Mr. P, a 50-year-old single white man with history of schizophrenia, was admitted to the psychiatry ward of a hospital with complaints of increasing paranoia and auditory hallucinations. He had had multiple admissions over last few months and had poor control of symptoms with regular first line agents. As such, in this admission, he was offered a trial of clozapine, which he agreed to.
Clozapine was started at a dose of 25 mg by mouth once everyday and increased in staggered amounts during a 4-week period to 325 mg daily. The patient started complaining of fatigue and diarrhea 2 weeks into therapy. He also had orthostatic dizziness and was found to have consistently increased heart rate on review of regular vital signs. About 1 week later, the patient developed shortness of breath on exertion with orthopnea and paroxysmal nocturnal dyspnea, which gradually worsened to dyspnea at rest.
His medical history was not significant for any cardiac disease. He was in treatment for systemic hypertension and regularly smoked one-half pack of cigarettes per day. He denied any history of illicit drug use, including cocaine. No significant family history of cardiac diseases was elicited. This was his first exposure to clozapine.
An initial examination revealed a disheveled, obese man sitting up in bed with obvious respiratory distress. Vital signs revealed tachycardia (heart rate 115/min) and hypoxemia (pulse oximetry reading 85% on room air), with borderline low blood pressure. Jugular venous pressure was elevated. Chest examination was significant for coarse crepitations in bilateral bases. Bilateral lower extremity showed minimal ankle edema. No rashes were noticed.
These options could be considered as appropriate management strategies for the clinician:
Stop clozapine immediately
Request immediate cardiology consultation
Consider alternative antipsychoyic treatment
Continue ongoing psychiatric treatment.
In this case, options 1 and 2 were chosen. The psychiatry team realized the presence of congestive heart failure and its known association with use of clozapine. Clozapine was stopped, and cardiology consulation was obtained.
Mr. P was moved to the telemetry floor of the hospital. Initial laboratory blood test values were significant for elevated white blood cell count (13.8 × 109 cells/L) with marked eosinophilia (1.0 × 109/L). Troponin I was elevated to 2.04 ng/mL (normal is lower than 0.06), with B-type natiuretic peptide elevated to 1,740 pg/mL (normal is lower than 100). The electrocardiogram showed sinus tachycardia with nonspecific T-wave abnormalities.
In light of above clinical and laboratory data, various differentials were entertained. Given the patient's risk factors for coronary artery disease, non-ST-elevation myocardial infarction as a cause of the symptoms was considered. Results of further tests were as follows:
- Echocardiogram: Mild enlargement of the left ventricle, global hypokinesis with estimated ejection fraction of 40%.
- Chest radiograph: Vessel cephalization and cardiomegaly
- Coronary angiogram: Presence of mild atherosclerotic disease with reduced ejection fraction and absence of any evidence of recent ischemic event.
- Myocardial biopsy: Myocardium with diffuse interstitial infiltrate of eosinophils, lymphocytes and neutrophils with presence of necrotic cardiac fibers.
A definitive diagnosis of eosinophilic myocarditis and congestive heart failure, probably due to clozapine, was made on the basis of pathology results. Mr. P was treated with combination of diuretics, beta-blockers, and angiotensin receptor blocker therapy for the congestive heart failure. Alternative antipsychotic therapy was considered by the psychiatric team but was held until the patient's acute symptoms resolved, given the cardiac side effects of other antipsychotics, including QTc prolongation.
The patient responded well to above treatment. A follow-up echocardiogram in 4 weeks revealed improved cardiac function with stable heart rate and absence of any cardiac or respiratory symptoms.
This is a clear case of clozapine-associated myocarditis in a middle-aged man with long psychiatric history and no known past cardiac history. He developed the above during his first trial of clozapine, and a workup for alternative cardiac diseases was negative.
Clozapine, a novel antipsychotic drug, was introduced in the United States in 1989. It is a tricyclic dibenzodiazepine with strong affinity for D4-receptors and potent serotonin and noradrenergic antagonism. It is used for treatment refractory schizophrenia. Serious adverse effects include agranulocytosis and seizures. More common side effects are sedation, orthostatic symptoms, tachycardia, and weight gain. Myocarditis also has been described in association with clozapine use. The potential mechanisms described include IgE-mediated hypersensitivity reaction (type 1 allergic reaction) and direct cardiac toxicity.
Various case series have documented the risk of cardiac disease with clozapine. Estimates of incidence of myocarditis have varied widely, with highest estimate of myocarditis being 1 case in 500 patients in first month of clozapine therapy versus 3.3 cases in 107 people per month in the general population.1–4 Most of the cases are recognized within the first 4 weeks of therapy and usually start with nonspecific symptoms progressing on to frank congestive heart failure. Signs and symptoms found to be associated with clozapine associated myocarditis are listed in the Sidebar.6 Many of these signs and symptoms are nonspecific, but if any occur in a clozapine-treated patient, especially if the onset is sudden or unexpected, suspicions should be raised followed by prompt cardiologic assessment.
Signs and Symptoms Associated With Clozapine-related Myocarditis
- Flulike symptoms: unexplained fever, fatigue, lethargy
- Chest discomfort (often vague or angina pectoris); palpitations
- Respiratory symptoms: tachypnea, dyspnea, orthopnea, paroxysmal nocturnal dyspnea
- Abnormal vital signs: hypotension, narrowed pulse pressure, persistent resting tachycardia
- Cardiovascular signs: raised jugular venous pressure, presence of third or fourth heart sound, pericardial friction rub, muffled first heart sound, mitral or tricuspid regurgitation, peripheral edema
- Respiratory signs: crackles on auscultation
- Electrocardiographic changes: sinus tachycardia, atrial or ventricular arrythmias, left-ventricular hypertrophy, diffuse non-specific ST-segment and T-wave abnormalities, low voltage and intraventricular conduction defects
- Chest radiograph changes: possible cardiac enlargement, pulmonary venous congestion, pulmonary edema
- Bloodwork changes: hypereosinophilia
Signs and Symptoms Associated With Clozapine-related Myocarditis
When the clinician suspects the diagnosis of myocarditis, clozapine must be stopped immediately. Given the role of hypersensitivity reaction in the pathophysiology of the disease, any further exposure to clozapine must be avoided scrupulously. The presenting syndrome dictates treatment of cardiac symptoms. In the case described here, congestive heart failure was treated by standard therapy. Patients have been shown anecdotally to recover heart function completely after management of the initial disease; however, there are no long-term studies of cardiac morbidity or mortality in these patients.
Risk factors for development of clozapine-associated myocarditis have not been recognized. No studies look prospectively at development of myocarditis and there are no described absolute cardiac contraindications to clozapine use. However, it is recommended that patients with any personal or family history of cardiac disease be identified before therapy initiation for close monitoring. The threshold for medical evaluation of patients with cardiovascular or respiratory symptoms must be low, especially given the overlap of benign side effects of clozapine with symptoms of myocarditis (eg, tachycardia, flu-like symptoms, hypotension, eosinophilia).6 It is also recommended that the increase in dose of clozapine should be slow and should not exceed 50 mg every 2 days.7
The patient described in this case showed complete recovery from cardiac symptoms and was doing well when examined about 6 months after the initial medical admission.
Editor's Note: This monthly presentation describes a case of a psychiatric disorder, discusses past treatment attempts, offers options for continuing treatment, and explains the reasons the solution was selected. Submissions of interesting psychiatric case reports are being accepted for this department. Please e-mail
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This case is presented by Neha Gauri, MD, resident, Department of Psychiatry, State University of New York at Buffalo, Buffalo, NY; and Vikas Grover, MBBS, hospitalist, Department of General Internal Medicine, Buffalo General Hospital, Buffalo, NY.
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