Abstract
To the Editor
Novel strategies for prevention and early detection of clozapine-associated myocarditis (CLAM) are needed.
Ronaldson et al. (2015) evaluated 109 subjects with CLAM: blood C-reactive protein (CRP) elevation preceded troponin and eosinophil increments. A marked variability was observed, suggesting heterogeneous mechanisms in CLAM.
A 30-year-old man with schizophrenia received clozapine 200 mg/day for 10 years. Eight months ago, clozapine was withdrawn at the patient’s request and he then commenced olanzapine, 10 mg/day. After a severe relapse, clozapine was restarted without titration (200 mg/day) and was monitored as follows:
Day 5 of clozapine treatment: Tachycardia (120 bpm); troponin I levels and electrocardiogram (EKG) were normal.
Day 6: Reported by phone—severe anxiety, chest discomfort and mild dyspnea without fever.
Day 7: Tachycardia (144 bpm), normal blood pressure, no fever; qualitative troponin I reported positive, but CRP levels and eosinophil count (EC) were normal. The EKG showed a 1 mm ST segment elevation in V4, and the chest x-ray radiography was normal. Clozapine was immediately stopped and the symptoms remitted in 12 hours approximately.
Days 9 and 12: Troponin remained positive but then normalized. CRP and EC levels and the ST segment were normal. An echocardiogram at day 15 was normal with a left ventricular ejection fraction of 66%.
Troponin I was only qualitatively assessed, but the kit has sensitivity and specificity of 95% and 97%, respectively, compared to quantitative evaluation (Cardiac Triple Test, Humasis Co., Ltd).
This case is worth reporting because (a) it occurred after clozapine reinsertion in a subject with a normal echocardiogram during clozapine administration in 2013 (Serrano et al., 2014); (b) clozapine was restarted without titration, which is controversial; (c) only troponin I elevation, minimal EKG changes and cardiac symptoms were detected, suggesting a mild and transient myocarditis. Since eosinophilia is often observed during CLAM, mechanisms other than those involved in eosinophilia hypersensitivity myocarditis could be suspected.
Clozapine is a potent norepinephrine (NE) releaser, and this patient developed anxiety and tachycardia without a gross inflammatory syndrome, suggesting sympathetic system over-stimulation that could be involved in the final events leading to myocarditis.
NE over-stimulation may be an alternative pathological pathway to the proposed eosinophilic myocarditis in some subjects. This can be tested in young subjects in prospective studies. The NE deleterious effects may be prevented with angiotensin converting inhibitors and/or beta blockers (Rostagno et al., 2008) in young subjects when clozapine cannot be started at low doses.
Footnotes
Acknowledgements
The author thanks Françoise Salager-Meyer for her editorial assistance and to our patient for accepting the publication of this case.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.