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

https://doi.org/10.1016/j.schres.2011.10.014Get rights and content

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.

Introduction

Clozapine, the first atypical antipsychotic, was synthesized in 1958 and brought to the European market in the 1970s as a treatment for schizophrenia that was not associated with the risk of extrapyramidal syndrome seen with phenothiazines and butyrophenones (Stille and Hippius, 1971). Shortly after its introduction in Finland in 1975, 18 patients developed severe neutropenia and 8 of them died (Crilly, 2007), prompting the withdrawal of the drug until the mid-1980s. Its world-wide use followed a landmark study demonstrating its superior efficacy for patients with refractory schizophrenia compared with chlorpromazine (Kane et al., 1988). Since then, clozapine has remained the gold standard treatment for refractory patients with severe psychotic disorders (Lewis et al., 2006, McEvoy et al., 2006, Essali et al., 2009). For the past two decades, clozapine has remained the most effective drug for schizophrenia patients who fail to respond to treatment with other antipsychotics, with advantages in terms of burden of psychiatric symptoms, avoidance of hospitalization, potential for social and occupational rehabilitation (Whiskey and Taylor, 2007, Kane and Correll, 2010) and healthcare costs (Blieden et al., 1998, Davies et al., 2008). It is also important to note that clozapine has been shown to reduce suicidal behavior in schizophrenia (Meltzer et al., 2003).

The clozapine acceptance by patients and the frequency of its prescribing by clinicians have been hampered by apprehension regarding adverse effects with life-threatening potential, notably significant agranulocytosis and neutropenia (Alvir et al., 1993, Gerson, 1994), myocarditis (Pieroni et al., 2004, Reinders et al., 2004, Merrill et al., 2005), cardiomyopathy (Reinders et al., 2004), pericarditis (Rathore et al., 2007, Crews et al., 2010), alveolitis (Arias et al., 2011), pancreatitis (Bayard et al., 2005), hepatitis (Chang et al., 2009), nephritis (Au et al., 2004), colitis (Pelizza and Melegari, 2007), drug-induced lupus erythematosus (Rami et al., 2006), status epilepticus (Gandelman-Marton et al., 2008), diabetic ketoacidosis and hyperosmolar coma (Cohen and Correll, 2009), and neuroleptic malignant syndrome (Miller et al., 1991).

The life-threatening complications of clozapine are produced by pathophysiologic mechanisms that are not well understood. The occurrence of severe neutropenia and myocarditis is not dose-dependent (Alvir et al., 1993, Merrill et al., 2005), a finding suggesting that a direct toxic effect on the hematopoietic bone marrow or cardiomyocytes is unlikely. A genetic vulnerability for clozapine-induced agranulocytosis (Athanasiou et al., 2011) and the possibility that myocarditis is the result of an allergic-like hypersensitivity reaction (Pieroni et al., 2004) have been invoked. According to the package insert, treatment with clozapine is contraindicated in patients with history of clozapine-induced agranulocytosis or severe neutropenia and in patients with hypersensitivity to this drug (Micromedex).

In clinical practice, the discontinuation of clozapine is frequently followed by worsening of psychotic symptoms, functional status and quality of life (DasGupta and Young, 1991, Silvestrini et al., 2000, Mathewson and Lindenmayer, 2007, Bray, 2008, Ghaznavi et al., 2008, Crews et al., 2010). Advice regarding the risks of rechallenge is often sought by psychiatric care providers. In this analysis, we evaluated the published experience with clozapine rechallenge to identify the type of adverse effect for which a preponderance of evidence indicates a favorable outcome after clozapine rechallenge. In addition, we sought to identify pharmacological strategies that might help the clozapine rechallenge succeed.

Section snippets

Methods

We searched the literature for all studies that reported cases of patients who were rechallenged with clozapine after developing major adverse reactions during initial treatment with this antipsychotic. A search of the PubMed site jointly managed by the U.S. National Library of Medicine and National Institutes of Health for the period of 1972–July 2011 was performed using the search terms “clozapine” and “rechallenge”. Demographic and clinical data were extracted for patients of all ages.

Results

We identified 30 reports reporting on a total of 138 patients in whom clozapine rechallenge was attempted after a potentially life threatening adverse drug effect. The rechallenged group included 112 patients with neutropenia, 15 with agranulocytosis, 5 with neuroleptic malignant syndrome, 4 with myocarditis and one each of drug-induced systemic lupus and pericarditis. Patients were on average 36.3 years old, 65.7% were male, 57.6% were Caucasian, and virtually all patients had schizophrenia

Discussion

We analyzed data regarding 136 patients rechallenged with clozapine after developing neutropenia, agranulocytosis, neuroleptic malignant syndrome, and myocarditis. The outcome of rechallenge was favorable in 78/112 patients (69.6%, 95% CI, 60.6–77.4) after neutropenia, 3/15 (14.3%, 95% CI, 4–40) after agranulocytosis, 5/5 (100%, 95% CI, 56–100%) after neuroleptic malignant syndrome and 3/4 (75%, 95% CI, 30–95) after myocarditis. None of the rechallenged patients died. The findings are limited

Role of funding source

None.

Contributors

The authors contributed equally to the study design and analysis of the data. The data collection was performed by Drs. Sarpal, Muir and Manu. The manuscript was written by Drs. Manu, Sarpal, Muir, and Correll.

Conflict of interest

Dr. Kane has been a consultant to or has received honoraria from Astra-Zeneca, Biotis, Bristol-Myers Squibb, Cephalon, Eli Lilly, Janssen Pharmaceutica, Johnson and Johnson, Lundbeck, Otsuka, Pfizer Inc, PgXHealth, Proteus, Vanda and Wyeth, has served on the speaker's bureau of AstraZeneca, Bristol-Myers Squibb/Otsuka and Eli Lilly, and is a share holder of MedAvante. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Actelion, Biotis, AstraZeneca, Bristol-Myers

Acknowledgements

None.

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