Letter to the Editor
Clozapine-associated myocarditis
Miocarditis aguda secundaria a clozapina
Javier Molina Martín de Nicolás
, Juan José Parra Fuertes, Eloy Gómez Mariscal, Belén Díaz Antón
Corresponding author
Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain
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"javier.molina.mdn@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Juan José" "apellidos" => "Parra Fuertes" ] 2 => array:2 [ "nombre" => "Eloy" "apellidos" => "Gómez Mariscal" ] 3 => array:2 [ "nombre" => "Belén" "apellidos" => "Díaz Antón" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Miocarditis aguda secundaria a clozapina" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Myocarditis is a disorder difficult to diagnose and, despite the long list of causes, the etiology remains unknown in all but 22–33% of the cases.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> Described in 1999 by Kilian et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> clozapine is the only antipsychotic drug related to myocarditis, with a very low associated risk (1/500 to 1/10,000 treated individuals), with an overall incidence of 0.015–0.187%, reaching 1.2% in Australia,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">3</span></a> surpassing agranulocytosis (1%). Only 2 cases have been reported in Spain<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">4,5</span></a> but there is growing awareness of the cardiac side effects (myocarditis, pericarditis and dilated cardiomyopathy) of clozapine. Given that the prognosis is much less favorable if diagnosis is delayed, it is of great interest to recall this not so uncommon condition to the scientific community.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 43-year-old man, diagnosed with paranoid schizophrenia resistant to various antipsychotics, who was admitted to the department of psychiatry to start treatment with clozapine, with incremental doses of up to 200<span class="elsevierStyleHsp" style=""></span>mg/day. After 13 days of treatment, he presented with a lack of energy, fever peaks up to 38.5<span class="elsevierStyleHsp" style=""></span>°C, cough producing whitish sputum, and pleuritic chest pain. On physical examination, the patient was tachycardic and afebrile. He had elevated jugular venous pressure, grade III/IV systolic ejection murmur at left sternal border, S3 gallop, no pericardial rub and minor bibasilar crackles. An electrocardiogram (ECG) showed sinus tachycardia, and chest X-ray revealed signs of mild heart failure. Laboratory tests were remarkable for elevated inflammatory markers (mild leukocytosis, elevated C-reactive protein [CRP]: 17<span class="elsevierStyleHsp" style=""></span>mg/dL), and elevated cardiac enzymes, with peaks of creatine kinase reaching 1116<span class="elsevierStyleHsp" style=""></span>IU/L, high-sensitivity troponin T of 474<span class="elsevierStyleHsp" style=""></span>ng/L, and N-terminal pro-brain natriuretic peptide (NT-proBNP) of 5865<span class="elsevierStyleHsp" style=""></span>pg/mL. Transthoracic echocardiography (TTE) highlighted global left ventricular hypokinesis and moderate systolic dysfunction (38% by Simpson's biplane method); the pericardium was not thickened, but was hyperechogenic with mild effusion. As acute myocarditis was suspected, the patient was commenced on antiinflammatory doses of acetylsalicylic acid, beta-blockers and an angiotensin-converting enzyme inhibitor; and clozapine was discontinued. Two days later, cardiac enzymes and inflammatory parameters had normalized, as had NT-proBNP and TTE after a week. The patient could not undergo cardiac magnetic resonance imaging for being claustrophobic. The causal association between myocarditis and clozapine is inferred by the temporal sequence between the initiation of treatment and symptom onset (which is the interval most frequently reported in the literature) and by a patent improvement after drug discontinuation. Moreover, all other etiologies were considered less likely, given the fact that he was an inpatient, with no previous or intercurrent diseases and without drugs or toxics interactions.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The diagnosis of clozapine-related myocarditis requires a high degree of clinical suspicion. An Australian registry of 116 cases, the largest in the medical literature, reflects the variability and lack of specificity of signs and symptoms of this clinical condition.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">3</span></a> The most likely mechanism of action is an IgE-mediated hypersensitivity. The most frequent symptoms are fever, chest pain, dyspnea and flu symptoms. The most common signs are TTE and ECG abnormalities, tachycardia, elevated cardiac enzymes, leukocytosis, neutrophilia and eosinophilia. The severity of the condition ranges from subclinical forms to sudden death. Myocarditis develops within the first 2 months after the initiation of clozapine in 85% of the cases, from day 8 to day 21 in 63%, the median being day 17. Of note, leukocytosis and eosinophilia have been reported during treatment in the absence of signs of myocarditis, and its significance remains unclear. Hypotension and tachycardia can be a transient and benign effect during drug titration. Most cases resolve spontaneously without sequelae after drug discontinuation, but deaths have been reported. The Australian records reflect a mortality of 10% although, in some series, it reaches 23%,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">6</span></a> being higher in undiagnosed patients and those with a late diagnosis.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Clozapine, a tricyclic benzodiazepine, is an atypical neuroleptic indicated in antipsychotic-resistant schizophrenia. Gradual titration and avoidance of the concomitant use of valproic acid are recommended. Various strategies for monitoring cardiac involvement<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">7</span></a> using laboratory parameters (CRP, troponin, NT-proBNP), ECG and TTE have been put forward, but given the low prevalence of myocarditis and the limited use of the drug, they have not been widely implemented.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The purpose of this short review is to highlight that: (a) the diagnosis of myocarditis requires a high index of suspicion; (b) clozapine is a rare but possible cause; and (c) early diagnosis is necessary to improve the prognosis of these patients.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Molina Martín de Nicolás J, Parra Fuertes JJ, Gómez Mariscal E, Díaz Antón B. Miocarditis aguda secundaria a clozapina. 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