Clozapine and cardiac disease

Clozapine is an atypical antipsychotic agent and is contraindicated in patients with severe cardiac disorders.

• there is an increased incidence of myocardial disease in clozapine users (1)
  • rare cases of myocarditis have been reported, some of which have been fatal
  • very rare cases of cardiomyopathy have been reported
  • pericarditis and pericardial effusion have been associated with clozapine treatment
  • tachycardia
    • common side effect of clozapine treatment - occurs in 25% of users - particularly during dose titration in early treatment
    • also a key symptom of myocardial disease
      • essential that patients with persistent tachycardia at rest, particularly in the first 2 months of treatment, are closely observed for other signs and symptoms of myocarditis/cardiomyopathy (these include palpitations, arrhythmias, symptoms mimicking myocardial infarction, chest pain and other unexplained symptoms of cardiac failure)
  • if clozapine-induced myocarditis or cardiomyopathy is suspected, clozapine therapy should be discontinued promptly and the patient urgently referred to a cardiologist for diagnostic evaluation
    
    
• clozapine-induced myocarditis (CIM) (2)
  • clinically and pathologically defined as inflammation of the myocardium as a result of clozapine administration
  • pathogenesis of CIM is unclear
    • however, an immune-mediated mechanism responsible for the inflammation of the myocardium and pericardium has been postulated, given its early onset in clozapine treatment, and the presence of eosinophilic infiltrates in myocardium
    • hypothesised that may result form a direct selective cardiotoxic effect of clozapine metabolites owing to altered metabolism and oxidative stress
  • potentially fatal myocarditis with clozapine is estimated to be as low as 0.015-0.188% (2)

The UK Committe on Safety of Medicines has outlined information for prescribers relating to clozapine and cardiac safety (1):

• patients must have a history and physical examination before starting clozapine therapy. The treating physician should consider performing a pre-treatment ECG
• patients who have persistent tachycardia at rest, particularly during the first 2 months of clozapine treatment, should be closely observed for other symptoms or signs of cardiomyopathy or myocarditis. These include arrhythmias, palpitations, symptoms mimicking myocardial infarction, chest pain and other unexplained symptons of heart failure
• patients in whom cardiomyopathy or myocarditis is suspected should stop clozapine and undergo urgent diagnostic evaluation by a cardiologist
• patients with clozapine-induced myocarditis or cardiomyopathy must not be re-exposed to clozapine

A review has stated that (2):

• 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.

Reference:

• (1) Current problems in Pharmacovigilance (2002), 28, 8.
• (2) Segev A et al. Clozapine-induced myocarditis: electronic health register analysis of incidence, timing, clinical markers and diagnostic accuracy.The British Journal of Psychiatry 2021: 1-8.