Rechallenging With Clozapine Following Neutropenia: Treatment Options for Refractory Schizophrenia

Abstract

Clozapine, a second-generation antipsychotic, is the treatment of choice in refractory schizophrenia because of its proven efficacy over typical antipsychotics as well as other atypical antipsychotics (1). However, a major drawback to clozapine therapy is the increased risk of neutropenia and agranulocytosis (2). In patients who develop either of these serious side effects, clozapine is immediately discontinued. Unfortunately, trials of other antipsychotics often prove ineffective, and clinicians find themselves faced with the difficult decision of whether to rechallenge those patients with clozapine (3). Even more concerning for the clinician is the relative absence of any controlled data to suggest treatment options when clozapine cannot be used because of serious side effects, such as neutropenia or agranulocytosis. This case review highlights this particular aspect and provides some useful thinking points for clinicians and patients in this situation. Efforts at rechallenge with clozapine have met with some success (4–9). In a retrospective review of 53 cases of clozapine rechallenge in the United Kingdom and Ireland, 62% of the patients did not develop a blood dyscrasia on rechallenge (8). Of course, clozapine rechallenge is not without its risks. In the same retrospective review, it was found that among the 38% of cases who did develop a blood dyscrasia on rechallenge, in 85% of the cases, the blood dyscrasia occurred more quickly and was more severe than with the initial trial of clozapine. In addition, in 65% of the cases in which patients developed a blood dyscrasia on rechallenge, the blood dyscrasia lasted longer after discontinuation of clozapine following rechallenge than when clozapine was first discontinued. Thus, when deciding whether to rechallenge a patient with clozapine, the clinician must carefully weigh the risks and benefits of a clozapine rechallenge. Here we present a patient with refractory schizophrenia who successfully tolerated a clozapine challenge 2 years after developing clozapine-induced neutropenia and failing to respond to a subsequent clozapine rechallenge. We propose that polypharmacy may have contributed to the initial episode of neutropenia as well as the failed clozapine rechallenge in our patient. We also discuss logical issues in medical decision making before considering clozapine rechallenges in patients.