RAPID TITRATION INFLUENCING A LATE ONSET CLOZAPINE-INDUCED MYOCARDITIS IN A LOW-RESOURCE COUNTRY SETTING: AN INDONESIAN CASE REPORT AND NARRATIVE REVIEW
Authors: Sen *Lee Thung , Hanafi Enjeline , Khamelia Khamelia , Siste Kristiana 
Published: February 2025

Abstract

Background
Clozapine has been reported to induce cardiovascular adverse effects, including myocarditis. There has been growing evidence of heightened sensitivity among Asian population to clozapine-induced myocarditis (CIM).

Aims And Objectives
To illustrate a case of late-onset CIM in an Indonesian patient. Furthermore, to expand on the pragmatic monitoring of CIM in a low-resource country, probable application of the Asian clozapine titration, and an effective antipsychotic substitute.

Method
A case report and a narrative literature review.

Results
Mr. D, 32 years old, was admitted to the psychiatric ward due to worsening symptoms of aggressivity and hallucinatory behavior. He was diagnosed with recurrent episodic paranoid schizophrenia. After two days in the ward, the patient complained of chest pain and upon examination there was tachycardia (otherwise ECG was non-remarkable) as well as elevated levels of creatinine kinase (CK), C-reactive protein (CRP), and eosinophils. Perplexingly, the patient had been on clozapine for around a year. The patient had just received an increased dose of clozapine from 200 miligrams to 300 miligrams in the previous outpatient clinic. Moreover, the family reported that two weeks prior Mr. D also had chest discomfort, cold sweat, and a pale face. The patient was consulted to cardiology and the diagnosis for CIM was made. Echocardiography was not yet performed due to restricted resources.
Subsequently, the clozapine dosage was quickly tapered off in a week and switched to olanzapine 20 miligrams. Following another 10 days of care, the patient’ s psychotic symptoms and aggressivity improved and all laboratory and clinical findings returned to normal.

Discussion & Conclusions
The CIM is a detrimental though uncommon side effect of clozapine.1 Criteria to diagnose CIM are varied, with recommendations suggesting combinations of clinical symptoms (chest pain or flu-like symptoms), cardiological signs (tachycardia or other abnormal ECG), and supporting examinations (elevated CRP, troponin, CK/CK-MB, and eosinophilia).2,3 Typically, CIM appeared within the first couple of months of clozapine initiation.2 The patient in case demonstrated signs of CIM after a rapid titration, albeit having consumed clozapine in the past year. Rapid titration, higher age, and concurrent use with valproate have been found as risk factors. Rapid titration is defined as any increase of more than 250 miligrams in a span of 9 days (i.e., &gt;27.8 miligrams increment).4 A recent multiracial analysis had also demonstrated the varying threshold for appropriate dose titration and therapeutic dose range across each race. In particular, the Asian descent was shown to require lower dose of 75 miligrams to achieve therapeutic plasma concentration. Indonesian patients similar to Japanese patients may require much slower clozapine titrations.5 Furthermore, several registry studies have recommended olanzapine as a preferable substitution for clozapine, in light of lower relapse, rehospitalization, and mortality.6,7 In this case, switching to olanzapine resulted in clinical improvement (psychosis and aggressivity) and amelioration of cardiovascular side effects. Our experience might illustrate the benefits of early detection of CIM in low-resource setting and the possible preferable neuroleptic switching.

References
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