clozapine and Myocarditis

Due to its unique efficacy in treatment-resistant schizophrenia, discontinuation of treatment with clozapine is frequently associated with a significant worsening of symptoms, but also with an increased risk of suicide. Based on the literature, this review aims at summarizing different monitoring recommendations in order to be able to continue this therapy despite the occurrence of side effects. In addition, we provide recommendations when rechallenge of a previously stopped treatment with clozapine can be considered and when a definite discontinuation must take place.. Medline, the Guideline for the use of clozapine 2013 of the Netherlands Clozapine Collaboration Group, and the S3 Guideline for Schizophrenia of the German Association of Psychiatry, Psychotherapy and Psychosomatics were searched for relevant literature, the last query dating from April 28th, 2023.. If agranulocytosis or cardiomyopathy develops, treatment with clozapine must be discontinued and should not be resumed thereafter. In contrast, treatment with clozapine which had to be discontinued due to myocarditis or prolongation of the QTc interval may be continued if left ventricular function is normal or after normalization of the QTc interval. Other side effects are usually not absolute contraindications for rechallenge but often require the adjunctive use of additional pharmacologic and non-pharmacologic measures.. Taking into consideration various monitoring recommendations, cessation of treatment with clozapine can often be prevented or treatment with clozapine that has been discontinued due to side effects can be resumed.. HINTERGRUND: Auf Grund seiner unvergleichbaren Wirksamkeit bei therapieresistenten schizophrenen Störungen ist der Abbruch einer Behandlung mit Clozapin häufig mit einer erheblichen Verschlechterung der Krankheitssymptomatik, aber auch mit einem erhöhten Suizidrisiko verbunden. Ziel der vorliegenden Übersichtsarbeit ist es, auf Basis aktueller Fachliteratur verschiedene Monitoring-Empfehlungen zusammen zu fassen, um diese Therapie gegebenenfalls trotz auftretender unerwünschter Arzneimittelwirkungen (UAW) fortsetzen zu können. Des Weiteren wird ausgearbeitet, wann eine unterbrochene Therapie mit Clozapin wieder aufgenommen werden kann (Rechallenge) und wann ein definitiver Behandlungsabbruch erfolgen muss.. Die Datenbank Medline sowie die Guideline for the use of clozapine 2013 der Netherlands Clozapine Collaboration Group und die S3-Behandlungsleitlinie Schizophrenie der Deutschen Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde e.V. wurden nach relevanter Literatur untersucht, die letzte Abfrage erfolgte am 28.04.2023.. Bei Entwicklung einer Agranulozytose oder einer Kardiomyopathie muss die Behandlung mit Clozapin beendet werden und sollte auch im weiteren Verlauf nicht wieder aufgenommen werden. Dem gegenüber kann eine auf Grund einer Myokarditis bzw. einer unter der Behandlung auftretenden Verlängerung der QTc-Zeit abgebrochene Behandlung mit Clozapin bei regelrechter linksventrikulärer Funktion bzw. nach Normalisierung der QTc-Zeit gegebenenfalls fortgesetzt werden. Andere UAW stellen in der Regel keine absolute Kontraindikation für eine Rechallenge dar, erfordern jedoch häufig den adjuvanten Einsatz zusätzlicher pharmakologischer und nicht-pharmakologischer Maßnahmen.. Unter Berücksichtigung verschiedener Monitoring-Empfehlungen kann die Beendigung einer Behandlung mit Clozapin häufig verhindert bzw. eine auf Grund von UAW abgebrochene Behandlung mit Clozapin wieder aufgenommen werden.

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis; Psychotherapy; Schizophrenia

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.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Schizophrenia

Clozapine is the most effective medication for treatment-refractory schizophrenia, but it is associated with severe cardiac adverse events including myocarditis and cardiomyopathy. To aid treatment decision-making for clinicians, patients and their carers, we conducted a systematic review and meta-analysis to identify potential risk factors for clozapine-induced myocarditis and cardiomyopathy.. A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and cardiomyopathy among people on clozapine and potential risk factors. We calculated pooled effect sizes on risk factors using a random-effects meta-analytic model. Risk of publication bias was assessed using the Newcastle-Ottawa scale.. Seven studies met the inclusion criteria, of which six studies had quantitative data included in the meta-analysis. The odds of clozapine-induced myocarditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled OR 3.58, 95% CI 1.81-7.06), but were not significantly greater with the use of quetiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review identified conflicting results reported for increasing age and higher clozapine dose as risk factors for myocarditis. No other factors, including genetic risk, sex, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were associated with greater odds of myocarditis. No risk factors for cardiomyopathy were identified in the literature.. Concurrent use of sodium valproate increases the odds of clozapine-induced myocarditis. Thus, clinicians should consider the temporary cessation of sodium valproate during the initial titration phase of clozapine.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Myocarditis; Risk Factors; Valproic Acid

Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs.. PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles.. Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3 months, and almost all appear within 6 months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000 μg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000 μg/L.. Clozapine ADEs rarely require discontinuation.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Neutropenia; Seizures

BACKGROUND Myocarditis is cardiac muscle inflammation caused by infectious or noninfectious agents. Rarely, clozapine, an atypical antipsychotic drug used to treat resistant schizophrenia, has been reported to cause myocarditis, as we report in this case. CASE REPORT A 29-year-old man, who was known to have schizophrenia and was on olanzapine therapy, presented in our Emergency Department with active psychosis, and was subsequently admitted to the psychiatric ward for refractory schizophrenia. He was started on clozapine, which was cross-titrated with olanzapine. On day 20 of being treated with clozapine, he developed a high-grade fever and chest pain. EKG demonstrated new-onset prolonged QT corrected for heart rate (QTc), premature ventricular contractions, ST-T wave changes with an increased ventricular rate, and ventricular bigeminy with elevated troponin and inflammatory markers. Echocardiography showed a reduced left ventricular ejection fraction. Coronary angiography showed normal coronary arteries, low cardiac output, and cardiac index consistent with cardiogenic shock was also observed. Other pertinent laboratory results included negative respiratory viral panel, including COVID-19 PCR, negative blood cultures, and negative stool screen for ova and parasite. Clozapine was discontinued and the patient received management for heart failure with reduced ejection fraction. He improved clinically with return of EKG to normal sinus rhythm and improved left ventricular ejection fraction on repeat echocardiogram. CONCLUSIONS Acute myocarditis can occur due to a myriad of causes, both infectious and noninfectious; thus, determining the lesser-known causes, such as drug-related etiology, is essential to provide appropriate treatment for patients.

Topics: Adult; Clozapine; COVID-19; Humans; Male; Myocarditis; Olanzapine; Schizophrenia; Schizophrenia, Treatment-Resistant; Stroke Volume; Ventricular Function, Left

Clozapine was synthesized in 1958. The Food and Drug Administration approved it in 1989 when comprehensive pharmacokinetic studies were not required and it was not known that clozapine was metabolized by the cytochrome P450 1A2 (CYP1A2). Currently it is known that clozapine personalized dosing may be influenced by one's DNA ancestry (African, European and/or Asian/Indigenous American), sex/smoking subgroup, and the presence/absence of genetic/non-genetic poor metabolizer (PM) status. The literature does not properly reflect the concept of "clozapine-induced inflammation" during rapid titration. Elaborating upon this concept, this historical review discusses: 1) clozapine-induced fever, 2) the effects of inflammation on clozapine metabolism, 3) clozapine-induced myocarditis, 4) other clozapine-induced inflammations, 4) current support for "clozapine-induced inflammation" as a hypersensitivity reaction, 5) the difficulty in addressing such a concept to a readership with diverse beliefs about it and 6) the limitations of this review in convincing skeptics. Clozapine-induced fever in the absence of any concomitant infection was first described in 1972 and is a mild form of "clozapine-induced inflammation" during rapid titration, which also includes myocarditis and other localized inflammations. They may be part of a hypersensitivity reaction that has 3 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 is a clozapine PM. 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 auto-immune phenomenon leading to localized inflammation. Skeptical readers are challenged to try: 1) 6 titrations proposed for stratified dosing and 2) c-reactive protein (CRP) monitoring for personalized dosing in the absence of genetic testing for clozapine PM status.

Topics: Antipsychotic Agents; C-Reactive Protein; Clozapine; Cytochrome P-450 CYP1A2; Cytokines; Humans; Inflammation; Myocarditis

Clozapine-induced myocarditis in children (age ≤18 yo) was studied from a PubMed search (18 July 2022) (9 cases) and from the World Health Organization's pharmacovigilance database, called Vigibase, of adverse drug reaction (ADR) reports (72 non-duplicated cases). VigiBase uses a logarithmic measure of disproportionality called the information component (IC). A logistic regression model of presence/absence (40/32) of seriousness in VigiBase was developed.. VigiBase provided a significant myocarditis IC = 4.2 with an IC. These 41 cases of at least possible clozapine-induced myocarditis indicated that this ADR can definitively occur in children, particularly in the first 30 days of up-titration. Children's and adult cases appeared similar.

Topics: Adolescent; Australia; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Pharmacovigilance

Clozapine is underutilized due, in part, to concerns about rare but severe adverse drug reactions, including cardiac inflammation and injury (myocarditis). Risk factors for clozapine-induced myocarditis are limited and predictors for the successful rechallenge of clozapine after an episode of myocarditis are even more poorly understood. We conducted a systematic review, in accordance with the PRISMA recommendation, of published case reports to describe demographic and clinical characteristics of patients with clozapine-induced myocarditis and identify potential markers of clozapine rechallenge success. A total of 180 cases from 88 articles were evaluated. Male cases of clozapine-associated myocarditis were more frequently reported than female cases by a ratio of 6:1. Less than half of patients reported the presence of chest pain (35%) or flu-like symptoms (43%) but increases in troponin or C-reactive protein were present in 87% of cases. Clozapine rechallenge was carried out in 34 (2 female) cases, with successful reintroduction in 22 (2 female) cases (64.7%) and one fatality (2.9%). No demographic or clinical markers were significantly associated with rechallenge success after correction for multiple testing. Standardized reporting of clozapine-induced myocarditis cases is needed to facilitate the identification of factors associated with successful rechallenge.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Myocarditis; Schizophrenia

Clozapine is the most effective medication for treatment refractory schizophrenia, but is associated with cardiac adverse drug reactions. Myocarditis and cardiomyopathy are the most serious cardiac adverse drug reactions although reported rates of these conditions vary in the literature. We systematically reviewed and meta-analysed the event rates, the absolute death rates and case fatality rates of myocarditis and cardiomyopathy associated with clozapine.. PubMed, EMBASE and PsycINFO were searched for studies that reported on the incidence of cardiomyopathy or myocarditis in people exposed to clozapine. Data were meta-analysed using a random effects model, with subgroup analysis on study size, time frame, region, quality, retrospective vs prospective, and diagnostic criteria of myocarditis or cardiomyopathy.. 28 studies of 258,961 people exposed to clozapine were included. The event rate of myocarditis was 0.007 (95% confidence interval [CI] = [0.003, 0.016]), absolute death rate was 0.0004 (95% CI = [0.0002, 0.0009]) and case fatality rate was 0.127 (95% CI = [0.034, 0.377]). The cardiomyopathy event rate was 0.006 (95% CI = [0.002, 0.023]), absolute death rate was 0.0003 (95% CI = [0.0001, 0.0012]) and case fatality rate was 0.078 (95% CI = [0.018, 0.285]). Few included studies provided information on criteria for diagnosis of myocarditis and cardiomyopathy. Event rates of cardiomyopathy and myocarditis were higher in Australia.. Clarity of diagnostic criteria for myocarditis remains a challenge. Observation bias may, in part, influence higher reported rates in Australia. Monitoring for myocarditis is warranted in the first 4 weeks, and treatment of comorbid metabolic syndrome and diabetes may reduce the risk of cardiomyopathy. The risks of myocarditis and cardiomyopathy are low and should not present a barrier to people with treatment refractory schizophrenia being offered a monitored trial of clozapine.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Myocarditis; Prospective Studies; Retrospective Studies

To review the published literature on clozapine associated cardiotoxicity (CACT), summarize diagnostic features, and evaluate monitoring procedures for safe clozapine re-challenge.. Clozapine-associated Myocarditis (CAM) - Incidence of early myocarditis (≤2 months) is infrequent but serious. Clinical diagnosis is confounded by variability in presentation and non-specificity of symptoms. Re-challenge considerations include clozapine impact on symptomatic severity and associated disability and risk of suicidality. Re-challenging is recommended only after full clinical resolution of myocarditis and cardiac function impairment, under closely controlled conditions, starting at very low dosage, extremely slow titration and frequent assays of lab and cardio biomarkers. Clozapine associated cardiomyopathy (CAC) -develops later but mortality has been reported at 12.5-24.0%. Re-challenge is generally not recommended due to paucity of outcome data. Monitoring Cardiac Toxicity: Plausible steps include closer clinical monitoring, repeated assays of biomarkers, and echocardiographic studies, and cardiac MRI changes with unremarkable findings of cardiac dysfunction with echocardiography. Subclinical clozapine associated cardiotoxicity is more prevalent than CAM and CAC. Diagnosis is often challenging due to non specific presentation. Active monitoring is recommended. Rechallenging is feasible but should be done under close monitoring conditions. A protocol is proposed based on literature review and clinical experience in order to reduce the risk of CACT.. Clozapine-associated myocarditis and cardiomyopathy may have been underreported worldwide. Identification of subclinical cardiotoxic effects can improve outcomes by earlier recognition before clinical manifestations of cardiac impairments. A pragmatic close clinical monitoring protocol including cardiac biomarkers aimed at timely detection of cardiac toxicity, in the initial phase of treatment is proposed.

Topics: Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Humans; Myocarditis; Schizophrenia

This review discusses the rare but potentially life-threatening cardiovascular side-effects of myocarditis and dilated cardiomyopathy associated with the use of Clozapine. The clinical presentation of these conditions is non-specific, making it difficult to both risk-stratify and identify patients who develop these consequences. This review aims to examine the proposed aetiologies, diagnostic approaches and subsequent management strategies of cardiotoxicity associated with clozapine use; offering guidance to psychiatrists and general physicians. Current evidence highlights the importance of accurate diagnosis to prevent premature and unnecessary cessation of clozapine. Guidance on monitoring and reintroduction of the drug is emerging and current practice recommends a combination of regular monitoring of biomarkers and imaging to make a diagnosis of cardiotoxicity although further work is needed to establish evidence-based guidelines.

Topics: Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Humans; Myocarditis; Psychiatry

To identify the clinical determinants of fever in clozapine users and their impact on management of clozapine treatment.. Articles published in English or French identified with a MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search, from inception through February 2019, using the term "clozapine" in combination with "fever" OR "hyperthermia" OR "body temperature" OR "pyrexia" OR "febrile" OR "heat" OR "thermoregulation". Information extracted for each medical condition were frequency, time to onset after initiation of clozapine treatment, characteristics of fever, associated symptoms, laboratory tests used for diagnosis, course, lethality, discontinuation of clozapine. Data were synthesized narratively.. Our search yielded 394 unique hits published from 1993 to 2018. We included 73 articles in the review: two meta-analyses, 14 reviews, six epidemiological studies, 11 clinical studies and 40 case reports. During clozapine initiation, fever is most frequently benign and transient but should be closely monitored as it may be the first stage of potentially life-threatening adverse drug reactions (ADR) (agranulocytosis, neuroleptic malignant syndrome myocarditis, hepatitis, pancreatitis, nephritis, colitis, etc.). Other ADR associated with fever are independent of duration of exposure to clozapine (heat stroke, pneumonia, pulmonary embolism, necrotizing colitis). If fever is due to intercurrent infection, therapeutic drug monitoring is recommended to adjust clozapine daily dosage.. Benign causes of fever are much more frequent than life-threatening ADR during clozapine treatment. Discontinuation should not be considered as automatic in the event of fever, especially during the early phase of clozapine initiation.

Topics: Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Colitis; Dose-Response Relationship, Drug; Drug Monitoring; Fever; Hepatitis; Humans; Infections; Lupus Erythematosus, Systemic; Myocarditis; Nephritis; Neuroleptic Malignant Syndrome; Pancreatitis; Pneumonia; Pulmonary Embolism; Schizophrenia; Serositis

Clozapine has been shown to be the most efficacious therapy for treatment resistant schizophrenia, estimated at one third of all schizophrenia cases. There is significant morbidity and mortality associated with clozapine including risk of agranulocytosis, aspiration pneumonia, bowel ischemia, myocarditis, seizures, and weight gain. Here we present a case of a 62-year-old man with chronic paranoid schizophrenia refractory to numerous antipsychotics who was started on clozapine therapy during an acute inpatient psychiatric admission. Within three weeks of starting clozapine, the patient developed flu-like symptoms, pleuritic chest pain, and was sent to a medical hospital for evaluation. After transfer, the patient had a rapidly deteriorating course with newly developed congestive heart failure, acute respiratory failure requiring intubation, and cardiovascular collapse requiring vasopressors. The patient expired within two days of transfer and four days after initial symptoms developed. The underlying etiology in this case is likely clozapine induced myocarditis leading to rapid cardiovascular collapse and death. Mortality with clozapine induced myocarditis has been estimated up to 24%. Given that 90% of clozapine cardiotoxic sequelae are seen in the first month post-initiation, more rigorous post-initiation surveillance is recommended for the first four weeks of clozapine with weekly cardiac enzymes (troponins, creatinine kinase-MB), EKG, and acute inflammatory markers (C-reactive protein, and erythrocyte sedimentation rate).

Topics: Antipsychotic Agents; Clozapine; Fatal Outcome; Humans; Male; Middle Aged; Myocarditis; Schizophrenia, Paranoid

The use of clozapine requires monitoring the absolute neutrophil count because of the risk of agranulocytosis, but other potentially fatal adverse events associated with clozapine (specifically, myocarditis and cardiomyopathy) do not have mandatory procedures. We performed a systematic review of English-language articles to synthesize an evidence-based approach for myocarditis and cardiomyopathy monitoring. Articles published from January 1988 through February 2017 were identified through a search of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Google Scholar. Selected articles were required to relate to myocarditis or cardiomyopathy in humans from exposure to clozapine. A total of 144 articles were included. Recommendations varied widely. Some authors recommended baseline laboratory monitoring, with or without follow-up testing, for C-reactive protein, creatine kinase MB, and troponin. Electrocardiography was commonly recommended, and echocardiography was less commonly recommended. The expense of monitoring was a consideration. A unanimous recommendation was to stop the use of clozapine and seek a cardiovascular consultation if myocarditis or cardiomyopathy is suspected. Although there is general agreement on which tests to perform for confirming myocarditis and cardiomyopathy, preemptive screening for these clozapine-induced conditions is controversial, and cost and barriers for the use of clozapine are concerns. For asymptomatic patients receiving clozapine, testing could include baseline electrocardiography, echocardiography as part of a cardiac consultation if patients have cardiac disease or risk factors, and monitoring of C-reactive protein and troponin as indicated.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Monitoring, Physiologic; Myocarditis; Schizophrenia

Clozapine is an atypical antipsychotic that is beneficial to some patients who failed to have an adequate clinical response to other antipsychotic drugs. Its clinical use is limited due to several potentially fatal adverse reactions including myocarditis. Careful monitoring of patients on clozapine is required.. We conducted a systematic review of the literature on myocarditis associated with clozapine therapy. The search engines used to identify cases were MEDLINE, EMBASE, PsycINFO and Cochrane reviews. The references included in the manuscripts reviewed were searched to identify additional reports.. We identified a total of 3347 articles that addressed the cardiac complications of clozapine. Of these, 82 articles detailed cases of clozapine-induced myocarditis. The median age of patients and dose of clozapine at presentation was 30years and 250mg/day respectively. Symptoms and signs of myocarditis developed in 87% of patients within the first month of treatment. Clinical presentation included: shortness of breath (67%), fever (67%) and tachycardia (58%). Cardiac markers were elevated in 87% of the 54 cases that reported these markers. Global ventricular dysfunction was the predominant echocardiogram finding (57%).. Patients on clozapine require routine monitoring for symptoms and signs of myocarditis during the first three months of therapy. This adverse drug reaction is difficult to diagnose due the non-specific nature of the symptoms and signs. Alternate causes of myocarditis should be ruled out before attributing the myocarditis to clozapine.

Topics: Antipsychotic Agents; Clozapine; Echocardiography; Humans; Myocarditis

Myocarditis occurs in about 3% of those initiated on clozapine but monitoring reduces the risk of serious outcome. Cardiomyopathy may develop after myocarditis, or from prolonged tachycardia. Monitoring using echocardiography is not deemed cost effective. Tachycardia, orthostatic hypotension and reduced heart rate variability are a group of clozapine-related adverse effects associated with autonomic dysfunction and may have serious consequences in the long term. Elevated heart rate and poor heart rate variability can be treated with a β-blocker or a non-dihydropyridine calcium channel blocker, while orthostatic hypotension can be alleviated by increased fluid intake and abdominal binding, but may require pharmacological intervention. Adequate correction for heart rate may show that clozapine does not prolong the QT interval. Other cardiovascular effects, pulmonary embolism, metabolic syndrome, sudden cardiac death and particularly the excessive mortality from cardiovascular disease events may be more strongly associated with the combination of mental illness, lifestyle factors and poor treatment of cardiovascular disease and its risk factors than with clozapine treatment. In view of the efficacy of clozapine and the evidence of reduced mortality relative to other antipsychotics, clozapine should be prescribed when indicated and recipients should be enrolled in lifestyle programmes to increase exercise and improve diet, and referred for diagnosis and treatment of cardiovascular disease and its risk factors.

Topics: Antipsychotic Agents; Cardiomyopathies; Cardiovascular Diseases; Clozapine; Drug Monitoring; Humans; Life Style; Myocarditis; Risk Factors

Patients with schizophrenia die on average 25 years earlier than the general population, and this gap appears to be increasing. Most of the excess mortality is due to premature cardiovascular deaths rather than suicide. Many psychotropic agents are orexigenic and can increase weight and promote dyslipidaemia. Traditional cardiac risk factors are undertreated among patients with schizophrenia, and they are less likely to receive cardiac revascularisation than those without a mental illness. Clozapine is an atypical antipsychotic medication effective for treatment of refractory schizophrenia, but is associated with the risk of myocarditis and cardiomyopathy. Established protocols in Australia screen for myocarditis for patients who are initiating clozapine therapy and for long term monitoring for cardiomyopathy with echocardiography. Coordinated care between tertiary providers, general practitioners and primary health care professionals should monitor the physical health of people with psychosis or schizophrenia at least annually and treatment should be offered accordingly.

Topics: Antipsychotic Agents; Australia; Cardiomyopathies; Cardiovascular Diseases; Clozapine; Delivery of Health Care; Echocardiography; Humans; Mass Screening; Mental Health Services; Metabolic Syndrome; Myocarditis; Risk Factors; Schizophrenia

Topics: Antipsychotic Agents; Australia; Clozapine; Cost-Benefit Analysis; Drug Utilization; Echocardiography; Female; Health Care Costs; Humans; Male; Myocarditis; Practice Patterns, Physicians'; Risk Assessment; Schizophrenia; Severity of Illness Index; Unnecessary Procedures

Topics: Antipsychotic Agents; Clozapine; Heart; Humans; Male; Myocarditis; Psychotic Disorders; Young Adult

We review the published cases of clozapine-induced myocarditis and describe reasons for the higher incidence in Australia (>1%) than elsewhere (<0.1%).. Medline was searched to September 2014 using 'clozapine' as the sole term.. A total of around 250 cases of clozapine-induced myocarditis have been published. Fever among patients commencing clozapine has been reported internationally, and very few of these cases were investigated for myocarditis. The time to onset of fever is consistent with its being part of a prodrome of undiagnosed myocarditis, and the risk factors are similar to those for myocarditis. In more severe cases, clozapine is discontinued, avoiding fatalities which may occur with myocarditis. Furthermore, cases of sudden death and respiratory illness may well have been undiagnosed myocarditis. The diagnosis of myocarditis is confounded by the non-specific nature of the signs and symptoms, and it depends on appropriate investigations being conducted at the time of myocardial involvement or, for fatal cases, the affected area of the myocardium being sampled for histology.. It is likely that the incidence of myocarditis is around 3%. Implementation of monitoring procedures will increase case ascertainment and result in more patients benefiting from this valuable medication.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Australia; Clozapine; Female; Humans; Incidence; Male; Middle Aged; Myocarditis; Risk Factors; Young Adult

Clozapine is widely prescribed for treatment refractory patients with schizophrenia, but its use is limited by potentially life threatening adverse effects. Rechallenge after these complications has been occasionally attempted in patients with severe psychotic symptoms.. To review the outcome of clozapine rechallenge after potentially life threatening adverse effects.. Electronic, all-language, literature search (1972-2011) followed by demographic and clinical data extraction. The outcome of rechallenge was considered favorable when the lower bound of the 95% confidence interval (CI) of the proportion of patients who could continue clozapine was >50%.. Altogether, 138 patients (mean age: 36.3years, 65.7% male, 57.6% Caucasian, virtually all with schizophrenia spectrum diagnosis) underwent clozapine rechallenge after developing neutropenia (n=112), agranulocytosis (n=15), neuroleptic malignant syndrome (NMS) (n=5), myocarditis (n=4), pericarditis (n=1) and lupus erythematosus (n=1). Rechallenge strategies were heterogeneous and not systematically evaluated. Clozapine rechallenge was successful in 78/112 patients (69.6%, CI: 60.6-77.4) after neutropenia, 3/15 (20%, CI: 7.1-45.2) after agranulocytosis, 5/5 (100%, CI: 56-100) after NMS, 3/4 (75%, CI: 30-95) after myocarditis, 1/1 after pericarditis, and 0/1 after clozapine-induced lupus. Successfully rechallenged patients were followed for 16-96weeks. None of the rechallenged patients died.. Although controlled studies are clearly needed, using a priori, confidence interval-based criteria, case reports/series suggest that in refractory patients who benefited from clozapine, careful rechallenge can be considered after neutropenia and NMS, but not after agranulocytosis and myocarditis.

Topics: Adult; Antipsychotic Agents; Clozapine; Databases, Bibliographic; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Myocarditis; Neuroleptic Malignant Syndrome; Neutropenia; Young Adult

Clozapine, an atypical antipsychotic, is a dibenzodiazepine derivative and its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. In accordance to several studies, it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia. Moreover, clozapine appears to be particularly beneficial in patients with schizophrenia who are suicidal and in those with comorbid substance use disorder. However, despite its efficacy, the general use of clozapine in clinical practice is somewhat limited because of the risk of several serious adverse effects such as agranulocytosis and thromboembolism. Clozapine may be associated with fatal myocarditis and cardiomyopathy in physically healthy young adults. Consequently, the FDA and the drug's manufacturer have strengthened warnings to include that a potentially fatal myocarditis may occur when taking clozapine. In the present paper the literature on clozapine-related myocardis will be reviewed and practical advice will be given concerning the diagnosis and management of such potentially fatal adverse effect.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Drug Labeling; Humans; Myocarditis; Schizophrenia; United States; United States Food and Drug Administration

Clozapine is often referred to as the gold standard for the treatment of schizophrenia and yet has also been described as the most underutilized treatment for schizophrenia supported by solid evidence-based medicine. In 2008, it was used to treat only 4.4% of patients with schizophrenia in the U.S., which is ~10-20% of those with approved indications for clozapine for which there is no alternative of equal efficacy. Its use is much higher in Scandinavian countries and China. The primary indications for clozapine are: 1) treatment-resistant schizophrenia or schizoaffective disorder, defined as persistent moderate to severe delusions or hallucinations despite two or more clinical trials with other antipsychotic drugs; and, 2) patients with schizophrenia or schizoaffective disorder who are at high risk for suicide. Concerns over a number of safety considerations are responsible for much of the underutilization of clozapine: 1) agranulocytosis; 2) metabolic side effects; and, 3) myocarditis. These side effects can be detected, prevented, minimized and treated, but there will be a very small number of fatalities. Nevertheless, clozapine has been found in two large epidemiologic studies to have the lowest mortality of any antipsychotic drug, mainly due to its very large effect to reduce the risk for suicide. Other reasons for limited use of clozapine include the extra effort entailed in monitoring white blood cell counts to detect granulocytopenia or agranulocytosis and, possibly, minimal efforts to market it now that it is largely generic. Awareness of the benefits and risks of clozapine is essential for increasing the use of this lifesaving agent.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Metabolic Diseases; Myocarditis; Risk Factors; Schizophrenia

Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based.. The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected.. 16 studies that provided incidence rates or data from which these rates could be calculated were included.. We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate.. The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect.. In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

Topics: Agranulocytosis; Clozapine; Constipation; Diabetic Ketoacidosis; Humans; Incidence; Leukocyte Count; Mass Screening; Myocarditis; Practice Guidelines as Topic

Treatment with clozapine can affect the heart, leading to serious complications such as myocarditis and cardiomyopathy. When in their early stages both illnesses are difficult to diagnose; this can have serious consequences. Recent analyses of clozapine data suggest that particularly myocarditis is possibly more common than has been assumed hitherto.. To determine the frequency of these complications and to find out what diagnostic tests are available and whether it is necessary or possible to adjust current guidelines on these complications.. The relevant literature was consulted via PubMed, Embase Psychiatry and Psycinfo on the basis of the keywords 'clozapine' and 'myocarditis', 'cardiomyopathy' and 'heart failure'.. Studies showed that the incidence of myocarditis varied from 0.015 to 1.3%. Cardiomyopathy was the subject of fewer studies, one study reported an incidence of 0.022%. More than 50% of the cases of myocarditis developed during the first few weeks of treatment, the average time being about 15 days. For an early diagnosis it is important to monitor the patient's symptoms carefully, especially during the first four weeks following the start of medication. Monitoring should include laboratory tests and electrocardiography. Echocardiography and MRI can be useful additions to the diagnostic process.. Early diagnosis of myocarditis is important because it is a serious condition. Timely recognition of subclinical myocarditis could possibly prevent later complications such as cardiomyopathy. Clinical guidelines are proposed on the basis of the literature.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Female; Humans; Male; Middle Aged; Myocarditis; Prevalence; Psychotic Disorders

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Brain; Cardiomyopathies; Child; Clozapine; Dyskinesia, Drug-Induced; Energy Metabolism; Feeding Behavior; Female; Gene Expression; Genetic Association Studies; Humans; Male; Myocarditis; Olanzapine; Pericarditis; Risperidone; Tourette Syndrome; Twin Studies as Topic; Weight Gain

Clozapine was the first atypical 'broad spectrum' antipsychotic drug to be marketed and the first agent approved for the treatment of schizophrenia refractory to other medications. It is also effective for the treatment of aggressive behaviour in schizophrenic and demented patients and in the management of psychosis and aggression in Parkinson's disease and Lewy body dementia.. The aim of this review is to study the safety of clozapine for use in elderly patients.. An extensive Medline search was made. Some studies that were referenced in reports from our pharmacovigilance centre and from regulatory agencies such as the FDA, EMEA and WHO were included.. Clozapine treatment in the elderly requires a careful geriatric assessment. However, its use is strongly limited by the possibility of onset of severe adverse effects such as potentially fatal agranulocytosis, myocarditis and others such as seizures, weight gain and metabolic adverse effects.

Topics: Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Geriatric Assessment; Humans; Mental Disorders; Myocarditis; Parkinson Disease

Clozapine is an antipsychotic medication associated with a lower suicide rate compared with other antipsychotic agents. Clozapine is used specifically in patients for whom previous therapy was inadequate or not tolerated, and is the only antipsychotic agent associated with the development of myocarditis.. To retrospectively review all adverse drug reaction reports voluntarily submitted to the Australian Adverse Drug Reactions Unit mentioning suspected myocarditis in clozapine-treated patients.. We accessed all electronic database entries and case reports citing suspected myocarditis associated with clozapine therapy from January 1993 through to December 2003, inclusive.. 116 case reports of suspected myocarditis amongst clozapine-treated patients were identified during the specified time frame (incidence between 0.7% and 1.2% of treated patients). Median patient age for these cases was 30 years (SD 11.1 years) compared with 37 years from the Clopine registry. The condition developed within a median 16 days (mean 19.8 days; SD 17.3 days) of commencing clozapine for the bulk of patients developing myocarditis within 6 months (n=93, 80.2%). For all cases with known treatment commencement and cessation dates (n=106), the condition developed within a median 17 days (mean 171.7 days, SD 530.9 days). Over nine-tenths of cases were prescribed clozapine within the dose range of 100 mg/day to 450 mg/day. Sixty patients (51.8%) recovered from their episode when reported or during follow-up reports, whereas 17 patients (14.7%) had not yet recovered: 27 patients (23.3%) had unknown outcome when reported and the remaining 12 patients (10.3%) died.. Clozapine is uncommonly but importantly related to myocarditis, often fatal or near fatal and sometimes in relatively young patients with early onset after treatment initiation. The most striking feature about this condition is the wide diversity of nonspecific symptoms that occur in afflicted patients. Additional pharmacovigilance, improved reporting systems and further investigation of mechanisms of drug-induced myocarditis and related cardiovascular conditions (such as heart failure) are clearly warranted. A case-control study would be suitable for investigation of baseline predictors.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Australia; Clozapine; Female; Humans; Male; Middle Aged; Myocarditis

To review the published literature on serious adverse cardiac events associated with the atypical antipsychotic agent, clozapine, and to make recommendations for cardiac assessment of candidates for clozapine treatment and for monitoring of cardiac status after treatment is initiated.. We searched the PubMed and MEDLINE databases for articles published from 1970 to 2004 that contain the keywords "clozapine and myocarditis," "clozapine and cardiomyopathy," "clozapine and cardiotoxicity," "clozapine and sudden death" or "clozapine and mortality." We also manually searched the bibliographies of these articles for related sources.. We reviewed the 30 case reports, case series, laboratory and clinical trials, data mining studies, and previous reviews identified by this search.. Recent evidence suggests that clozapine is associated with a low (0.015% to 0.188%) risk of potentially fatal myocarditis or cardiomyopathy. The drug is not known to be independently associated with pathologic prolongation of the QTc interval, but it may contribute to pathologic QTc prolongation in patients with other risk factors for this condition.. The low risk of a serious adverse cardiac event should be outweighed by a reduction in suicide risk for most patients taking clozapine. We provide recommendations for assessing and monitoring cardiac status in patients prior to and after initiation of treatment with clozapine.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Death, Sudden, Cardiac; Heart Diseases; Humans; Myocarditis

Clozapine is known to cause cardiac side-effects, including myocarditis, pericarditis and cardiomyopathy. Prompted by a case of clozapine-related pericarditis in our hospital we undertook a review of the literature for reports of myocarditis, pericarditis and cardiomyopathy occurring in patients treated with clozapine. This is the first comprehensive review of the literature on this topic.

Topics: Cardiomyopathies; Clozapine; Humans; Myocarditis; Pericarditis

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Diabetes Mellitus; Humans; Muscle, Skeletal; Myocarditis; Neutropenia; Psychotic Disorders; Risk Factors; Seizures; Weight Gain

Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings.. A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached.. Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations.. The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Cataract; Clozapine; Diabetes Mellitus, Type 2; Health Status; Humans; Hyperlipidemias; Hyperprolactinemia; Long QT Syndrome; Monitoring, Physiologic; Myocarditis; Obesity; Practice Guidelines as Topic; Schizophrenia; Sexual Dysfunctions, Psychological; Weight Gain

The pharmacotherapy of schizophrenia remains an ongoing challenge for researchers and clinicians alike. Current medications remain suboptimal to effectively treat this illness despite the recent surge of what are considered to be better antipsychotics: the atypicals. The atypicals cause fewer extrapyramidal symptoms and tardive dyskinesia, but there is growing concern regarding the significant long-term metabolic and cardiac adverse effects of these novel antipsychotics. There are differences among the atypicals in their propensity to produce these adverse effects, and clinicians should weigh the risk-benefit ratio for each drug with each individual patient. Diabetes, heart disease, obesity, and unhealthy lifestyle choices are on the rise in the general population, and individuals with chronic schizophrenia are even more at risk. The dilemma clinicians face in trying to avoid the neurological morbidity of the typicals (extrapyramidal side effects and tardive dyskinesia) is the risk of consequently exposing patients to both the morbidity and potential mortality of the atypicals (cardiovascular, endocrine, and metabolic adverse effects). The importance of baseline investigations and monitoring at regular intervals as well as identification of patients at risk for obesity, diabetes, and cardiovascular morbidity has become crucial. Informed decision making is essential for successful antipsychotic pharmacotherapy. For a condition, which often necessitates long-term pharmacotherapy, the importance of prevention and (or) minimization of morbidity and mortality related to adverse effects of such pharmacotherapy cannot be understated.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Diabetes Mellitus; Humans; Hyperlipidemias; Long QT Syndrome; Myocarditis; Schizophrenia; Torsades de Pointes

Myocarditis has in several case reports been associated with use of clozapine. Eight cases of myocarditis during treatment with clozapine that were submitted to the Swedish Adverse Drug Reaction Advisory Committee and 18 cases that were reported in the literature are summarized. As part of the routine signal detection process on the World Health Organization (WHO) Program on International Drug Monitoring database, which contains more than two million case reports of spontaneously reported suspected adverse drug reactions, a Bayesian confidence propagation neural network (BCPNN) is used. This article also shows the retrospective output of the BCPNN over time for clozapine and myocarditis and discusses its implications. In 19 (79%; duration of treatment not stated for 2 patients) of 24 patients with myocarditis, the symptoms occurred within the first 6 weeks of clozapine treatment. Many patients shared a similar clinical course, with symptoms such as an influenza-like illness, fever, sinus tachycardia, hypotension, chest discomfort, and heart failure. The reaction was fatal in 12 (46%) of these patients. The other patients generally had a prompt recovery. By using the BCPNN technique, a quantitative association between clozapine and myocarditis was demonstrated, and the association might have been high-lighted for clinical review in 1994 had this BCPNN method been in use at the WHO center at the time. Myocarditis seems to be a rare and potentially lethal adverse effect of clozapine. Admittance for observation, interruption of the clozapine treatment, and treatment with corticosteroids should be considered for patients in whom this reaction is suspected.

Topics: Adult; Antipsychotic Agents; Bayes Theorem; Clozapine; Databases, Factual; Female; Humans; Male; Myocarditis; Schizophrenia; Sweden

Clozapine, a superior treatment for treatment-resistant schizophrenia can cause potentially life-threatening myocarditis and dilated cardiomyopathy. While the occurrence of this condition is well known, its molecular mechanisms are unclear and may be multifactorial. Putative mechanisms warrant an in-depth review not only from the perspective of toxicity but also for understanding the molecular mechanisms of the adverse cardiac effects of clozapine and the development of novel therapeutic approaches. Clozapine-induced cardiac toxicity encompasses a diverse set of pathways, including (i) immune modulation and proinflammatory processes encompassing an IgEmediated (type I hypersensitivity) response and perhaps a cytokine release syndrome (ii) catecholaminergic activation (iii) induction of free radicals and oxidative stress (iv) activation of cardiomyocyte cell death pathways, including apoptosis, ischemia through impairment in coronary blood flow via changes in endothelial production of NO and vasoconstriction induced by norepinephrine as well as other factors released from cardiac mast cells. (v) In addition, an extensive examination of the effects of clozapine on non-cardiac cellular proteins demonstrates that clozapine can impair enzymes involved in cellular metabolism, such as pyruvate kinase, mitochondrial malate dehydrogenase, and other proteins, including α-enolase, triosephosphate isomerase and cofilin, which might explain clozapine-induced reductions in myocardial energy generation for cell viability as well as contractile function. Pharmacologic antagonism of these cellular protein effects may lead to the development of strategies to antagonize the cardiac damage induced by clozapine.

Topics: Apoptosis; Clozapine; Humans; Myocarditis; Myocardium; Myocytes, Cardiac

Topics: Antipsychotic Agents; Clozapine; Electroconvulsive Therapy; Humans; Myocarditis

Topics: Adolescent; Antipsychotic Agents; Clozapine; Fibrosis; Humans; Magnetic Resonance Imaging; Myocarditis

Topics: Antipsychotic Agents; Clozapine; COVID-19; COVID-19 Vaccines; Humans; Myocarditis; RNA, Messenger; Vaccination

Clozapine, an antipsychotic medication used to treat treatment-refractory schizophrenia, has been associated with various dangerous side effects, including myocarditis. However, there have been few published cases reporting on patients with clozapine-induced myocarditis confirmed by cardiac magnetic resonance imaging or the management, treatment, and follow-up of these patients.. This report describes 2 cases of patients with treatment-refractory schizophrenia evidencing transient clozapine-induced myocarditis. Detailed information including laboratory values, imaging results, and clinical notes were gathered.. The 2 cases demonstrated differing manifestations of clozapine-induced myocarditis. Both cases showed that such myocarditis can be transient and can be treated clinically with close observation without discontinuation of clozapine.. These cases show that clozapine-induced myocarditis is transient at times and can self-resolve without discontinuation of clozapine. These observations may suggest a change in clinical practice so that, with close observation, we can avoid risking psychiatric decompensation in select patients with a history of treatment-resistant schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Magnetic Resonance Imaging; Myocarditis

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis; Schizophrenia

Objectives: Clozapine-induced myocarditis may be a hypersensitivity reaction due to titration that was too rapid for a patient's clozapine metabolism. Obesity, infections, and inhibitors (e.g., valproate) may lead to clozapine poor metabolizer (PM) status. The hypothesis that 4 patients with clozapine-induced myocarditis from two United States hospitals were clozapine PMs was tested by studying their minimum therapeutic clozapine doses and titrations. Methods: Using methodology from a prior myocarditis case series of 9 Turkish patients, we studied: 1) the concentration-to-dose (C/D) ratio; 2) minimum therapeutic dose required to reach 350 ng/ml (a marker for PM status); and 3) titration speed. Results: All 4 patients were possible clozapine PMs (their respective minimum therapeutic doses were: 134, 84, 119 and 107 mg/day). The identified possible contributors to clozapine PM status were: 1) valproate in Cases 1, 2 and 4; 2) obesity and a urinary tract infection in Case 2; and 3) obesity and very rapid titration in Case 4. Case 3, who was given a normal US titration, appeared to be a genetic clozapine PM. He developed clozapineinduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome after rechallenge using 12.5 mg/day > 3 months later. The results were similar to 9 Turkish cases, all of which were PMs (6 on valproate, 4 with obesity, 1 with infection and 1 possibly genetic). Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced myocarditis could be explained by lack of individualized titration. (Neuropsychopharmacol Hung 2022; 24(1): 29-41).

Topics: Antipsychotic Agents; Clozapine; Hospitals; Humans; Male; Myocarditis; Obesity; Schizophrenia; Valproic Acid

One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.

Topics: Antipsychotic Agents; Clozapine; Genome-Wide Association Study; Humans; Myocarditis; Schizophrenia

Clozapine is a highly effective medication used in management of treatment-resistant schizophrenia. Clozapine-associated myocarditis (CAM) is a rare but increasingly recognised complication of clozapine titration. Following an episode of CAM, clinicians can face a challenging dilemma of balancing the risks of recurrent myocarditis against the harms of ongoing psychosis. We describe the case of a woman in her 60s who developed acute myocarditis during clozapine titration and was then cautiously rechallenged with a successful outcome.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Myocarditis; Psychotic Disorders; Schizophrenia

Clozapine-induced myocarditis and pericarditis are uncommon adverse effects of clozapine treatment. However, in most cases, they lead to clozapine discontinuation. Here, we describe a case of successful clozapine rechallenge after clozapine-induced myopericarditis. The patient, a 31-year-old male with treatment-resistant schizophrenia (TRS), developed dyspnea on exertion and chest pain on day 19 after the start of clozapine titration. An electrocardiogram (ECG) showed widespread, mild, convex ST interval elevation. While troponin levels were mildly elevated, the echocardiogram was unremarkable. A myopericarditis diagnosis was formulated, and clozapine was stopped, with a progressive resolution of clinical, laboratory and ECG abnormalities. After 6 months, a rechallenge with clozapine was attempted. A very slow titration scheme was adopted, along with close monitoring of clinical, laboratory and ECG parameters. Clozapine target dose was reached without the occurrence of any abnormality. Given the unique role of clozapine in the management of TRS, clozapine rechallenge may be considered after pericarditis, even with troponin levels elevation. Further studies are needed to update current clinical guidelines.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Pericarditis; Troponin

Clozapine has superior efficacy in the treatment of refractory schizophrenia; however, use of clozapine is limited due to severe side effects, including myocarditis. Using non-integrative Sendai virus, we generated induced pluripotent stem cell lines from peripheral blood mononuclear cells of two patients with refractory schizophrenia, one clozapine-tolerant and one clozapine-induced myocarditis. Both cell lines exhibited a normal karyotype and pluripotency was validated by flow cytometry, immunofluorescence and their ability to differentiate into the three germ layers. These lines can be used to generate 2D and 3D patient-specific human cellular models to identify the mechanism by which clozapine induces myocardial inflammation.

Topics: Antipsychotic Agents; Cell Differentiation; Clozapine; Humans; Induced Pluripotent Stem Cells; Leukocytes, Mononuclear; Myocarditis; Schizophrenia; Schizophrenia, Treatment-Resistant

Objectives: An international guideline recently provided certain personalized schedules for titrating clozapine in adult inpatients by considering: 1) DNA ancestry group, 2) sexsmoking subgroup, and 3) presence/absence of clozapine poor metabolizer (PM) status. Measuring CRP levels at baseline and during the first 4 weeks is recommended. Titrations too fast for the metabolism of specific patients can lead to clozapine-induced inflammations and CRP elevations. Methods: Three published cases are reinterpreted. Better outcomes might have been obtained by using the guideline. Results: Case 1 was a Chinese male non-smoker, a clozapine PM due to an underlying inflammation. Case 2 was a Turkish female non-smoker who developed clozapine-induced myocarditis in the context of 4 risk factors (undiagnosed infl ammation, obesity, valproate and olanzapine co-prescription). Case 3 was a United States patient of European ancestry with no known risk factors who developed myocarditis after a routine titration and had an unsuccessful rechallenge with 12.5 mg/day. Application of the international clozapine titration guideline may have prevented: 1) Case 1 by recommending against clozapine titration for a patient with an abnormal CRP level, 2) Case 2 by considering 4 risk factors and using a slow titration for clozapine PMs, and 3) Case 3 by using CRP elevations for early identification of a possible genetic PM. Conclusions: When baseline or prior CRPs are normal and then become abnormal during a clozapine titration, this indicates: 1) clozapine-induced inflammation associated with too-rapid titration for that specific patient, and/or 2) co-occurrence of an infection. Prospective studies need to verify this hypothesis.

Topics: Adult; Antipsychotic Agents; C-Reactive Protein; Clozapine; Female; Humans; Inflammation; Male; Myocarditis; Prospective Studies

Topics: Antipsychotic Agents; Autism Spectrum Disorder; Clozapine; Humans; Myocarditis; Schizophrenia

Clozapine is a second-generation antipsychotic often used for treatment-refractory schizophrenia and has many adverse effects. Cardiac adverse events potentiated by clozapine include myocarditis which is a black box warning. Even more rarely, there are multiple cases of pericarditis reported in the literature. This is a case report of a 32-year old male with paranoid schizophrenia who developed pericarditis after initiation and titration of clozapine in the inpatient psychiatry unit. Patient presented with chest pain, persistent tachycardia, and orthostatic hypotension two weeks after titration of clozapine. The diagnosis of pericarditis was supported by the repeat electrocardiogram which revealed PR depressions, the audible friction rub, and the pleuritic/episodic nature of the chest pain. All other possible causes of pericarditis were ruled out and clozapine was suspected as the most likely explanation. The pericarditis resolved with treatment of colchine and ibuprofen on evidence from a repeat echocardiogram. This case report demonstrates and supports few cases of clozapine induced pericarditis in the literature. Cardiac events of clozapine can be life-threatening; therefore, greater baseline and subsequent cardiac monitoring may be implicated in the future.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Pericarditis; Schizophrenia, Paranoid

Clozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences.. To examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects.. A retrospective analysis of the record database for 247 621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined.. Of 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation.. Suspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The 'critical period' for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.

Topics: Antipsychotic Agents; Biomarkers; Clozapine; Drug-Related Side Effects and Adverse Reactions; Electronics; Humans; Incidence; Myocarditis; Retrospective Studies; Tachycardia; Troponin

To describe the implementation and efficacy of a pharmacist-driven clozapine myocarditis monitoring protocol including 2 cases of clozapine-induced myocarditis identified using this protocol.. In February 2015, the health system formulary committee approved changes to an existing pharmacist-driven protocol to allow for myocarditis monitoring in patients initiated on clozapine therapy based on an algorithm published by Ronaldson et al in 2011. The monitoring includes the measurement of C-reactive protein (CRP; via high-sensitivity CRP [hsCRP] serum test) and troponin at baseline and then weekly for 4 weeks. Patients initiated on clozapine therapy between March 2015 and February 2017 and monitored according to the aforementioned protocol are described in this article.. A total of 38 patients were initiated on clozapine therapy during the specified data collection period. Of these 38 patients, 4 screened positive for early signs of myocarditis according to the monitoring protocol, and 2 of those 4 patients were confirmed by cardiology consultation to have clozapine-induced myocarditis. Both of these patients experienced a full cardiac recovery upon discontinuation of clozapine.. A pharmacist-driven myocarditis monitoring protocol for clozapine-naïve patients may help to identify early signs of clozapine-induced myocarditis and therefore mitigate potentially life-threatening complications by prompting early discontinuation of the inciting drug.

Topics: Antipsychotic Agents; Clozapine; Humans; Inpatients; Myocarditis; Pharmacists

Topics: Antipsychotic Agents; Cardiomyopathies; Causality; Clozapine; Humans; Myocarditis

Clozapine (CLZ) represents an effective treatment for resistant schizophrenia. However, myocarditis, recently reported in about 66% of the psychiatric patients treated with CLZ, has raised concerns about its safety. β-blocking agents have shown to be helpful in the management of myocarditis. Moreover, Vimentin (VIM) and Connexin-43 (CX43) are important structural proteins play key roles in cytoskeletal functions and cellular communication and have complex implications in pathophysiology. The present work aimed to study the mechanisms behind the protective effect of propranolol (PRO) against CLZ-induced myocarditis and the possible involvement of VIM and CX43. The effect of PRO (5 and 10 mg/kg, oral) on the myocarditis induced by CLZ (25 mg/kg/d, i. p.) treatment for 21 days in rats, was assessed biochemically, and immunohistochemically. CLZ treatment increased the serum levels of cardiac injury (CK-MP, LDH and cTn-I) and cardiac levels of oxidative stress (TBARS and NO) markers, proinflammatory cytokines (IL-1β and TNF-α), and mRNA expression of VIM and CX43 with decreased the antioxidant defenses (GSH and GSH-Px). Immunohistochemical study showed increased cardiac expression of VIM, CX43 and caspase-3 proteins. Coadministration of PRO with CLZ, dose-dependently decreased the biochemical and immunohistochemical hallmarks of CLZ-induced myocardial injury and significantly decreased mRNA expression of VIM and CX43. Taken together, our results demonstrate that the cardioprotective effects of PRO on CLZ-induced myocarditis are related in addition to its β-blocking activity to protection of myocardial VIM and CX43 proteins through antagonizing the CLZ-induced oxidative stress and inflammatory response, and preventing cell apoptosis.

Topics: Adrenergic beta-Antagonists; Animals; Antipsychotic Agents; Apoptosis; Cardiotonic Agents; Caspase 3; Clozapine; Connexin 43; Creatine Kinase; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; L-Lactate Dehydrogenase; Male; Myocarditis; Myocardium; Oxidative Stress; Propranolol; Rats, Wistar; Troponin I; Vimentin

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis

Clozapine is a uniquely effective antipsychotic indicated for treatment-resistant schizophrenia. However, its use is underutilised and often delayed for years due to potential adverse reactions including myocarditis and cardiomyopathy. The purpose of this study was to conduct a retrospective review of the clinical records of patients initiating clozapine in the Auckland District Health Board (ADHB) region to determine the incidence of clozapine-associated myocarditis and cardiomyopathy and to identify potential risk factors associated with these cardiotoxicities. The incidence of clozapine-associated myocarditis and cardiomyopathy over a two-year period in the ADHB region was 3.8% and 1.3% respectively.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Incidence; Myocarditis; New Zealand; Retrospective Studies; Risk Factors

BACKGROUND Clozapine, a second-generation antipsychotic, is often prescribed for refractory schizophrenia; however, it can cause life-threatening adverse events including agranulocytosis and myocarditis. Making the diagnosis of clozapine-induced myocarditis can be challenging given the non-specific presentation as well as risk involved in obtaining an endomyocardial biopsy. As clozapine-induced myocarditis carries a mortality risk of up to 30%, timely recognition, diagnosis, and management are vital. This report presents a case of clozapine-induced myocarditis in a 25-year-old man with refractory schizophrenia who was diagnosed using non-invasive imaging with cardiovascular magnetic resonance (CMR). CASE REPORT A 25-year-old man with refractory schizophrenia was admitted with severe psychotic symptoms and started on a rapid titration of clozapine. During his hospitalization he developed somnolence, fever, and tachycardia with leukocytosis, elevated inflammatory markers, and cardiac biomarkers concerning for clozapine-induced myocarditis. Alternative etiologies were ruled out and CMR was used to confirm the diagnosis. The patient's symptoms resolved following discontinuation of clozapine and initiation of supportive therapies. CONCLUSIONS Clozapine-induced myocarditis is challenging to diagnose due to a lack of consensus on diagnostic criteria, reliance on voluntary reporting, and non-specific presentation. This report highlights that myocarditis can be associated with clozapine pharmacotherapy in patients with schizophrenia and demonstrates the value of diagnosis using non-invasive CMR. Additional studies are needed to understand the mechanism of clozapine-induced myocarditis and how clozapine titration may affect risk.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Magnetic Resonance Spectroscopy; Male; Myocarditis; Schizophrenia

Clozapine use is associated with myocarditis. In this study, we investigated what clinical signs and symptoms, and/or laboratory test(s), alert clinicians to presumptive myocarditis (PrMy) most accurately and at the earliest time point. We also investigated the incidence of PrMy during the initial exposure to clozapine versus in patients restarted on clozapine after extended interruption of prior prolonged treatment.. 100 patients admitted to state psychiatric hospital started on clozapine were recruited into the study. 76 patients were treated with clozapine for the first time and 24 patients were restarts. Creatine kinase (CK), troponin I (TROP), eosinophil count (EOS), and C-reactive protein (CRP) were obtained at baseline and weeks 1, 2, 3, and 4. Descriptive statistics were calculated for demographic and clinical variables. Student's t test and chi-squared test were used to compare means and proportions between initial exposure and restart groups.. Clinical features and laboratory tests suggestive of PrMy were seen in 4 patients (5.3%) in initial exposure group and none in restart group. 3.5% of TROP levels were abnormal in initial exposure group and no abnormal levels were found in the restart group. 30% and 46% of CK, 23% and 39% of CRP, and 14% and 23% of EOS were abnormal in initial exposure group and restart groups, respectively.. PrMy was common (5.3%) during clozapine initiation. Prospective management through serial laboratory monitoring with weekly TROP levels was sensitive enough to allow for timely clozapine discontinuation.

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis; Prospective Studies; Troponin

Clozapine is an important treatment option in patients with treatmentresistant schizophrenia and bipolar disorder. Clozapine has multiple systemic side effects with myocarditis and cardiomyopathy being considered as serious cardiovascular outcomes. Although the aetiology of myocarditis is still unknown, its frequent occurrence in the early stages of clozapine use suggests that type 1 drug hypersensivity may underlie. Although rare, the cardiovascular side effects can be lifethreatening and must be recognized and treated promptly. The nonspecific clinical presentation of these conditions makes risk evaluation and identification of the affected patients difficult. A consensus has not yet been formed on following up the patients without the suspected clinical cardiac symptoms. In this article we presented two cases of myocarditis associated with clozapine. We aimed to emphasize that C-Reactive Protein and troponin monitoring, in accordance with the current clozapine guidelines, was practical and useful for early detection of myocarditis in asymptomatic patients. We also wanted to draw attention to the factors that may increase the cardiovascular risk such as polypharmacy and concomitant use of lithium and valproate with clozapine.

Topics: Antipsychotic Agents; C-Reactive Protein; Clozapine; Early Diagnosis; Humans; Myocarditis; Troponin

Protocol for clozapine rechallenge in patients with a history of clozapine-induced myocarditis.. Clozapine-related cardiovascular adverse effects including myocarditis and cardiomyopathy have limited its widespread use in treatment-resistant schizophrenia. Here, we present a case of clozapine-induced myocarditis and successful cautious rechallenge. Ms. AA, a young female patient with severe psychosis developed myocarditis during her initial clozapine titration phase, which was thus discontinued. Subsequent response to other medications was poor, and she remained significantly disabled. We reviewed blood-based biomarkers identified during the emergence of her index episode of myocarditis and developed a successful clozapine rechallenge protocol, based on careful monitoring of changes in these indices and a very slow clozapine re-titration.. This protocol may have utility in the management of patients with a history of clozapine-induced myocarditis.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Myocarditis; Psychotic Disorders; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis; Product Labeling

Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the astroglial transmission associated with connexin43 (Cx43), which is the most principal expression in astrocytes and myocardial cells, and expression of Cx43 in primary cultured astrocytes. Both acute and subchronic administrations of CLZ concentration-dependently increased Cx43-associated astroglial release of l-glutamate and d-serine, whereas therapeutic-relevant concentration of CLZ acutely did not affect but subchronically increased astroglial release. In contrast, after the subchronic administration of therapeutic-relevant concentration of valproate (VPA), acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43-associated astroglial releases. VPA increased Cx43 expression in cytosol fraction without affecting plasma membrane fraction, whereas CLZ increased Cx43 expression in both fractions. Acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43 expression in the plasma membrane fraction of astrocytes subchronically treated with VPA. The present findings suggest that CLZ-induced the activation of Cx43-associated channel activity and transported Cx43 to plasma membrane, probably contribute to the double-edged sword clinical action of CLZ, such as improvement of cognitive dysfunction and CLZ-induced myocarditis.

Topics: Antipsychotic Agents; Astrocytes; Cell Membrane; Clozapine; Connexin 43; Glutamic Acid; Humans; Myocarditis; Schizophrenia; Serine; Valproic Acid

Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genome-Wide Association Study; Humans; Myocarditis; Schizophrenia

BACKGROUND Clozapine plays a unique role in the management of treatment-resistant schizophrenia (TRS). Clozapine re-challenge following an episode of myocarditis is controversial, with a very limited literature, although it may be crucial in the recovery of certain patients. To date and to the best of our knowledge, only 10 of 22 studied cases reported successful clozapine retrial after myocarditis. CASE REPORT We present the case of a 22-year-old Hispanic man with treatment-resistant schizophrenia and polysubstance use disorder (methamphetamine, cannabis, and alcohol) initiated on aggressive clozapine titration after lack of response to several other therapies. Approximately 16 days after clozapine trial, the patient developed cardiac function impairment, presenting with chest pain, notable elevation in several biomarkers (troponin: 0.72 ng/ml, ESR >100 mm/h, CRP: 20.8 mg/dl, and BNP: 999 ng/ml), and a depressed ejection fraction at 25%. Further assessments also showed positive hepatitis A serology. Following discontinuation of clozapine and providing supportive care, the patient's physical symptoms resolved. He had a relapse of psychotic symptoms, which were refractory to treatment with other antipsychotic agents. Subsequently, the patient underwent a second clozapine trial under close monitoring, with resolution of his psychosis. Repeated echocardiography demonstrated improved EF to 50%, transaminitis was resolved, repeat blood test results were normalized, and the patient was discharged while he was stabilized and asymptomatic. CONCLUSIONS This case adds to the previous case reports and suggests that clinicians may consider clozapine re-challenge following an episode of myocarditis based on clinical judgment, on a case-by-case basis, and under close monitoring. We highlight the need for development of clinical guidelines for clozapine re-challenge.

Topics: Adult; Antipsychotic Agents; Clozapine; Echocardiography; Humans; Male; Myocarditis; Schizophrenia; Young Adult

Clozapine is an atypical antipsychotic proven to be superior in the treatment of treatment-resistant schizophrenia. Myocarditis is a rare, but well-known complication of treatment with clozapine. Only few cases have been reported in which nausea and vomiting were prominent symptoms. This is the first described report in which nausea and vomiting were the only presenting symptoms of clozapine-induced myocarditis.. We report a case of a 58-year-old woman, suffering from schizoaffective disorder, who is being treated with clozapine. Two weeks after initiation of clozapine, she developed nausea and vomiting, in absence of any other clinical symptoms. Laboratory examination and magnetic resonance imaging confirmed the diagnosis of clozapine-induced myocarditis. Clozapine was discontinued and the patient recovered fully.. This case emphasizes the importance of recognizing myocarditis as a cause of isolated nausea and vomiting in patients treated with clozapine. Early recognition improves clinical outcome and reduces mortality.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Middle Aged; Myocarditis; Nausea; Vomiting

Clozapine, atypical antipsychotic drug, is widely used in patients with schizophrenia, for whom previous therapy was inadequate or not tolerated. Clozapine-induced myocarditis (CIM) is a relatively rare but potentially life-threatening complication of clozapine therapy; however, the underlying mechanism has not been so far well elucidated. Factors predisposing to CIM include a rapid dose titration, advanced age and co-administration of sodium valproate. In this paper, we present a case of a 22-year-old male patient with refractory schizophrenia who developed CIMduring low-dose clozapine treatment with co-administration of valproate and risperidone. On the basis of our case and literature review, we point out that during the first weeks of clozapine treatment patients should be actively, daily monitored for the presence of symptoms suggesting CIM. The low dose of clozapine and concurrent use of valproate are unique aspects of the report, adding new information to the discussion on safety of concomitant use of clozapine and valproate. Further investigation is required to better understand the role of co-administration of valproate and risperidone in the pathogenesis of CIM.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Male; Myocarditis; Schizophrenia; Valproic Acid; Young Adult

Topics: Antipsychotic Agents; Clozapine; Electrocardiography; Humans; Male; Myocarditis; Schizophrenia; Young Adult

Topics: Adult; Antipsychotic Agents; Biopsy; Clozapine; Computed Tomography Angiography; Coronary Angiography; Diagnosis, Differential; Dyspnea; Electrocardiography; Fatigue; Follow-Up Studies; Humans; Magnetic Resonance Imaging, Cine; Male; Myocarditis; Myocardium; Nausea

Topics: Antipsychotic Agents; Canada; Clozapine; Humans; Myocarditis; Schizophrenia; Treatment Outcome

Clozapine, an antipsychotic reserved for management of treatment-resistant schizophrenia, is associated with severe adverse effects, including myocarditis. This study aims to determine the incidence of clozapine-induced myocarditis at a large tertiary hospital compared to what is reported in the literature.. Medical records of adult patients admitted to psychiatry units receiving clozapine between January 1, 2010, and July 31, 2016, were retrospectively reviewed. Cases of clozapine-induced myocarditis were defined as having elevated C-reactive protein (CRP) or detectable troponin and at least 1 sign or symptom of myocarditis, in the absence of alternative plausible aetiologies. The primary outcome was incidence of clozapine-induced myocarditis during the study period. Secondary outcomes included rate and description of the management of clozapine-induced myocarditis.. In total, 316 patients were screened; 10 patients met the case definition for clozapine-induced myocarditis. The incidence of this adverse drug reaction over the study period was 3.16%. Reduced left ventricular ejection fraction was observed in 60% of cases, and electrocardiography changes were noted in 60% of cases. Clozapine was discontinued in all cases. Rechallenge was performed in 2 patients; recurrent CRP elevation resulted in discontinuation in each case. Medications for management of myocarditis were used in 50% of cases. Although 2 patients required transfer to critical care, the in-hospital mortality rate was 0%.. The incidence of clozapine-induced myocarditis at the study hospital was consistent with the higher range reported in the literature. Further research is necessary to elucidate risk factors, definitive diagnostic criteria, and effective management of clozapine-induced myocarditis.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Male; Middle Aged; Myocarditis; Retrospective Studies; Schizophrenia; Tertiary Care Centers

The aim of this study was to investigate and compare the incidence of suspected or definite cases of clozapine induced myocarditis (SDM) and clinical factors which could influence its onset in two different time periods, defined by pre- and post-cardiac monitoring at an inpatient setting, during the initiation phase of clozapine treatment. Hospital records of patients started on clozapine in the inpatient unit between 2011 and 2018 were investigated. Eight in 38 patients (11.3%) were classified as SDM after the initiation of the monitoring protocol, whereas only 1 in 33 patients (1.4%) was classified as SDM, before. Monitored and non-monitored patient groups were similar with regard to demographic and clinical variables. Diagnosis of schizoaffective disorder and use of concominant lithium, valproic acid and atypical antipsychotics were higher in patients with SDM, while clozapine dose titration was similar compared to the rest of the patients. Cardiac monitoring seems to be the main factor leading to the increase in the detection of clozapine induced myocarditis (CIM). If not monitored, the outcome of CIM can be fatal without any warning signs and symptoms. Concominant use of mood stabilizers including valproic acid and lithium, are important risk factors for the development of CIM.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Incidence; Inpatients; Lithium; Male; Middle Aged; Monitoring, Physiologic; Myocarditis; Psychotic Disorders; Risk Factors; Valproic Acid; Young Adult

Using national Danish registers, we estimated rates of clozapine-associated cardiac adverse events. Rates of undiagnosed myocarditis were estimated by exploring causes of death after clozapine initiation.. Through nationwide health registers, we identified all out-patients initiating antipsychotic treatment (January 1, 1996-January 1, 2015). Rates of clozapine-associated myocarditis and pericarditis within 2 months from clozapine initiation and rates of cardiomyopathy within 1-2 years from clozapine initiation were compared to rates for other antipsychotics. Mortality within 2 months from clozapine initiation was extracted.. Three thousand two hundred and sixty-two patients of a total 7932 patients initiated clozapine as out-patients (41.12%). One patient (0.03%) developed myocarditis, and no patients developed pericarditis within 2 months from clozapine initiation. Two (0.06%) and four patients (0.12%) developed cardiomyopathy within 1 and 2 years respectively. Rates were similar for other antipsychotics. Twenty-six patients died within 2 months from clozapine initiation. Pneumonia (23.08%) and stroke (11.54%) were the main causes of death. We estimated the maximum rate of clozapine-associated fatal myocarditis to 0.28%.. Cardiac adverse effects in Danish out-patients initiating clozapine treatment are extremely rare and these rates appear to be comparable to those observed for other antipsychotic drugs.

Topics: Adult; Aged; Ambulatory Care; Antipsychotic Agents; Bipolar Disorder; Cardiomyopathies; Clozapine; Denmark; Female; Humans; Male; Middle Aged; Myocarditis; Pericarditis; Psychotic Disorders; Registries; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis

Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia.. Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993-2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia.. There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively.. The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial.

Topics: Adult; Antipsychotic Agents; Australia; Cardiomyopathies; Clozapine; Female; Humans; Male; Myocarditis; Neutropenia; Schizophrenia; Young Adult

Topics: Adult; Antipsychotic Agents; Clozapine; Diagnosis, Differential; Foodborne Diseases; Humans; Male; Myocarditis; Schizophrenia

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Australia; Clozapine; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis

Topics: Adult; Aged; Antipsychotic Agents; C-Reactive Protein; Clozapine; Early Diagnosis; Female; Humans; Male; Myocarditis; Predictive Value of Tests

Topics: Adult; Antipsychotic Agents; Clinical Protocols; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Myocarditis; Schizophrenia

Topics: Adolescent; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Schizophrenia

Clozapine is the cornerstone of therapy for refractory schizophrenia; however, the potential for cardiotoxicity is an important limitation in its use. In the current analysis we sought to evaluate the long term cardiac outcomes of clozapine therapy.. All-cause mortality, incidence of sudden death and time to myocarditis were assessed in a cohort of patients maintained on clozapine between January 2009 and December 2015. All patients had regular electrocardiograms, complete blood count, clozapine levels and echocardiography as part of a formal protocol.. A total of 503 patients with treatment-resistant schizophrenia were maintained on clozapine during the study period of which 93 patients (18%) discontinued therapy with 29 (6%) deaths. The incidence of sudden death and myocarditis were 2% (n=10) and 3% (n=14) respectively. Amongst patients with sudden death, 7 out of 10 (70%) were documented to have used illicit drugs prior to death, with a tendency to weight gain also noted. The mean time to myocarditis post clozapine commencement was 15±7days. The reduction in left ventricular ejection fraction in those with myocarditis was 11±2%.. Myocarditis and sudden cardiac death are uncommon but clinically important complications in a cohort of patients followed while maintained on clozapine undergoing regular cardiac assessment. Further studies are required to document the role of preventive measures for left ventricular dysfunction and sudden cardiac death in this population.

Topics: Adult; Aged; Antipsychotic Agents; Australia; Clozapine; Cohort Studies; Death, Sudden, Cardiac; Electrocardiography; Female; Humans; Incidence; Male; Middle Aged; Myocarditis; Prospective Studies; Time Factors

To explore the evidence around clozapine re-challenge following myocarditis.. This case adds to the 17 cases of clozapine re-challenge following myocarditis, of which 71% were successful (12 cases). This demonstrates that re-challenge could be performed safely and effectively in the context of clozapine-induced myocarditis, if accompanied by a strict and rigorous monitoring protocol.

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis

Clozapine-induced myopericarditis is a well-described adverse drug reaction. Clozapine is also the most efficacious agent in refractory schizophrenia. We report a case of a patient who was successfully re-trialled on clozapine two years after developing myopericarditis, after which multiple lines of alternative treatment failed. We propose a protocol for safely attempting a re-trial of clozapine in such cases.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Schizophrenia; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis

Myocarditis occurs more frequently during clozapine (CLZ) administration than during treatment with other antipsychotic drugs (APs). In this observational study, we transversally screened outpatients for myocarditis by comparing a CLZ group of 132 subjects, with a non-CLZ group taking other APs (n = 371) only, and in 21 CLZ-treated patients and 18 subjects treated with other APs who had been followed for more than one year. The protocol included a) assessment of symptoms such as dyspnea, tachycardia, chest discomfort, fever, cough, and edema, b) blood pressure and heart auscultation; c) a standard electrocardiogram after a 5-minute rest, d) white cell count, and qualitative determination of troponin I, creatine-kinase-MB and myoglobin, and e) a cardiologist evaluation of subjects with suspected myocarditis. Only one case of myocarditis was detected, providing an approximation of the frequency of myocarditis of 1.6% in the first month of treatment. This was a 30-year-old man with schizophrenia who developed symptoms at day 6 after starting a treatment with 200 mg of CLZ a day without titration. Myocarditis was not observed during prolonged CLZ or other AP administration. These results support the proposal of starting CLZ treatment with a low dose and the feasibility of a simple protocol for myocarditis detection in psychiatry primary care.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Child; Clozapine; Cross-Sectional Studies; Female; Humans; Longitudinal Studies; Male; Middle Aged; Myocarditis; Young Adult

We present a case of clozapine-related myocarditis, with a rising C-reactive protein as the only initial evidence supporting the diagnosis.. An otherwise healthy young male presenting with treatment-resistant schizophrenia was started on clozapine. Monitoring was performed.. At day 18 he developed fever, tachycardia and a raised C-reactive protein, while troponin levels and echocardiogram remained normal.. Current protocols monitoring for myocarditis have their limitations and can often only be used to support a presumptive diagnosis of myocarditis. In keeping with the current clozapine monitoring guidelines, we demonstrate that a rise in C-reactive protein levels can be a critical early sign of myocarditis warranting close monitoring and serious consideration for cessation of clozapine.

Topics: Adult; Antipsychotic Agents; C-Reactive Protein; Clozapine; Early Diagnosis; Humans; Male; Myocarditis; Time Factors; Troponin

To determine the incidence of clozapine-induced myocarditis and cardiomyopathy and identify risk factors.. A cohort of 129 patients initiated on clozapine at Toowoomba Mental Health Service from year 2000 until 2011 was examined to evaluate cases of myocarditis and cardiomyopathy. Risk factors were analysed using multivariable logistic regression.. The incidence of clozapine-induced myocarditis and cardiomyopathy was 3.88% and 4.65% (or 2.26 per 100 patient years), respectively. A significant association was identified between clozapine-induced myocarditis and SSRI use (p = 0.043). Subclinical cardiomyopathy was identified in the absence of symptoms in the majority of cases.. These results illustrate a high incidence of clozapine-induced myocarditis as well as cardiomyopathy, reinforcing the need for a standardised, mandatory monitoring scheme. Concomitant SSRI use as one such potential predictor merits further study.

Topics: Adult; Aged; Antipsychotic Agents; Australia; Cardiomyopathies; Clozapine; Female; Humans; Incidence; Male; Mental Health Services; Middle Aged; Myocarditis; Retrospective Studies; Risk Factors; Young Adult

Clozapine is an atypical antipsychotic which is often effective in patients who fail to respond to other antipsychotics, but its use carries substantial risk. Myocarditis is one of the life-threatening adverse effects, which occurs in about 1% of exposed patients. Rechallenge with clozapine is controversial, particularly shortly after the occurrence of the myocarditis, and when there is clear and convincing evidence of cardiac damage. Aggressive use of clozapine, however, may be critical for the recovery of patients early in the course of their illness. Here we report a successful case of clozapine rechallenge following an initial aggressive dosage titration in an inpatient setting.

Topics: Antipsychotic Agents; Clozapine; Hospitalization; Humans; Male; Myocarditis; Retreatment; Schizophrenia; Young Adult

Topics: Antipsychotic Agents; C-Reactive Protein; Catatonia; Clozapine; Creatine Kinase; Dantrolene; Drug Monitoring; Drug Substitution; Echocardiography; Humans; Lorazepam; Male; Myocarditis; Neuromuscular Agents; Psychotic Disorders; Treatment Outcome; Troponin; Withholding Treatment; Young Adult

Clozapine is the archetypical atypical antipsychotic, its primary indication being treatment resistant schizophrenia. Severe side effects caused by clozapine, including leukopenia, agranulocytosis, and myocarditis, are well known. A rarely described side effect is concurrent perimyocarditis and parenchymal lung disease.. A previously physically healthy 23-year-old male Caucasian that suffered from schizophrenia presented with flu-like symptoms 1 week after starting clozapine treatment. Treatment with clozapine was discontinued. He developed respiratory distress. Investigations showed significant parenchymal infiltration in both of the lungs, pericardial fluid, and heart failure. He initially received treatment for suspected malignant neuroleptic syndrome and later for suspected infection, but these tentative diagnoses were not confirmed. The patient's condition gradually improved. In retrospect, clozapine-induced parenchymal lung disease and perimyocarditis were deemed the most probable causes.. Concurrent perimyocarditis and parenchymal lung disease are rare side effects of clozapine. Clozapine-induced disease in general is considered an exclusion diagnosis. Lacking a verifiable diagnosis when suspecting a side effect of clozapine, clinicians might treat the most likely and serious condition presenting and consider discontinuing clozapine until the diagnostic uncertainty is reasonably resolved.

Topics: Adult; Antipsychotic Agents; Clozapine; Diagnosis, Differential; Humans; Lung Diseases; Male; Myocarditis; Pericarditis; Schizophrenia; Young Adult

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis

Topics: Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Myocarditis

Topics: Antipsychotic Agents; C-Reactive Protein; Case-Control Studies; Clozapine; Eosinophils; Humans; Leukocyte Count; Myocarditis; Troponin

Topics: Adult; Antipsychotic Agents; Biomarkers; Clozapine; Electrocardiography; Fever; Humans; Leukocytosis; Male; Myocarditis; Schizophrenia, Paranoid; Tachycardia; Ultrasonography

Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples.. To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia.. We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group).. Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine.. Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; DiGeorge Syndrome; Dose-Response Relationship, Drug; Drug Substitution; Female; Hospitalization; Humans; Male; Middle Aged; Myocarditis; Neutropenia; Schizophrenia; Seizures; Treatment Outcome; Young Adult

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Myocarditis

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Myocarditis

A 46-year-old man with a history of paranoid schizophrenia was admitted with a recurrence of psychotic symptoms. Improvement was noted after the initiation of clozapine. After 2 weeks of clozapine therapy, chest pressure and abnormal cardiac biomarkers (in the presence of a normal coronary angiogram) raised suspicion of myocarditis. That diagnosis was confirmed by means of cardiac magnetic resonance imaging. Discontinuation of the clozapine led to resolution of the cardiac symptoms. Clozapine-induced myocarditis is rare and can be missed for lack of specific clinical findings. In order to prevent disease progression and a possibly fatal outcome, early recognition of the condition and prompt discontinuation of clozapine are necessary.

Topics: Antipsychotic Agents; Clozapine; Humans; Image Enhancement; Magnetic Resonance Imaging; Male; Middle Aged; Myocarditis; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Schizophrenia

Topics: Adolescent; Antipsychotic Agents; Clozapine; Humans; Magnetic Resonance Imaging; Male; Myocarditis

Clozapine (CLZ) is the most effective therapeutic alternative in the treatment of resistant schizophrenia. However, the cardiotoxicity of CLZ, particularly in young patients, has raised concerns about its safety. Captopril is a well-known angiotensin-converting enzyme inhibitor with antioxidant properties effective in treating hypertension and heart failure. The aim of this study was to investigate the protective effect of captopril against clozapine-induced myocarditis in rats and the possible mechanisms behind this effect. The effect of captopril treatment [5 or 10mg/kg/d, injected intraperitoneally (i.p.) for 21days] on the cardiotoxic effect of coadministered CLZ (25mg/kg/d, i.p.) was assessed. Myocarditis was assessed histopathologically, immunohistochemically and biochemically. Frozen heart specimens were used to determine the amount of lipid peroxides product (MDA), nitric oxide (NO), reduced glutathione (GSH), glutathione peroxidase (GSH-Px) activity, proinflammatory cytokines (TNF-α and IL-10) and DNA degradation product(8-OHdG). Coadministration of captopril with the tested doses of CLZ decreased the histological hallmarks and biochemical markers (CK-MP and LDH) of myocarditis. In addition, captopril attenuated the effects of CLZ on oxidative stress parameters, NO and serum and cardiac 8-OHdG levels. Captopril significantly attenuated the effect of CLZ on all measured parameters in a dose-dependent manner. These results suggested that captopril exerts a protective action against CLZ-induced myocarditis. Multiple mechanisms contribute to this effect, including a decrease in cardiac oxidative stress and proinflammatory cytokines production, modulation of antioxidant status and protection from oxidative DNA damage. Hence, captopril may be effective in reducing the incidence and severity of CLZ-induced myocarditis in humans.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antipsychotic Agents; Captopril; Clozapine; Cytokines; Deoxyguanosine; DNA Damage; Gene Expression Regulation; Male; Myocarditis; Oxidative Stress; Rats; Rats, Wistar

Clozapine is an atypical antpsychotic medication with established efficacy in patients diagnosed of resistant schizophrenia. However, clozapine has multiple side effects. Cardiac complications such as myocarditis and cardiomyopathy have always been related with treatment with clozapine.. A 42 year old Caucasian male, with history of schizophrenia developed a acute myocarditis after commencement of clozapine.. The patient recovered with intensive medical support. The symptoms occurred approximately 20 days after starting clozapine.. Myocarditis is an ingreasingly recognized complication associated with clozapine. Use of clozapine must be based on a balance of its risks and benefits on an individual basis which for the most part defines its use in treatment refractory schizophrenia. Appropriate monitoring of adverse events is an essential part of the clinical usage of clozapine and should be charted for at least two years.

Topics: Adult; Antipsychotic Agents; Clozapine; Coronary Vessels; Humans; Male; Myocarditis; Radiography; Schizophrenia

Although many patients with schizophrenia fail to respond adequately to trials of 2 or more antipsychotics, utilization of clozapine for these patients remains low, despite recommendations for its use by accepted treatment guidelines. Some experts estimate that 5-10 times more patients could benefit from clozapine than who are now receiving it. Learning how to manage the unique side effect profile of clozapine can potentially remove barriers to prescribing this agent and thus unlock its unique therapeutic efficacy for more patients.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Constipation; Diabetes Mellitus; Eosinophilia; Humans; Myocarditis; Neuroleptic Malignant Syndrome; Neutropenia; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia; Sialorrhea; Tachycardia; Weight Gain

We present a case of confirmed clozapine-induced myocarditis in a patient who was not naïve to the drug.. This patient, who had been stable on clozapine for 10 years, relapsed following self-cessation. Asymptomatic throughout inpatient re-titration, serum cardiac enzymes were nonetheless routinely taken.. Occult myocarditis was only discovered due to an elevated Troponin I, and was confirmed by cardiac imaging.. Once thought to be the preserve of initial exposure to the medication, clozapine-induced myocarditis can occur at any re-titration point if the immunological milieu permits. We therefore recommend routine monitoring of serum cardiac enzymes with all patients undergoing titration of clozapine, regardless of whether they have previously been stable on the drug.

Topics: Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Myocarditis

Topics: Adult; Antipsychotic Agents; Clozapine; Echocardiography; Electrocardiography; Humans; Male; Myocarditis; Schizophrenia; Tomography, X-Ray Computed; Treatment Outcome; Withholding Treatment

Topics: Antipsychotic Agents; Clozapine; Eosinophilia; Humans; Male; Myocarditis; Schizophrenia, Paranoid; Time Factors; Treatment Outcome; Young Adult

Several detailed case reports have described cardiac muscle disorders (cardiomyopathy and myocarditis) in patients treated with quetiapine, some of which have been fatal. The symptoms included shortness of breath and oedema. The disorders sometimes resolved on withdrawal of quetiapine. Quetiapine is chemically similar to clozapine and olanzapine, which are known to sometimes provoke this type of adverse effect. In practice, a patient who develops dyspnoea or other signs of heart failure during quetiapine therapy may benefit if the drug's role is recognised and quetiapine withdrawn.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Dibenzothiazepines; Dyspnea; Edema; Humans; Myocarditis; Quetiapine Fumarate

Topics: Antipsychotic Agents; Chest Pain; Clozapine; Diagnostic Imaging; Echocardiography, Doppler; Electrocardiography; Humans; Magnetic Resonance Imaging; Myocarditis; Pericarditis, Constrictive; Young Adult

Topics: Adult; Antipsychotic Agents; Cardiomyopathies; Clozapine; Echocardiography; Female; Humans; Male; Myocarditis; Retrospective Studies

Topics: Antipsychotic Agents; Clozapine; Contraindications; Humans; Myocarditis; Recurrence; Schizophrenia

Topics: Adult; Antipsychotic Agents; Australia; Clozapine; Diagnosis, Differential; Echocardiography; Electrocardiography; Guidelines as Topic; Humans; Male; Myocarditis

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Myocarditis; Psychotic Disorders

Despite the implementation of cardiac monitoring guidelines, clozapine-induced myocarditis continues to cause deaths in Australia, and the risk is a barrier to prescription of this effective drug for the treatment of schizophrenia. This study was designed to identify clinical and phenotypic risk factors for clozapine-induced myocarditis.. Possible cases of clozapine related myocarditis occurring between June 1993 and November 2009 and a comparative group of controls taking clozapine for at least 45days without cardiac disease were documented from the patients' medical records.. 105 cases, with time to onset of 10-33days, and 296 controls were included in the study. In multivariate analysis, the risk of myocarditis increased by 26% for each additional 250mg of clozapine administered in the first nine days of clozapine titration (odds ratio 1.26; 95% confidence interval 1.02-1.55; p=0.03) and concomitant sodium valproate more than doubled the risk (2.59; 1.51-4.42; 0.001). Further, each successive decade in age was associated with a 31% increase in risk (1.31; 1.07-1.60; 0.009). Nevertheless, 33 cases received less than 920mg of clozapine during the first nine days of dose titration, did not take sodium valproate and were aged less than 40years; and nine control patients received sodium valproate and more than 920mg of clozapine in the first nine days without developing myocarditis.. Clozapine should be initiated by slow dose titration and sodium valproate is best avoided, if clinically feasible, during this period. All patients commencing clozapine should be monitored for myocarditis up to Day 28.

Topics: Adolescent; Adult; Age Factors; Aged; Anticonvulsants; Antipsychotic Agents; Area Under Curve; Body Mass Index; Case-Control Studies; Clozapine; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Male; Middle Aged; Myocarditis; Retrospective Studies; Schizophrenia; Time Factors; Valproic Acid; Young Adult

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Humans; Male; Myocarditis

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Humans; Male; Myocarditis

Topics: Antipsychotic Agents; Clozapine; Constipation; Diabetic Ketoacidosis; Humans; Mass Screening; Myocarditis; Practice Guidelines as Topic

Topics: Adult; Clozapine; Humans; Male; Myocarditis; Schizophrenia

Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of 10 fatal cases of myocarditis with clozapine and identify factors associated with fatality.. Cases of myocarditis were documented from the patient's medical records and fatal cases also from autopsy reports.. The fatal cases of myocarditis occurred 1996-2009 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and in none was myocarditis suspected before death. Duration of clozapine for the fatal cases was 14-33 days with an outlier at 4.5 months. Only 3 cases had significant coronary artery disease at autopsy. Comparison of these ten cases with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (60% vs. 26%; p < 0.03) and duration of clozapine was significantly longer for fatal cases (20.8 vs. 17.0 days; p < 0.006), after exclusion of one outlier. Creatine kinase (CK) > 1000 U/L was also associated with death (p = 0.0004).. Routine monitoring for myocarditis for the first 4 weeks of clozapine, and discontinuation of clozapine in the presence of evidence consistent with myocarditis may assist to prevent fatalities occurring from early-onset myocarditis. Investigation by cardiac imaging will give a measure of severity and need for intervention. Obesity may increase the risk of mortality and CK > 1000 U/L may indicate life-threatening illness.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Body Mass Index; Cardiac Imaging Techniques; Clozapine; Fatal Outcome; Female; Humans; Male; Middle Aged; Myocarditis; Retrospective Studies; Schizophrenia

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Myocarditis; Psychotic Disorders

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.

Topics: Adult; Aged; Antipsychotic Agents; C-Reactive Protein; Case-Control Studies; Clinical Protocols; Clozapine; Drug Monitoring; Echocardiography; Female; Humans; Male; Middle Aged; Myocarditis; Troponin

Clozapine is considered as a strong psychopharmaceutic agent in symptom control of psychotic disturbances. However, possible side effects to hematologic, metabolic and cardiologic systems are still entailing a defensive application in psychiatric praxis.. A patient suffering from schizoaffective disorder clinically developed symptoms of cardial disturbances under the psychopharmacotherapy of Clozapine. Specific laboratory analysis and technical procedures were applied, clarifying the background of this serious event.. ECG and specific myocardial enzymes (CK, Troponine-I) requesting an acute myocardial infarction were negative. Specific laboratory analysis revealed positive inflammation markers with elevated C-reactive protein and interleukin-6. Additionally, there was increasing of TNF-alpha and C3 as well as an eosinophilia at differential blood cell count. Echocardiography found an unspecific dyskinesia of the left ventricle, but contrast-enhanced cardial MRI showed structural intramyocardial inhomogeneities suggesting a myocarditis.. In spite of the striking psycho-pharmacotherapeutic benefit, Clozapine may be associated with serious cardial events. We discuss these cardiological problems in association to a Clozapine therapy in regard to its clinical relevance in treatment of psychotic disturbances.

Topics: Adult; Antipsychotic Agents; Clozapine; Crisis Intervention; Dangerous Behavior; Delusions; Dose-Response Relationship, Drug; Humans; Male; Myocarditis; Patient Admission; Psychotic Disorders; Ventricular Dysfunction, Left

Topics: Adult; Antipsychotic Agents; Chest Pain; Clozapine; Heart Function Tests; Humans; Male; Myocarditis; Schizophrenia, Paranoid; Troponin; Ultrasonography; Violence

This is the case of a young man suffering from schizophrenia and treated with clozapine. He developed acute heart failure associated with pericardial effusion and midventricular dyskinesia with severe systolic dysfunction and left ventricular dilatation at echocardiogram, readily resolved after the suspension of clozapine therapy. The segmental wall motion abnormalities observed at echocardiogram in this case are peculiar and have never been described before. The possible cardiotoxic effects of clozapine have been reported previously in the literature. Because of its serious potential side effects this drug is not considered the first choice for treatment of schizophrenia. Before beginning treatment, patients should undergo a cardiac evaluation, and they should also be periodically followed up with echocardiograms.

Topics: Acute Disease; Antipsychotic Agents; Clozapine; Heart Failure; Humans; Male; Myocardial Contraction; Myocarditis; Pericardial Effusion; Schizophrenia; Ultrasonography; Ventricular Dysfunction; Ventricular Function, Left; Ventricular Function, Right; Young Adult

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Hypersensitivity; Humans; Male; Myocarditis; Olanzapine; Psychotic Disorders; Retreatment

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.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Australia; C-Reactive Protein; Case-Control Studies; Clozapine; Echocardiography; Eosinophilia; Female; Fever; Gated Blood-Pool Imaging; Humans; Male; Middle Aged; Myocarditis; Tachycardia; Troponin

Clozapine is an atypical, neuroleptic medication that can cause myocarditis. While the "gold standard" for diagnosis of myocarditis is perceived to be via myocardial biopsy, cardiovascular magnetic resonance (CMR) has also proven its utility in this respect, primarily through its ability to detect myocardial scar by late-gadolinium enhancement (LGE). Until recently, however, clozapine-induced myocarditis specifically has not been known to be associated with LGE on CMR. In that particular case, LGE was demonstrated in a patient with clozapine-induced myocarditis. However, quite important, that patient also had specific abnormalities on the electrocardiogram (ECG) and echocardiogram that corresponded to the area of LGE demonstrated by CMR. We highlight a case series of three patients with clozapine-induced myocarditis and provide a literature review to discuss and critically appraise the true incremental diagnostic value of CMR in such patients with normal ECG and echocardiography.

Topics: Adolescent; Antipsychotic Agents; Cardiovascular Diseases; Chest Pain; Clozapine; Echocardiography; Electrocardiography; Humans; Magnetic Resonance Imaging; Male; Myocarditis; Schizophrenia

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Incidence; Myocarditis

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.

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis; Pericarditis; Risk Factors; Schizophrenia

Myocarditis is a rare but life threatening adverse effect of clozapine. Some symptoms of myocarditis--elevated temperature, tachycardia and fatigue--appear commonly during the onset of treatment with clozapine and during the dose titration. We present a case of a patient with concurrent schizoaffective disorder and Parkinson's disease, who twice developed clozapine-induced myocarditis. All symptoms disappeared after the discontinuation of the drug. Early diagnosis, discontinuation of clozapine and supportive therapy of myocarditis lower the risk of a fatal outcome.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Parkinson Disease; Periodicity; Psychotic Disorders; Recurrence

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Myocarditis; Retreatment; Troponin I

Topics: Adult; Clozapine; Drug Monitoring; Humans; Male; Myocarditis; Troponin I

Clozapine, an atypical antipsychotic, is very effective in the treatment of resistant schizophrenia. However, cardiotoxicity of clozapine, particularly in young patients, has raised concerns about its safety. Increased catecholamines have been postulated to trigger an inflammatory response resulting in myocarditis, dilated cardiomyopathy, and death, although this has not yet been thoroughly studied. Here, we used the mouse to study whether clozapine administration could cause adverse myocarditis associated with an increase in catecholamines. Male Balb/C mice, age ~6 weeks, were administered 5, 10 or 25 mg/kg clozapine daily for 7 and 14 days; one group was administered 25 mg/kg clozapine plus 2 mg/kg propranolol for 14 days. Saline-treated mice served as controls. Heart sections were stained with hematoxylin and eosin for histopathological examination. Plasma catecholamines were measured with HPLC. Myocardial TNF-alpha concentrations were determined by ELISA. Histopathology of clozapine-treated mice showed a significant dose-related increase in myocardial inflammation that correlated with plasma catecholamine levels and release of TNF-alpha. Propranolol significantly attenuated these effects. A hypercatecholaminergic state induced by clozapine could explain the occurrence of myocarditis in some patients. Our data suggest that a beta-adrenergic blocking agent may be effective in reducing the incidence and severity of clozapine-induced myocarditis.

Topics: Adrenergic beta-Antagonists; Animals; Antipsychotic Agents; Catecholamines; Clozapine; Cytokines; Enzyme-Linked Immunosorbent Assay; Male; Mice; Mice, Inbred BALB C; Myocarditis; Myocardium; Propranolol; Tumor Necrosis Factor-alpha

To examine a New Zealand case series of clozapine-associated myocarditis.. All cases of myocarditis in the Intensive Medicines Monitoring Programme's (IMMP) clozapine database were identified and reviewed.. 25 cases of myocarditis associated with the use of clozapine have been reported to the IMMP. The majority of cases (84%) were male and the mean age was 35.5 years. Myocarditis occurred at daily clozapine doses ranging from 12.5 mg to 500 mg. Eighty percent of the cases developed within 1 month of starting the medicine, although in three cases the onset was more than a year after commencing clozapine. Of the 25 cases, 2 patients died.. This New Zealand case series of clozapine-associated myocarditis is similar to a recent Australian case series. Clozapine-associated myocarditis most often occurs within 1-2 months of starting clozapine, but it may develop at any time while on the medicine, and can occur even at very low doses. A data-linkage study using national morbidity and mortality datasets could estimate the incidence of clozapine-associated myocarditis in New Zealand.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Clozapine; Cohort Studies; Databases, Factual; Female; Humans; Male; Middle Aged; Myocarditis; New Zealand; Retrospective Studies; Risk Factors; Survival Rate

Clozapine is the drug of choice for treatment-resistant schizophrenia. Prompted by a patient who developed reversible clozapine-induced myocarditis after long-term treatment with clozapine for several years for chronic-resistant schizophrenia, we undertook a review of the relevant literature. Concerning the myocarditis, the patient recovered rapidly by withdrawal of clozapine and with supportive management. Psychiatric stabilisation of the patient was at least possible with a combination of quetiapine (600 mg) and amisulpride (800 mg). Well-designed studies with the aim to specifically investigate treatment options after clozapine are limited and clinical possibilities are discussed in this paper. Olanzapine and combinations using non-clozapine atypical neuroleptics have partly shown improvement, whereas evidence for successful augmentation with mood stabilisers, anticonvulsants or electroconvulsive therapy in treatment-resistant schizophrenia is limited.

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Humans; Male; Middle Aged; Myocarditis; Quetiapine Fumarate; Schizophrenia; Sulpiride

Topics: Adult; Antipsychotic Agents; Clozapine; Creatine Kinase; Electrocardiography; Female; Follow-Up Studies; Humans; Myocarditis; Schizophrenia; Tachycardia

Topics: Adult; Antipsychotic Agents; Clozapine; Contrast Media; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Male; Myocarditis; Schizophrenia

A case of acute myocarditis associated with the commencement of clozapine is described, highlighting the onset, course and possible contributing factors. There is an urgent need to raise awareness about this potentially fatal complication of clozapine use.. A 20-year-old male with schizophrenia developed a sudden onset of myocarditis after commencement of clozapine. The patient recovered with intensive medical support. The symptoms occurred around 2 weeks after starting clozapine in an inpatient setting. Possible contributing factors may have been concomitant antidepressant use and unaccustomed physical activity.. Myocarditis is an increasingly recognized complication associated with the use of clozapine. It can be fatal if not recognized and treated early. Considering that clozapine remains the gold standard in treatment of resistant psychosis, there is an urgent need to raise awareness among medical and paramedical staff involved in the care of these patients. There are also implications for recommendations and regulations regarding the use of clozapine.

Topics: Acute Disease; Adult; Antidepressive Agents; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Fluoxetine; Humans; Lithium Compounds; Male; Myocarditis; Psychotic Disorders; Risk Factors

Recently, there has been an increased recognition of the association of clozapine with myocarditis and myocardiopathy. Commonly used diagnostic tests have very limited sensitivity in diagnosing this potentially life-threatening complication. We present 3 case reports of clozapine-induced myocarditis/cardiomyopathy that illustrate the development of a combined approach involving a clinical questionnaire and diagnostic testing at our hospital. This combination approach helped in the early recognition and successful treatment of clozapine myocarditis in one of our patients. Given the increasing recognition of this adverse reaction, we felt it timely to report our experience in diagnosing and treating this clinical syndrome.

Topics: Adult; Antipsychotic Agents; Cardiomyopathies; Clozapine; Drug Monitoring; Female; Hospitals, University; Humans; Male; Middle Aged; Myocarditis; Psychotic Disorders; Surveys and Questionnaires

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Myocarditis; Psychotic Disorders

The need to consider myocarditis as one cause of flu-like symptoms in patients taking clozapine should be well entrenched. Suspicion should be heightened if the symptoms develop during the first 6-8 weeks of therapy. The FDA and the drug's manufacturer have strengthened warnings to include that a potentially fatal myocarditis may occur when taking clozapine. We aim to highlight the side effects of clozapine and increase awareness of this condition associated with the usage of the drug.

Topics: Adolescent; Clozapine; Electrocardiography; Humans; Male; Myocarditis; Schizophrenia; Serotonin Antagonists

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis

The case concerns the sudden death of a 29-year-old male during clozapine therapy started 2 weeks before. He had a history of treatment-resistant chronic schizophrenia. A complete immunohistochemical study was performed on heart specimens. Histologically, the heart presented diffuse eosinophilic infiltrates located around perivascular structures and focal myocyte necrosis with numerous interstitial eosinophils admixed with histiocytes. The diagnosis of acute myocarditis with an eosinophilic infiltrate was established as the cause of death. The autopsy findings and a detailed medical history supported the conclusion that clozapine-induced hypersensitivity myocarditis was the most likely cause of death.

Topics: Adult; Antipsychotic Agents; Clozapine; Death, Sudden, Cardiac; Fatal Outcome; Humans; Hypersensitivity, Delayed; Male; Myocarditis; Schizophrenia

Clozapine is known to cause cardiac side effects, including myocarditis, pericarditis, and cardiomyopathy. Prompted by a case of clozapine-related pericarditis in an adolescent, we undertook a retrospective chart review to discover whether any unrecognized cases of myocarditis, pericarditis, or cardiomyopathy were among the children, adolescents, and young adults we had treated with clozapine. The sample comprised a total of 36 patients, who were monitored regularly over a period ranging from 2.5 to 79 months. The average observation period was 7.5 months. Patients were assessed for potential indicators of myocarditis, pericarditis, or cardiomyopathy. In more than 66% of all patients, at least one of several parameters potentially indicative of pericarditis, myocarditis, or cardiomyopathy was abnormal in at least one instance during the observation period. In all cases in which abnormalities were discovered, the abnormalities were found to be unspecific for myocarditis, pericarditis, or cardiomyopathy. With the exception of the case which prompted our study, none of the patients were found to have developed any such disorder in the course of further treatment with clozapine.

Topics: Adolescent; Antipsychotic Agents; Aspartate Aminotransferases; Body Temperature; Cardiomyopathies; Child; Clozapine; Creatine Kinase; Electrocardiography; Female; Humans; L-Lactate Dehydrogenase; Leukocyte Count; Male; Myocarditis; Pericarditis; Retrospective Studies; Schizophrenia

A rare, but frequently fatal, side effect of the antipsychotic drug clozapine is myocarditis. We report a case of hypersensitivity myocarditis secondary to clozapine administration that was diagnosed in vivo for the first time through endomyocardial biopsy and was successfully treated with corticosteroids. Histologic diagnosis was based on the evidence of eosinophilic infiltration of the endomyocardium and eosinophil degranulation. Endomyocardial biopsy was performed in order to establish or exclude a clear-cut relationship between cardiac dysfunction and clozapine, and was crucial to establish a correct diagnosis and appropriate treatment. Clozapine withdrawal and targeted 8-day, low-dose corticosteroid therapy resolved the symptoms and restored cardiac function.

Topics: Clozapine; Drug Hypersensitivity; Female; Humans; Male; Myocarditis

Topics: Age Factors; Aged; Antipsychotic Agents; Clozapine; Cohort Studies; Health Behavior; Humans; Hypertension; Middle Aged; Myocardial Infarction; Myocarditis; Risk Assessment; Stroke; United States

Topics: Adolescent; Antipsychotic Agents; Clozapine; Electrocardiography; Female; Humans; Myocarditis; Pericarditis; Schizophrenia; Troponin I

Topics: Adult; Antipsychotic Agents; Canada; Cardiomyopathies; Clozapine; Female; Humans; Male; Myocardial Infarction; Myocarditis; Retrospective Studies; Risk Factors

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Schizophrenia

To examine the relation between antipsychotic drugs and myocarditis and cardiomyopathy.. Data mining using bayesian statistics implemented in a neural network architecture.. International database on adverse drug reactions run by the World Health Organization programme for international drug monitoring.. Reports mentioning antipsychotic drugs, cardiomyopathy, or myocarditis.. A strong signal existed for an association between clozapine and cardiomyopathy and myocarditis. An association was also seen with other antipsychotics as a group. The association was based on sufficient cases with adequate documentation and apparent lack of confounding to constitute a signal. Associations between myocarditis or cardiomyopathy and lithium, chlorpromazine, fluphenazine, haloperidol, and risperidone need further investigation.. Some antipsychotic drugs seem to be linked to cardiomyopathy and myocarditis. The study shows the potential of bayesian neural networks in analysing data on drug safety.

Topics: Antipsychotic Agents; Bayes Theorem; Cardiomyopathies; Clozapine; Databases, Factual; Drug Monitoring; Humans; Myocarditis; Neural Networks, Computer; Pharmacoepidemiology; World Health Organization

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Myocarditis; United States

(1) Clozapine, a neuroleptic known to carry a risk of agranulocytosis, can also induce myocarditis and dilated myocardiopathy. (2) Patients taking clozapine who develop dyspnoea, fatigue, chest pain or collapse should be screened for myocarditis, especially during the first weeks of treatment.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Clozapine; Humans; Myocarditis

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Death, Sudden, Cardiac; Humans; Myocarditis; Risk Factors

Topics: Antipsychotic Agents; Clozapine; Death, Sudden, Cardiac; Humans; Myocarditis; Risk Factors

Topics: Adult; Antipsychotic Agents; Cardiomyopathies; Clozapine; Death, Sudden, Cardiac; Factor V; Female; Humans; Myocarditis; Pulmonary Embolism; Risk Factors; Schizophrenia

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Australia; Clozapine; Humans; Incidence; Male; Myocarditis; Schizophrenia

Topics: Adult; Aged; Antipsychotic Agents; Cardiomyopathies; Clozapine; Death, Sudden, Cardiac; Drug Hypersensitivity; Female; Humans; Male; Myocarditis; Parkinson Disease; Schizophrenia

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

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Australia; Cardiomyopathy, Dilated; Clozapine; Fatal Outcome; Female; Humans; Incidence; Male; Middle Aged; Myocarditis; Retrospective Studies; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Electrocardiography; Humans; Male; Myocarditis; Pericarditis; Schizophrenia, Paranoid

Drugs have different kinds of adverse effects, one of the most serious being myocarditis. This condition is usually reported as an incidental finding, but can also be fatal. The drug clozapine, available on the European market since the 1970s, can cause myocarditis. This report describes the myocardial findings in a patient who died suddenly after taking increasing doses of clozapine. An allergic adverse reaction to clozapine is suspected. The immediate cause of death was an embolus of the central pulmonary artery.

Topics: Adult; Antipsychotic Agents; Clozapine; Fatal Outcome; Female; Humans; Myocarditis; Pulmonary Embolism

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Overdose; Electrocardiography; Fatal Outcome; Humans; Male; Myocarditis; Schizophrenia

Clozapine is a high-dose neuroleptic, which is recommended only for those cases in which patients have failed to respond adequately to standard antipsychotic drugs. This report describes a 45 year old man with ischaemic heart disease who died of cardiogenic shock 11 days after starting treatment with clozapine. Autopsy showed apart from coronary atherosclerosis and interstitial fibrosis a considerable infiltration of eosinophilic granulocytes in the myocardium suggesting myocarditis as the cause of death.

Topics: Clozapine; Electrocardiography; Fatal Outcome; Humans; Male; Middle Aged; Myocarditis; Myocardium

Topics: Acute Disease; Adult; Clozapine; Death, Sudden; Dibenzazepines; Humans; Male; Myocarditis