during the first month of clozapine therapy should be monitored closely for any other signs of developing myocarditis. If suspicion of myocarditis arises, clozapine should be discontinued immediately and a complete cardiac evaluation sought.Patients who develop clozapine-related myocarditis should not be restarted on the drug once the myocarditis resolves as postmarketing data also revealed the majority of cases recur upon reinitiation of the drug.Novartis and the FDA are urging psychiatrists to report any and all adverse events in patients taking clozapine to either the company’s surveillance program or the FDA’s MedWatch program, regardless of whether a direct connection to the medication is suspected.Adverse events in patients taking clozapine should be reported to Novartis (for those taking the Clozaril brand) at (800) 448-5938 or online at www.novartis.com. Reports involving both the Novartis brand and the available generic may be reported to the FDA’s MedWatch program by phone at (800) FDA-1080, by fax at (800) FDA-0178, or on the Web at www.accessdata.fda.gov/scripts/medwatch. ▪ ISSUES NewArchived