Avoiding Clozapine-Related Risks in Refractory Schizophrenia

A 25-year-old man with treatment-refractory schizophrenia presents to the University of Pittsburgh Medical Center with drowsiness and a fever of 40.3°C, noting that he started treatment with clozapine (Clozaril) about 2 weeks previously and that he has no chest pain.

His medical history includes treatment failures with haloperidol (Haldol), risperidone (Risperdal), and olanzapine (Zyprexa), and there was a recent episode of severe psychosis that led to his starting on clozapine 12.5 mg. The dose had been increased to 250 mg daily over 10 days, with a corresponding improvement in his psychotic symptoms.

At that point, testing showed clozapine serum levels of 287 mcg/L (therapeutic reference range is 350-600 ng/mL). As a result, the prescribing clinicians had increased the dose to 300 mg 1 week prior to his presentation.

Findings of the physical exam at the time of presentation are unremarkable except for an elevated heart rate of 140 bpm. Clinicians perform an electrocardiogram, which reveals diffuse ST-segment elevations without reciprocal changes, suggestive of pericarditis.

Laboratory tests reveal leukocytosis without eosinophilia, and elevated inflammatory and cardiac biomarkers.

Specific findings include:

• White blood cell count: 12,600 cells/mm³ (reference range 3,800-10,600 cells/mm³)

• C-reactive protein (CRP): 19.9 mg/dL (reference range <0.8 mg/dL)

• Erythrocyte sedimentation rate: 91 mm/h (reference range 0-23 mm/h)

• Troponin: 17.53 ng/mL (reference range <0.1 ng/mL)

Clinicians follow up with a transthoracic echocardiogram, which reveals a small pericardial effusion, but is otherwise normal. The clinical constellation of tachycardia, fever, elevated inflammatory markers, and diffuse ST-segment elevations in a patient who has started clozapine treatment within about 2 weeks is suggestive of clozapine-induced myocarditis, a known adverse effect of clozapine treatment.

The medical team performs cardiovascular magnetic resonance (CMR) imaging, which shows diffuse epicardial and patchy myocardial late gadolinium enhancement with edema on T2-weighted imaging (figure). The patient has a left ventricular ejection fraction of 38%, and since there is no evidence of pericardial thickening or enhancement, pericarditis is therefore not suspected.

Findings of an infectious work-up are negative, and clinicians discontinue the patient's clozapine after a diagnosis of clozapine-related myocarditis. Within 48 hours of discontinuing the antipsychotic, the patient's fever and leukocytosis resolve and his heart rate returns to normal. The team then starts supportive therapy with colchicine (Mitigare), lisinopril (Qbrelis), and metoprolol (Toprol).

Discussion

Clinicians reporting this case note that it shows that myocarditis can be associated with clozapine treatment in patients with schizophrenia and demonstrates the value of diagnosis using non-invasive CMR.

Clozapine is a second-generation antipsychotic used to treat patients with refractory schizophrenia, typically improving the ability to live independently and reducing the rate of hospital admissions. Unfortunately, however, the drug is also associated with increased risks for agranulocytosis and myocarditis, but since the presentation of myocarditis is generally nonspecific, diagnosis can not only be challenging, but the use of endomyocardial biopsy itself carries risks.

The case authors note that because there is no consensus about the diagnostic criteria, the reported incidence and mortality rates for clozapine-induced myocarditis are estimates only, based on voluntary reports and nonspecific presentations; the best current incidence estimates are 0.7% to 8.5% of patients being treated with clozapine, and of these cases, the estimated mortality rates are 10% to 30%. (A monograph from drugmaker Novartis puts the incidence of clozapine-induced myocarditis at one per 14,000 patient-years, and a mortality rate of 23%.)

The case authors reviewed suggested recommendations in the literature where CMR was used to diagnose acute myocarditis in general (i.e., not specifically related to clozapine), noting that these suggest using a combination of T2-weighted findings and increased myocardial T1, extracellular volume, or late gadolinium enhancement to demonstrate evidence of myocardial edema and nonischemic myocardial injury, respectively.

The authors note that while there are many reports of patients who had elevations in CRP prior to peak troponin levels as well as peripheral eosinophilia, it is known that clozapine-induced myocarditis can occur in patients with neither. In addition, the condition has various presentations, including chest pain and flu-like symptoms, often characterized by elevated cardiac and inflammatory biomarkers within the first 4 weeks of starting clozapine.

The group notes that case reports have ruled out alternative causes, and included evidence of clinical improvement after clozapine was discontinued. One of those two cases involved cessation of other medications that may have been contributing factors, and the other involved a patient found to have atrial fibrillation with rapid ventricular response, which ultimately necessitated admission to the intensive care unit and use of supportive therapy. Furthermore, neither imaging nor endomyocardial biopsy were used to confirm the presence of myocardial inflammation in these two cases.

In another report, the authors had ruled out obstructive coronary artery disease with cardiac catheterization and common causes of infection to reach the conditional diagnosis of clozapine-induced myocarditis, although illicit substance use had not been ruled out, and CMR had not been used to confirm the diagnosis.

The authors of the current case report note that they had followed a similar approach to assess their patient's symptoms, with CMR confirmation using the updated Lake Louise Criteria. "This provided increased confidence that the patient was receiving the most appropriate therapy to resolve his symptoms and reduce risk of recurrence," the team wrote. "The timely discontinuation of clozapine along with supportive care led to an improvement in symptoms for our patient, as well as those previously described."

The authors note that use of endomyocardial biopsy has declined due to the risk of perforation (approximately one in 250 cases) and death (one in 1,000 cases). In addition, sensitivity is limited by the transient nature of inflammatory infiltrates, and pathologists frequently disagree on interpretation of the biopsy specimens.

For these reasons, biopsy has generally been replaced with non-invasive CMR, which is associated with rates of 84% sensitivity, 74% specificity, and diagnostic accuracy of 79%.

As in the patient reported here, and in other cases, clozapine-induced myocarditis develops within the first month of use, the authors note, citing a reported median dose at presentation of 250 mg/day, with the most common symptoms of fever (67%), dyspnea (67%), and tachycardia (58%), along with elevated cardiac biomarkers (87%).

These observations are reflected by another analysis of 75 cases of clozapine-induced myocarditis and a control group of 94 patients taking clozapine for at least 45 days without cardiac disease, in which 83% of cases developed between days 14 and 21. Given that 90% of the cases had at least twice the upper limit of normal troponin, while five cases had CRP levels above 100 mg/L and evidence of left ventricular impairment by echocardiography without a clinically significant rise in troponin, those researchers proposed the following monitoring protocol in 2011:

• Obtain baseline troponin I and troponin T, CRP, and echocardiography

• Monitor troponin and CRP on days 7, 14, 21, and 28

• Discontinue clozapine if troponin is more than twice the upper limit of normal or CRP is over 100 mg/L -- together, these two parameters have an estimated sensitivity for symptomatic clozapine-induced myocarditis of 100%, although sensitivity for asymptomatic disease is unknown

While the mechanism involved in clozapine-induced myocarditis is poorly understood, one hypothesis is that cardiotoxicity may be due to a type-1 hypersensitivity reaction resulting in myocardial damage and inflammatory infiltrate, perhaps as a result of rapid titration, the case authors speculate, adding, however, this was not supported by findings of a 2016 case review in which most inflammatory infiltrates were not eosinophilic.

Other possible explanations for these cardiotoxic effects include a type-3 allergic reaction or a direct toxic effect of clozapine or its metabolites, or that unfavorable pharmacogenetics result in clozapine accumulation that reaches toxic levels. The authors cited a case-control study showing that over the first 9 days of clozapine titration, the risk of myocarditis increased by 26% for each 250 mg administered (OR 1.26, 95% CI 1.02-1.55, P=0.03).

"Our patient received therapy consistent with FDA guidelines, which suggest titration up to 300-450 mg daily over the course of 2 weeks, resulting in a cumulative dose of 2,075 mg at the onset of his tachycardia," the authors wrote. By contrast, Australian guidelines advise more gradual titration of clozapine over 2 weeks to a dose of 200 mg daily to reach a cumulative dose of less than 1,500 mg, with subsequent increases limited to no more than 100 mg weekly. To address the potential risk of agranulocytosis, patients must be monitored weekly for the first 18 weeks of therapy, the authors stress.

Conclusion

The case authors conclude that their report of this patient highlights that myocarditis can be associated with clozapine treatment in patients with schizophrenia and demonstrates the value of diagnosis using non-invasive CMR. Such an approach enables prompt diagnosis and management without the risk of endomyocardial biopsy. Additional studies are warranted to establish whether rapid titration is a risk factor for clozapine-induced myocarditis.

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