When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature

Abstract

Background Clozapine is widely prescribed for treatment refractory patients with schizophrenia, but its use is limited by potentially life threatening adverse effects. Rechallenge after these complications has been occasionally attempted in patients with severe psychotic symptoms. Objective To review the outcome of clozapine rechallenge after potentially life threatening adverse effects. Methods Electronic, all-language, literature search (1972–2011) followed by demographic and clinical data extraction. The outcome of rechallenge was considered favorable when the lower bound of the 95% confidence interval (CI) of the proportion of patients who could continue clozapine was >50%. Results Altogether, 138 patients (mean age: 36.3 years, 65.7% male, 57.6% Caucasian, virtually all with schizophrenia spectrum diagnosis) underwent clozapine rechallenge after developing neutropenia (n=112), agranulocytosis (n=15), neuroleptic malignant syndrome (NMS) (n=5), myocarditis (n=4), pericarditis (n=1) and lupus erythematosus (n=1). Rechallenge strategies were heterogeneous and not systematically evaluated. Clozapine rechallenge was successful in 78/112 patients (69.6%, CI:60.6–77.4) after neutropenia, 3/15 (20%, CI:7.1–45.2) after agranulocytosis, 5/5 (100%, CI:56–100) after NMS, 3/4 (75%, CI:30–95) after myocarditis, 1/1 after pericarditis, and 0/1 after clozapine-induced lupus. Successfully rechallenged patients were followed for 16–96 weeks. None of the rechallenged patients died. Conclusions Although controlled studies are clearly needed, using a priori, confidence interval-based criteria, case reports/series suggest that in refractory patients who benefited from clozapine, careful rechallenge can be considered after neutropenia and NMS, but not after agranulocytosis and myocarditis.

A systematic review of clozapine induced cardiomyopathy

“…This occurred after they developed neutropenia (n = 112), agranulocytosis (n = 15), neuroleptic malignant syndrome (NMS) (n = 5), myocarditis (n = 4), pericarditis (n = 1) and lupus erythematosus (n = 1). Notably none of them were rechallenged after cardiomyopathy so continued and severe caution is recommended [37].…”

Monitoring Clozapine Adverse Effects Calls for the Integration of Protocol and Good Clinical Practice

“…7 Agranulocytosis is a life-threatening and well known adverse side effect of clozapine. It is most prevalent within the first 4-5 months after initiating treatment.…”

Clozapine linked to nanocapsules minimizes tissue and oxidative damage to biomolecules lipids, proteins and DNA in brain of rats Wistar

“…(Bergemann et al 2007). Another dangerous complication is myocarditis induced by clozapine that may progress to dilated cardiomyopathy, a condition characterized by cardiac dysfunction and often symptoms of congestive heart failure (Haas et al 2007;Manu et al 2012). The treatment with clozapine requires clinical monitoring and screening haematological obligatory, considering that the majority of hematological effects induced by clozapine occurs primarily during the first months of therapy with the highest risk during the first 6 to 18 weeks of treatment (Atkin et al 1996;Gaszner, Makkos, and Kosza 2002).…”