clozapine and Cardiomyopathies

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

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

Clozapine is an alternative antipsychotic medication used to control symptoms of schizophrenia and to reduce risks of suicidal behavior in patients who did not adequately respond to standard medication. Due to severe side effects including cardiomyopathy and myocarditis its clinical use is limited.. A 31-year-old man of east European descent presented to the emergency medical department with fatigue, shortness of breath and chest pain. Due to a schizoaffective disorder he was treated with clozapine and lithium. Echocardiography revealed severely impaired left ventricular systolic function. After exclusion of coronary artery disease by coronary angiography an endomyocardial biopsy was performed according to the guidelines. This confirmed the clinically suspected toxic cardiomyopathy. Therefore, antipsychotic treatment was immediately changed and state of the art heart failure medication was started resulting in a clear improvement of left ventricular function.. In patients treated with clozapine or lithium and clinical signs of heart failure, toxic cardiomyopathy should be considered.

Topics: Adult; Antipsychotic Agents; Biopsy; Cardiomyopathies; Chest Pain; Clozapine; Dyspnea; Echocardiography; Fatigue; Heart; Humans; Male; Myocardium; Psychotic Disorders; Treatment Outcome

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

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

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

Clozapine is exceptionally effective in psychotic disorders and can reduce suicidal risk. Nevertheless, its use is limited due to potentially life-threatening adverse effects, including myocarditis and cardiomyopathy. Given their clinical importance, we systematically reviewed research on adverse cardiac effects of clozapine, aiming to improve estimates of their incidence, summarize features supporting their diagnosis, and evaluate proposed monitoring procedures. Incidence of early (≤2 months) myocarditis ranges from <0.1 to 1.0 % and later (3-12 months) cardiomyopathy about 10 times less. Diagnosis rests on relatively nonspecific symptoms, ECG changes, elevated indices of myocardial damage, cardiac MRI findings, and importantly, echocardiographic evidence of developing ventricular failure. Treatment involves stopping clozapine and empirical applications of steroids, diuretics, beta-blockers, and antiangiotensin agents. Mortality averages approximately 25 %. Safety of clozapine reuse remains uncertain. Systematic studies are needed to improve knowledge of the epidemiology, avoidance, early identification, and treatment of these adverse effects, with effective and practicable monitoring protocols.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Drug Monitoring; Humans; Psychotic Disorders

Clozapine is a unique anti-psychotic medication that is most effective in the treatment of refractory schizophrenia and reducing suicidality. Cardiomyopathy is among the side effects of this medication that limits its use. There are a number of case reports, case series and expert opinion papers discussing clozapine induced cardiomyopathy, but there is no evidence-based review of the subject to guide clinicians.. We undertook a systematic review of the literature on cardiomyopathy associated with clozapine. The primary systemic search was in MEDLINE but EMBASE, PsycINFO, and Cochrane were searched and manufacturers of clozapine were contacted for cases. Articles were then individually reviewed to find additional reports.. We identified 17 articles detailing 26 individual cases and 11 additional articles without individual case data. The mean age at time of diagnosis was 33.5 years. The mean dose of clozapine on presentation was 360 mg. Symptoms developed at an average of 14.4 months after initiating clozapine. The clinical presentation was generally consistent with heart failure: including shortness of breath (60%) and palpitations (36%). Echocardiography at presentation showed dilated cardiomyopathy in 39% of cases and was not specified in other cases.. There should be a low threshold in performing echocardiography in suspected cases of clozapine induced cardiomyopathy. Clozapine should be withheld in the setting of cardiomyopathy without other explanation. There is limited data on the safety of drug re-challenge in clozapine induced cardiomyopathy. Re-challenge may be considered in carefully selected cases but close monitoring and frequent echocardiography are required.

Topics: Animals; Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Ultrasonography

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

The heart is a target of injury for many chemical compounds, both medically prescribed and not medically prescribed. Pathophysiologic mechanisms underlying the development of chemical-induced cardiomyopathies vary depending on the inciting agent, including direct toxic effects, neurohormonal activation, altered calcium homeostasis, and oxidative stress. Numerous chemicals and drugs are implicated in cardiomyopathy. This article discusses examples of medication and nonprescribed drug-induced cardiomyopathies and reviews their pathophysiologic mechanisms.

Topics: Amphetamine; Anabolic Agents; Anthracyclines; Antineoplastic Agents; Cardiomyopathies; Chloroquine; Clozapine; Cocaine; Doxorubicin; Ephedra; Ethanol; Heart; Humans; Methylphenidate; Nonprescription Drugs; Prescription Drugs; Testosterone

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

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

Atypical antipsychotic medications (second-generation antipsychotics) have been increasingly used in the treatment of a number of psychotic disorders since their introduction in 1988, with the newest medication introduced in 2002. Justification for their use includes claims of equal or improved antipsychotic activity over first-generation antipsychotics, increased tolerability, and decreased side effects. However, there are still significant adverse effects and toxicities with this class of medications. Toxicologic exposures and fatalities associated with atypical antipsychotics continue to increase in the United States, with 32,422 exposures and 72 deaths in 2003. There have also been Food and Drug Administration warnings in the past year about how some atypical antipsychotics have been marketed to minimize the potentially fatal risks and claiming superior safety to other atypical antipsychotics without adequate substantiation, indicating the toxicologic potential of these agents may be underestimated.. Continued research to evaluate adverse effects and tolerability of atypical antipsychotics compared with first-generation antipsychotics and each other is reviewed. This article also reviews the pharmacodynamics, pharmacokinetics, and drug interactions with these medications. New therapeutic monitoring recommendations for this class of medications have also been proposed. Finally, clinical toxicity in overdose and management are reviewed.. While new atypical antipsychotic medications may have a safer therapeutic and overdose profile than first-generation antipsychotic medications, many adverse and toxic effects still need to be considered in therapeutic monitoring and overdose management.

Topics: Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Benzodiazepines; Cardiomyopathies; Child; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Drug Interactions; Drug Overdose; Dry Eye Syndromes; Humans; Hyperlipidemias; Hypotension; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Seizures; Thiazoles

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

Topics: Antipsychotic Agents; Benzodiazepines; Cardiomyopathies; Catatonia; Clozapine; Heart Failure; Humans; Olanzapine; Rhabdomyolysis

A patient in a medium secure psychiatric unit with a 19-year history of treatment-resistant schizophrenia and violence whose mental illness only responded to clozapine, was noted to have a sustained tachycardia. Echocardiography revealed mild biventricular cardiomyopathy. The patient was not significantly affected by this. Initial recommendation from Cardiology was to consider discontinuation of clozapine. It was decided, however, that the risk of worsening psychosis and resultant violence outweighed the risk of the patient's relatively mild cardiomyopathy. The patient was commenced on ramipril, and later bisoprolol. The patient no longer requires treatment in a medium secure unit and has remained on clozapine with follow-up from cardiology.

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

Topics: Antipsychotic Agents; Cardiomyopathies; Causality; 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

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Memantine; Schizophrenia

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

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

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

The antipsychotic drug (APD) clozapine (CLZ) is under-prescribed because of concerns about its safety. We evaluated in separate protocols the frequency of cardiomyopathy and hyponatraemia, which are adverse drug effects, where few comparative studies are available.. Cross-sectional studies in subjects treated for at least 3 consecutive months with the same drug were conducted. Cardiomyopathy: Patients undergoing treatment either with CLZ (n = 125) or with other typical or atypical APDs (n = 59) were examined by a cardiologist who also recorded echocardiograms and electrocardiograms in order to diagnose cardiomyopathy. Hyponatraemia: Fasting sodium levels were assessed in patients receiving any of the following treatments: CLZ (n = 88), other atypical APDs (n = 61), typical APDs (n = 23), typical + atypical APDs (n = 11), and other drugs/drug-free (n = 36).. Cardiomyopathy: No case of cardiomyopathy was detected. The frequency of abnormal ventricular ejection fraction (< 55%) was similar in both treatment groups (p = 1). Hyponatraemia: The frequency of hyponatraemia (percentage; 95% CI) was: CLZ (3.4%; -0.7, 7.1); other atypical APDs (4.9%; -0.5, 10.3); typical APDs (26.1%; 8.2, 44.0); typical + atypical APDs (9.1%; -7.8, 26.0); other drugs/drug-free (0%). None of the CLZ hyponatraemia subjects were on monotherapy.. Our results are at odds with previous studies of CLZ-associated cardiomyopathy. However, they must be compared to further cross-sectional or prospective studies because most published data come from either case reports or pharmacovigilance systems. The frequency of hyponatraemia during CLZ administration was similar to that observed with other atypical APDs, and it was significantly lower than that recorded with typical agents. These results, along with numerous case reports on the effects of CLZ in patients with polydipsia and water intoxication, point to a safe or even positive profile of CLZ on electrolytic regulation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Cardiomyopathies; Clozapine; Cross-Sectional Studies; Female; Humans; Hyponatremia; Male; Middle Aged; Venezuela; Young Adult

We aimed to identify the baseline prevalence of cardiac dysfunction in patients commencing clozapine, assess adherence with echocardiographic monitoring recommendations, and evaluate the utility and cost of echocardiographic monitoring for the development of clozapine-associated myocarditis and cardiomyopathy.. A retrospective longitudinal cohort study was undertaken of 159 consecutive patients from a major tertiary centre commencing clozapine in the period January 2002 to July 2009.. Some 73% of patients had a baseline study, and 11% had a six-month follow-up study. Nine patients had abnormal left ventricular function at baseline. Myocarditis was identified in three patients, with all cases occurring within the first month of treatment and suspected on clinical grounds before an echocardiogram was performed. One case of possible cardiomyopathy was identified. The cost of echocardiographic screening in the first year of treatment was estimated at $AUD 209,356 per case of cardiomyopathy detected.. The prevalence of cardiac dysfunction in patients commencing clozapine is high, and there are challenges in adhering with the recommended protocol for monitoring. Routine echocardiography is not useful in the detection of clozapine-associated myocarditis. Although cardiomyopathy may be identified, it is rare and associated with significant cost. Recommendations for routine echocardiographic monitoring should be re-examined.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cardiomyopathies; Clozapine; Cohort Studies; Echocardiography; Female; Humans; Male; Middle Aged; Practice Guidelines as Topic; Prevalence; Retrospective Studies; Schizophrenia; Ventricular Function, Left

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; Cardiomyopathies; Clozapine; Humans; Japan; Male; Schizophrenia; Young Adult

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

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

Available information regarding clozapine-related cardiomyopathy is limited to reports of severe left ventricular dysfunction not rarely with fatal clinical evolution. A subclinical cardiotoxic effect might be diagnosed using echocardiography and N-terminal pro-B-type natriuretic peptide assay.. Thirty-eight patients with psychotic disorder in chronic therapy with clozapine (24 male and 14 female subjects; mean age, 38.4 years) were enrolled. Left ventricular ejection fraction (LVEF) was measured by area-length method (average of 5 measurements).. Twelve patients showed a mild depression of left ventricular function (LVEF between 50% and 55%), 2 LVEF less than 50% and 1 less than 30%. The area under the receiver operating characteristic curve for N-terminal pro-B-type natriuretic peptide as a predictor of left ventricular dysfunction was 0.87.. A subclinical left ventricular dysfunction was found in 3 of 38 patients, whereas a mild impairment of the left ventricular systolic function occurred in 1 of 3 of young, previously healthy, clozapine-treated patients A prospective study in clozapine-naive patients may be useful to better understand cardiotoxic effects of clozapine.

Topics: Adult; Antipsychotic Agents; Biomarkers; Cardiomyopathies; Clozapine; Female; Humans; Male; Mental Disorders; Natriuretic Peptide, Brain; Peptide Fragments; ROC Curve; Ultrasonography; Ventricular Dysfunction, Left

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

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Cardiomyopathies; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Olanzapine; Schizophrenia; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Cardiomyopathies; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Humans; Male; Schizophrenia

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: Adult; Cardiomyopathies; Clozapine; Depressive Disorder; Humans; Male; New South Wales

Topics: Adult; Antipsychotic Agents; Cardiomyopathies; Clozapine; Female; Humans; Schizophrenia, Paranoid

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

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

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

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