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One of my patients had a long, horrible phase of complex depression with little or no response to many medication trials, and eventually, we came around to clozapine. Less than 2 weeks into his treatment, I get a text. He’s been hospitalized with chest pain and possible clozapine-induced myocarditis. You know the feeling of anxiety and dread. Did I assess and explain the risks and benefits properly? Will we be able to continue the clozapine trial?
Hi! Jim Phelps here for the Psychopharmacology Institute. Let’s review clozapine and myocarditis courtesy of Dr. Aviv Segev and his colleagues at King’s College London. We’ll get an updated assessment of how common this problem is and learn what lab tests work best to identify myocarditis so that if your patient has just started clozapine and calls to report dizziness and a high heart rate, you’ll know what steps to take. Because, of course, there’s another risk here—stopping clozapine when that’s not really necessary.
Using electronic records in their large mental health consortium, Dr. Segev and colleagues looked at nearly 250,000 anonymized patient records and used a language algorithm to identify 350 possible cases of myocarditis, 250 of which were still tagged as suspected after Dr. Segev himself looked through their charts. And the results? Eighty percent of the cases who were suspected of myocarditis did not have it. The gold standard for this determination was echocardiogram and cardiac MRI. Short of that, the key lab result was an elevated troponin level with a sensitivity of 83% and a specificity of 91%.
What are the symptoms that should make you think of myocarditis? How about chest pain? What percentage of patients with confirmed myocarditis had a presentation of chest pain? According to Dr. Segev and colleagues’ detailed chart review, just shy of 50%. So, you can’t rely on chest pain being present. Malaise, just over 50%. Shortness of breath, about 35%. So, those wouldn’t do either. Moreover, patients who were not found to have myocarditis also had these symptoms, roughly 20% for each of the 3 symptoms —chest pain, malaise, and shortness of breath.
Notice that we’re not talking here about lethargy and dizziness, which are common side effects of clozapine. However, tachycardia—which is a common side effect of clozapine—is also a symptom of myocarditis. Almost 100% of confirmed cases had this, but over 90% of patients without myocarditis also had it. Well then, how is the diagnosis made? In addition to an EKG looking for ischemia, a cardiac echo is usually essential in establishing myocarditis.
And what’s the time frame of concern? In this study, the time from clozapine initiation to diagnosis of myocarditis averaged 17 days, but the range was large, from 2 days to 42 days, at clozapine doses from 25 mg to 300 mg.
A typical presentation of myocarditis would be a collection of suggestive symptoms —chest pain, malaise, tachycardia, dyspnea —within the first 6 weeks of treatment accompanied by a positive troponin. This presentation warrants clozapine cessation until confirmatory tests are performed, but the authors emphasized that this presentation should not lead to a diagnosis of myocarditis without additional tests and preferably cardiology consultation.
My patient presented with chest pain and fever. However, his troponin was over twice normal, his EKG indicated ischemia, and he ended up with a cardiac stent. Whether clozapine had played a role was never clear because this experience was enough to turn him toward ECT, which he had initially avoided because he feared he’d lose his job. Fortunately, he responded well to ECT, got a new job, and we avoided the key question that you might face, which is: Do you have to stop clozapine? Remember that in the study by Segev and colleagues of patients on clozapine with suspected myocarditis, 80% didn’t have it.
In summary, if your patient has tachycardia on clozapine, look for other symptoms—chest pain, malaise, shortness of breath. If you’re concerned but not quite enough to send them straight to the emergency department, consider a troponin level. If the troponin level is elevated, hold clozapine, but don’t fully stop it until an echocardiogram and hopefully a cardiology consult have been done to confirm myocarditis. Should you wish to see more, you’ll find graphs of symptom frequency and specificity for the various symptoms and tests in the article, which is linked here at the Psychopharmacology Institute.
Abstract
Background
Clozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences.
Aims
To examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects.
Method
A retrospective analysis of the record database for 247,621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined.
Results
Of 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation.
Conclusions
Suspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The ‘critical period’ for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.
Keywords
Antipsychotics; drug interactions and side-effects; psychotic disorders; schizophrenia; risk assessment.
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Reference
Segev, A., Iqbal, E., McDonagh, T. A., Casetta, C., Oloyede, E., Piper, S., Plymen, C. M., & MacCabe, J. H. (2021). Clozapine-induced myocarditis: Electronic health register analysis of incidence, timing, clinical markers and diagnostic accuracy. The British Journal of Psychiatry, 1-8.
