Clozapine-induced cardiac toxicity and successful rechallenge in children and adolescents: a systematic review and new case report

• Treatment-resistant schizophrenia and bipolar disorder are first-line indications for clozapine prescription. • Cardiac toxicity, including myocarditis and pericarditis, usually leads to clozapine discontinuation, with relapse into psychopathology. • This article systematically reviews all pediatric cases of clozapine rechallenge after cardiac toxicity and reports one new case. • Current evidence supports clozapine rechallenge after drug discontinuation due to cardiac toxicity in children and adolescents. • Factors and practices which maximize the probability of success of clozapine rechallenge after cardiac toxicity are presented. Treatment-resistant schizophrenia and bipolar disorder represent first-line indications for clozapine prescription in children and adolescents, who display treatment-resistance significantly more often than adults. However, titrating clozapine up to reach an effective dose may become impossible if serious adverse events occur, forcing drug discontinuation. Here we systematically review all articles available in PubMed regarding clozapine-associated cardiac toxicity in children and adolescents, primarily including myocarditis and pericarditis, and focus on the feasibility of clozapine rechallenge after drug discontinuation. Our systematic review identifies 12 articles reporting 13 pediatric cases of clozapine-associated cardiac toxicity. Seven patients discontinued the drug and no rechallenge was attempted. Five underwent clozapine rechallenge: 4 (80.0 %) were successfully titrated up to an effective clozapine dose without recurrence of cardiac toxicity, whereas 1 (20.0 %) displayed signs of myocarditis soon after restarting clozapine; in one case, clozapine was not stopped and the initial signs of cardiac inflammation quickly abated. We also report a new pediatric case of successful clozapine rechallenge following one episode of myocarditis and a subsequent pericarditis occurred during the titration phase. Clozapine treatment was successfully continued at a reduced, yet effective dose. Overall, the available evidence, though limited, supports clozapine rechallenge after drug discontinuation due to cardiac toxicity in children and adolescents. Ensuring full cardiac recovery before rechallenging with clozapine, starting with a low dose (6.5–12.5 mg/d), a slow titration rate (12.5-25 mg/d per week), avoiding the co-administration of valproic acid (Depakene), and frequent monitoring of cardiac and inflammatory parameters appear critical to the success of clozapine rechallenge.