Abstract

Clozapine is approved in treatment-resistant schizophrenia (TRS). It represents a very effective drug as most patients who demonstrate good tolerability may experience a remarkable improvement of their psychotic symptomatology as well as enhancement of their quality of life. However, as clozapine may induce severe and life-threatening adverse effects, its prescription and safety profile should be carefully considered by clinicians. Clozapine-induced pericarditis represents a relatively rare adverse event that may develop from 9 days to 7 years after clozapine initiation, but with a higher probability during the up-titration phase and in the first 5-6 weeks from its introduction. The presentation of clozapine-induced pericarditis may range from a nearly asymptomatic clinical picture (i.e., flu-like symptoms and elevated pro-inflammatory indices) up to fulminating cardiomyopathy resulting in death. A practical clinical flowchart on clozapine rechallenge is here proposed.

Clozapine Indications

Clozapine is a dibenzodiazepine first developed in 1961 as a multireceptor second-generation antipsychotic (SGA), first approved by the Food and Drug Administration (FDA) in the United States in 1989 for treatment-resistant schizophrenia (TRS).¹ Clozapine has been estimated to effectively manage two-thirds of schizophrenic patients who do not respond adequately to first-generation antipsychotic (FGA) or SGA² Furthermore, clozapine has also been given a FDA indication for the management of recurrent suicidality in individuals with schizophrenia and/or schizoaffective disorder.³ Moreover, international consensus guidelines recommend a trial of clozapine for individuals with schizophrenia with persistent hostility or violent behavior⁴ and comorbid substance use in schizophrenia.⁵

Common Clozapine Side Effects

Substantial evidence shows clozapine's efficacy in reducing suicidality amongst schizophrenic patients,⁶ in managing drug-induced tardive dyskinesia,⁷ in reducing aggressive behavior, comorbid alcohol and/or drug use, and treating both positive and negative symptoms.⁸ Despite this, clinicians are generally hesitant in prescribing clozapine for those schizophrenic patients who meet prescription criteria. This is mainly due to the clinicians' perceived burden of frequent blood monitoring (due to agranulocytosis and severe neutropenia) and fear of potentially severe and even life-threatening adverse events, including gastrointestinal hypomotility which may lead to a bowel infarction, pancreatitis, renal insufficiency, myocarditis and cardiomyopathy.^8-9 (see Table 1).

Table 1: Serious and potentially life-threatening adverse effects of clozapine

Common (≥1/100)	Uncommon (≥1/1000)	Rare (≥1/10000)
Sedation	Agranulocytosis (LT)	Myocarditis/pericarditis (LT)
Hypertension	Diabetes mellitus, hyperglycemia, diabetic ketoacidosis (LT)	Cardiomyopathy (LT)
Weight gain	Metabolic syndrome	Heat stroke (LT)
Seizure (LT)	Delirium	Hepatic failure (LT)
Hypersalivation, sialorrhea	Liver enzyme abnormalities	Colitis (LT)
Benign fever	Interstitial nephritis	Intestinal obstruction, paralytic ileus (LT)
Hypotension	Shuttering	Pancreatitis (LT)
Nausea	Thrombocytopenia	Pneumonia (LT)
Nocturnal enuresis	Dysphonia	Respiratory failure (LT)
Gastroesophageal reflux	Neuroleptic malignant syndrome (LT)	Vasculitis
Constipation		Skin rash
Tachycardia		Ocular pigmentation
Dizziness		Priapism
Blurred vision		Parotid gland swelling
Dysarthria		Rhabdomyolysis
Blood dyscrasias such as leukopenia, decreased white blood cells, neutropenia, eosinophilia, leukocytosis		QT prolongation (LT)
		Sudden death (LT)

III. Clozapine Cardiac Effects

Although uncommon, numerous cardiovascular side effects have been associated with clozapine treatment, including hypotension, cardiac conduction abnormalities, tachycardia, myocarditis, polyserositis, and pericarditis.^10-14 Wehmeier et al¹⁰ initially reported in their review around 65 cases of myocarditis, 52 cases of cardiomyopathy, and 6 cases of pericarditis occurring during clozapine treatment. A recent nationwide Danish register-based study documented that clozapine-associated cardiac adverse effects are rare, with 0.03% developing myocarditis and no patients were developing pericarditis within two months after clozapine initiation, and 0.12% developing cardiomyopathy within two years from introduction.¹² However, there are numerous case reports of clozapine-induced pericarditis and serositis, as illustrated in Table 2.

Table 2: Summary of studies describing clozapine-induced pericarditis

Author (s), (date of publication), Country	Characteristics of study and sample features	Clinical manifestations	Diagnostic and Treatment findings
Primary and Secondary Delusional Infestation
Murko et al. [22]	Case report (n=1), 43yy, M, Caucasian, paranoid schizophrenia, clozapine (750 mg/d) started 7 years before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: ziprasidone 160 mg/d, paroxetine 60 mg/d	Shortness of breath, fever, retrosternal chest discomfort and pain Pericardial effusion	Laboratory tests: NA ECG: sinus rhythm and nonspecific T-wave abnormalities Chest RX: stable cardiomegaly Echocardiogram: pericardial fluid suggestive of cardiac tamponade Chest TC: NA Therapy: pericardiocentesis and supplemental oxygen then furosemide Clinical remission after diuresis and clozapine discontinuation, switch to ziprasidone Asymptomatic during a follow-up of 3 months
Kay et al. [23]	Case report (n=1), 16yy, F, TRS, clozapine (100 mg BID) started 3 weeks before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: bentropine mesylate 2 mg/d, diazepam 2 mg/d	Palpitations, central and left-side chest pain, shortness of breath, tachycardia Pericarditis and pericardial effusion	Laboratory tests: ↑serum Troponin I ECG: p-mitral in lead I, T-wave flattening in lead III, ST-segment elevation concave up-ward across all leads, a biphasic P-wave in V1 Chest RX: NA Echocardiogram: NA Chest TC: NA Therapy: spontaneously resolved without clozapine discontinuation No data on follow-up
Wehmeier et al. [24]	Case report (n=1), 17yy, M, paranoid schizophrenia, clozapine (175 mg/d) started 3 weeks before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: NA	Epigastric pain Pericardial effusion and secondary pancreatitis	Laboratory tests: ↑pancreas amylase and lipase levels ECG: normal Chest RX: NA Echocardiogram: pericardial effusion Chest TC: pericardial effusion Therapy: pericardiocentesis Clinical remission after clozapine discontinuation, switch to haloperidol (and then to olanzapine) No data on follow-up
Boot et al. [25]	Case report (n=1), 21yy, M, Caucasian, paranoid schizophrenia, clozapine (150 mg/d) started 10 days before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: olanzapine (15 mg/d),	Flu-like symptoms, fever, generalized malaise, headache, anorexia, dry cough, pleuritic-type chest pain during clozapine titration and breathlessness	Laboratory tests: NA ECG: NA Chest RX: initially normal then enlarged cardiac silhouette and bilateral pleural effusion progressively resolved after clozapine discontinuation Echocardiogram: pericardial and pleural effusion with no comprise of cardiac function Chest TC: NA Clinical remission after clozapine discontinuation, switch to olanzapine No data on follow-up
Rathore et al. [26]	Case report (n=1), 47yy, M, Caucasian, paranoid schizophrenia, clozapine started few days before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: alcohol, tobacco Concomitant therapy: sertraline (300 mg/d)	Tachycardia, tachypnoea, fever	Laboratory tests: NA ECG: sinus tachycardia and non-specific ECG changes Chest RX: cardiomegaly with globular heart Echocardiogram: normal LV size and function, septal bounce, mild pericardial effusion and thickened pericardium posteriorly Chest TC: NA Clinical remission after clozapine discontinuation, switch to olanzapine Asymptomatic during follow-up of 4 months
Körtner et al. [27]	Case report (n=1), 22yy, M, Caucasian, paranoid schizophrenia, clozapine (350 mg/d) started 3 weeks before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: aripiprazole	Flu-like symptoms and mild diarrhea pericarditis	Laboratory tests: ↑eosinophilia; ↑CRP, ECG: mild sinus tachycardia Chest RX: NA Echocardiogram: normal ejection fraction and pericardial effusion Chest TC: NA Clinical remission after clozapine discontinuation, switch to perazine Asymptomatic during follow-up of 5 weeks
Raju et al. [28]	Case report (n=1), 33yy, M, Caucasian, schizophrenia, clozapine (200 mg BID) started 10 days before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: NA	Progressive shortness of breath, intermittent chest discomfort, tachycardia, tachypnea pericarditis	Laboratory tests: ↑CRP, ↑WBC, ECG: widespread ST elevation in all leas Chest RX: normal heart shadow Echocardiogram: pericardial effusion Chest TC: NA Clinical remission after clozapine discontinuation No data on follow-up
Dauner et al. [29]	Case report (n=1), 29yy, F, Caucasian, schizophrenia, clozapine (300 mg/d) started (no data on clozapine initiation) Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: olanzapine 10 mg/d; valproic acid 750 mg/d	shortness of breath, fatigue, tachycardia, tachypnea, 3-month history of leucocytosis pericarditis	Laboratory tests: ↑D-dimer, ↑WBC, ↑CRP ECG: NA Chest RX: negative Echocardiogram: large pericardial effusion with tamponade and ejection fraction of 45% to 50% Chest TC: negative for pulmonary embolism Therapy: pericardiocentesis and clozapine discontinuation No data on follow-up
Crews et al. [30]	Case report (n=1), 17yy, M, Caucasian, TRS, clozapine (350 mg/d) started 4 weeks before clinical onset Concomitant diagnoses: mild asthma Concomitant drugs of abuse: NA Concomitant therapy: NA	tachycardia, fever, mild gastrointestinal disturbance pericarditis	Laboratory tests: ↑CRP ECG: sinus tachycardia Chest RX: minimal bilateral pleural effusions Echocardiogram: large pericardial effusion Chest TC: NA Therapy: pericardiocentesis and clozapine discontinuation Clinical remission after clozapine discontinuation, switch to olanzapine (ineffective), hence, clozapine rechallenge with daily measurement of temperature, blood pressure, pulse rate and clinical signs and symptoms (i.e., chest pain, cough and dyspnoea), ECG monthly and echocardiogram every three months No data on follow-up
Jayathilake et al. [31]	Case report (n=1), 32yy, M, TRS, clozapine (350 mg/d) started 5 weeks before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: NA	Left-sided pleuritic chest pain, shortness of breath pericarditis	Laboratory tests: normal ECG: diffuse saddle shaped (concave) ST segment elevation with PR segment depression Chest RX: normal Echocardiogram: normal Chest TC: normal Therapy: pericardiocentesis and clozapine discontinuation Clinical remission after clozapine discontinuation, switch to amisulpride No data on follow-up
Markovic et al. [32]	Case report (n=1), 21yy, M, Caucasian, schizophrenia, clozapine (100 mg BID) started 5 months before clinical onset Concomitant diagnoses: none Concomitant drugs of abuse: tobacco Concomitant therapy: sertraline 50 mg/d	Chest pain, progressive shortness of breath, fever, tachycardia, dyspnea pericarditis	Laboratory tests: ↑CRP, ↑ fibrinogen ECG: sinus tachycardia Chest RX: increased dimensions of cardiac shadow with an enlarged left ventricle Echocardiogram: pericardial effusion suggestive of a cardiac tamponade Chest TC: NA Therapy: pericardiocentesis and clozapine discontinuation Clinical remission after clozapine discontinuation Asymptomatic during a follow-up up to 3 months
Albouaini et al. [33]	Case report (n=1), 21yy, unspecified diagnosis, clozapine started before clinical onset (unspecified dosage and clozapine initiation) Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: NA	Chest pain Constrictive perimyocarditis	Laboratory tests: ↑eosinophilia, ↑TnT ECG: unspecified Chest RX: NA Echocardiogram: small pericardial effusion with thickened pericardium and a striking postero-lateral echo-bright area, without clear delineation between fibrin clot and subepicardial inflammatory process Cardiac MRI: mild systolic dysfunction Therapy: unspecified Clinical remission after clozapine discontinuation No data on follow-up
De Berardis et al. [36]	Case report (n=1), 31yy, M, Caucasian, TRS, clozapine (175 mg/d) started 11 days before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: valproic acid (500 mg BID)	tachycardia, fever, chest pain, progressive shortness of breath, mild gastrointestinal disturbance, dyspnea  pericarditis	Laboratory tests: ↑CRP, ↑ creatine kinase, ↑ Troponin T, ↑ fibrinogen, ↑eosinophilia ECG: sinus tachycardia with diffuse alteration of anterolateral ST segment Chest RX: NA Echocardiogram: diffuse, moderate pericardial effusion without cardiac tamponade and myocardial dysfunction Chest TC: NA Therapy: pericardiocentesis and clozapine discontinuation, switch to aripiprazole Clinical remission after clozapine discontinuation Asymptomatic during a follow-up up to 16 months
Cadeddu et al. [37]	Case report (n=1), 29yy, F, schizoaffective disorder, clozapine (225 mg/d) started 3 weeks before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: oral contraceptive and antifungals	nausea, vomiting, palpitations pericarditis	Laboratory tests: ↑eosinophilia; ↑ CRP ECG: sinus tachycardia, ST segment depression and inversion of T-waves in inferior and lateral leads Chest RX: NA Echocardiogram: pericardial effusion suggestive of iatrogenic pericarditis Chest TC: NA Abdominopelvic TC: NA Clinical remission after clozapine discontinuation No data on follow-up
De Berardis et al. [38]	Case report (n=1), 27yy, F, schizoaffective disorder, clozapine (100 mg BID) started 7 days before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: LAI aripiprazole (400 mg OM), valproic acid (500 mg BID), lorazepam (1 mg/d)	Mild shortness of breath, mild elevation in body temperature pericarditis	Laboratory tests: ↑creatine kinase; ↑ CRP; ↑ troponin ECG: sinus tachycardia Chest RX: NA Echocardiogram: hyperkinetic cardiac activity with a preserved ventricular kinetic without dilation, mild pericardial effusion without cardiac tamponade or myocardial dysfunction Chest TC: NA Clinical remission after clozapine discontinuation and indomethacin administration No data on follow-up
Bath et al. [39]	Case report (n=1), 20yy, F, TRS, clozapine started 10 months before clinical onset (unspecified dosage) Concomitant diagnoses: NA Concomitant drugs of abuse: none Concomitant therapy: NA	Chest pain, shortness of breath, productive cough, tachypnea, tachycardia Pericarditis	Laboratory tests: ↑WBC; ↑ CRP ECG: NA Chest RX: NA Echocardiogram: pericardial effusion without cardiac tamponade Chest TC: left lower lobe pneumonia with large pericardial effusion Clinical remission after clozapine discontinuation Asymptomatic during a follow-up up to 3 months
Clozapine-induced polyserositis including pericarditis
Catalano et al. [41]	Case report (n=1), 21yy, M, Caucasian, paranoid schizophrenia, clozapine started 8 weeks before clinical onset Concomitant diagnoses: asthma Concomitant drugs of abuse: cannabis, alcohol, tobacco Concomitant therapy: sertraline 300 mg/d; buspirone 10 mg TID	Shortness of breath, diaphoresis, chills, fever, intermittent retrosternal chest and right-sided pleuritic chest discomfort and pain No clinical improvement after antibiotic treatment Pleural and pericardial effusion	Laboratory tests: ↑WBC ECG: sinus tachycardia and nonspecific ST changes Chest RX: cardiomegaly with areas of increased interstitial changes, some slight increase in pulmonary vascular marking and a wedge infiltrate in the right lower lobe; then, bilateral pleural effusions, a prominent cardiac silhouette and pulmonary vascular congestion Echocardiogram: mitral leaflet thickening with no stenosis or prolapse and mild dilation of both ventricles with normal wall motion; pericardial effusion and suggestive of cardiac tamponade Chest TC: pericardial and bilateral pleural effusions, suggestive of constrictive pericarditis Therapy: pericardiocentesis and supplemental oxygen then furosemide Clinical remission after diuresis and clozapine discontinuation, switch to risperidone Asymptomatic during a follow-up of 2 months
Branik and Nitschke [42]	Case report (n=1), 17yy, F, treatment-resistant BD, clozapine started 14 days before clinical onset Concomitant diagnoses: NA Concomitant drugs of abuse: NA Concomitant therapy: valproate (1500 mg/d), clopenthixol (5 mg/d)	Epigastric pain, nausea, vomiting, fever Pericarditis and polyserositis	Laboratory tests: ↑CRP, ↑WBC, ↑troponin-T, ↑GGT, ↑eosinophilia ECG: T-flattening with inversion Chest RX: NA Echocardiogram: pericardial effusion Chest TC: NA Abdominopelvic TC: enterocolitis Clinical remission after clozapine discontinuation No data on follow-up
Bhatti et al. [43]	Case report (n=1), 36yy, F, schizophrenia, clozapine (300 mg/d) started 14 days before clinical onset Concomitant diagnoses: seizure disorder Concomitant drugs of abuse: NA Concomitant therapy: quetiapine (400 mg/d), paroxetine 20 mg/d, aripiprazolo 15 mg BID, olanzapine 20 mg/d, ziprasidone 80 mg BID.	Tachycardia, tachypnea, hypoxemia, diffuse erythematous macular rash around neck and chest Pericarditis, pericardial tamponade, polyserositis and dermatologic symptoms	Laboratory tests: NA ECG: NA Chest RX: NA Echocardiogram: bilateral pleural effusions, pericardial effusion, small amount of ascites Chest TC: no thromboembolism Clinical remission after clozapine discontinuation No data on follow-up
Bugge et al. [44]	Case report (n=1), 23yy, M, schizophrenia, clozapine (300 mg/d) started 1 week before clinical onset Concomitant diagnoses: none Concomitant drugs of abuse: NA Concomitant therapy: NA	Flu-like symptoms, fever, nausea, non-productive cough, headache, muscle pain, hypertension, tachycardia Parenchymal infiltration in both of the lungs, pericardial fluid, heart failure and respiratory distress	Laboratory tests: ↑creatine kinase, ↑ LDH, ↑AST, ↑ CRP, ↑ myoglobin, ↑Troponin T, ↑ fibrinogen, ↑D-dimer, ↑WBC, ↑eosinophilia ECG: normal Chest RX: parenchymal infiltration in both lungs Echocardiogram: left ventricular ejection fraction of 54% and pericardial fluid Chest TC: NA Therapy: clozapine discontinuation Clinical remission after clozapine discontinuation Asymptomatic during a follow-up of 4 years
Trincas et al. [45]	Case report (n=1), 42yy, F, borderline personality disorder and schizophrenia, clozapine (400 mg/d) started 3 months before Concomitant diagnoses: none Concomitant drugs of abuse: tobacco Concomitant therapy: valproic acid (800 mg/d), sertraline (100 mg/d), zuclopenthixol (20 mg/d)	Fever, chest pain Pericarditis, polyserositis	Laboratory tests: ↑WBC, neutrophilia and monocytosis, ↑ CRP ECG: NA Chest RX: pleural effusion in lateral and back location, with enlarged heart especially in left ventricle Echocardiogram: NA Chest TC: NA Therapy: pericardiocentesis and supplemental oxygen then furosemide Clinical remission after diuresis and clozapine discontinuation, switch to risperidone Asymptomatic during a follow-up of 2 months

Clozapine treatment requires careful monitoring of patients to ensure that potentially severe and life-threatening adverse events are detected at an early stage and promptly managed. Overall, while it has been well documented that supratherapeutic dosages of clozapine may induce cardiac arrhythmia, respiratory depression, and other clinically relevant medical consequences, cardiovascular adverse events, including pericarditis, myocarditis, and polyserositis, can be reported at therapeutic dosages.^8,13,15-18 There are estimated epidemiological data only for myocarditis and cardiomyopathy, while the occurrence of clozapine-induced pericarditis has yet to be established, being reported only in isolated case reports (see Table 2).^8,11,19-23 For instance, an incidence has been documented of clozapine-induced myocarditis ranging from 0.7% to 3.0% amongst clozapine-treated patients (compared to 1.8 per 10.000.000 in the general population).^24-26 Cardiomyopathy (i.e., a chronic disease of myocardial contractile dysfunction) has been described with a reported incidence ranging from 0.02% and 0.1%.¹¹ Generally, cardiac adverse events occur most frequently during the initiation of clozapine therapy and during the acute treatment and dose-titration phase.¹⁰ For instance, myocarditis (i.e., an inflammatory disorder of the myocardium) has been reported to be a non-dose-dependent adverse event that frequently occurs within the first two months after clozapine initiation,¹¹ with the highest rate for the first month.¹²

Overall, the clinical presentation of clozapine-induced pericarditis may range from a fulminating onset resulting in death within hours to a mild flu-like picture accompanied by fever, tachycardia, and increased levels of troponin I and/or T as well as eosinophilia (see Table 2). Generally, clozapine may induce pericardial effusion and pericarditis from 7-9 days to 7 years after its initiation (see Table 2), and sometimes it may recur after rechallenging with clozapine.^18,23,28-29

There are no consensus guidelines for monitoring cardiac or pericardial adverse effects in clozapine-treated patients. In general, before initiating clozapine therapy, clinicians should perform an appropriate medical history and physical examination (including screening for possible underlying cardiac problems) as well as a family history for investigating premature coronary heart disease. Performing an ECG, measuring creatine phosphokinase-MB, C-reactive protein (CRP), troponin blood levels, and echocardiography is recommended in patients who manifest fever, flu-like symptoms, or other cardiopulmonary symptoms (i.e., tachycardia, chest pain, progressive shortness of breath, dyspnea). Some authors suggest careful monitoring of the onset of eosinophilia, as it might predict sub-clinical cardiac adverse events, including pericarditis.^{20,22-23,30-33} Eosinophilia usually occurs in 0.2% to 62% of all clozapine-treated patients and develops 3 to 5 weeks after clozapine initiation, disappears spontaneously after 4 weeks, and may reach more than 50% of white cells.^34-35 Layland et al¹¹ and Prisco et al³⁶ also suggest measuring brain natriuretic peptide (BNP) and pro-BNP levels to detect early and asymptomatic cardiac dysfunctions and clozapine-induced pericarditis. Furthermore, a preventive screening is indicated during the first three weeks with CPR, troponin T and I levels for all patients initiating clozapine.³⁷

Therefore, the decision to prescribe clozapine is mainly influenced by weighing the burden of psychosis and suicidality versus the risk of developing severe adverse effects, including cardiac consequences, and it should be undertaken on an individual basis, in close collaboration with the patient, and closely associated with early recognition of TRS, as there is strong evidence that earlier use of clozapine is associated with better response and management of this condition.³⁸

Managing Clozapine Cardiac Effects

The mainstay of acute management of clozapine-induced cardiac adverse events is to stop clozapine treatment and provide supportive care depending on the severity of illness, as early cessation may markedly improve clinical outcomes.¹¹ Furthermore, a challenging scenario may arise when patients responsive only to clozapine therapy develop clinical or echocardiographic evidence of cardiac adverse events, potentially severe and life-threatening, and clinicians should decide if and how to proceed with clozapine treatment. An initial study by Manu et al³⁹ found that 75% of clozapine-induced myocarditis and 100% of pericarditis were rechallenged with clozapine without further development of significant adverse drug effects. Later, Manu et al⁴⁰ added an additional 121 cases to their previous analysis by documenting a successful outcome in clozapine rechallenge after myocarditis in 64.7% of cases (n=11/17). Overall, published evidence^11,28,39-40 suggests that clozapine treatment may be rechallenged under close supervision, as illustrated in our proposed flow-chart (see Figure 1).

Figure 1: Proposed protocol for monitoring patients commenced on clozapine for clozapine-related cardiomyopathy, myocarditis and pericarditis

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Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Pericardial Disease, Heart Failure and Cardiac Biomarkers

Keywords: Clozapine, Troponin I, Troponin T, Myocarditis, C-Reactive Protein, Natriuretic Peptide, Brain, Pericardial Effusion, Serositis, Incidence, United States Food and Drug Administration, Quality of Life

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