Rechallenging With Clozapine Following Neutropenia: Treatment Options for Refractory Schizophrenia

Abstract

Cl ozapine, 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.Case Presentation "S.P." was a 55-year-old divorced African American man with a 30-year history of paranoid schizophrenia who was referred to our unit for medication adjustment after a 2-year gradual worsening of psychotic symptoms characterized by thought disturbance and behavioral disorganization. As a result of his worsening symptoms, 3 months before admission, S.P. went from living independently in a supervised care setting to requiring close supervision and help with activities of daily living. Two months before admission, he stopped bathing and washing his clothes and refused to socialize. S.P.'s relationship with his case manager, which had previously been good, ...

Continuation of clozapine during chemotherapy and a stem cell transplant

“…The risk of clozapine-induced agranulocytosis or neutropenia after one year of treatment is less than 1%. 7 In our case report the patient's cytopenia was almost certainly secondary to the ablation chemotherapy. However, one study has shown that of 53 patients rechallenged with clozapine following an initial blood dyscrasia, 38% developed a further leucopenia or neutropenia.…”

“…4,[6][7][8][9][10] Munshi et al 6 report a case of a patient who had been mentally stable for 15 years before developing B-cell lymphoma. As a predictable consequence of the R-CHOP chemotherapy regimen, the patient developed a red result and the community psychiatrist stopped the clozapine.…”

Successful rechallenge with clozapine following ‘red alert’

“…During clozapine rechallenge many patients are given treatments that have been shown to elevate neutrophil counts such as lithium and granulocyte colony-stimulating factor (G-CSF) 2 6 10. Lithium might be useful in keeping the WCC higher in patients with benign ethnic neutropenia who could potentially be discontinued from using clozapine due to confusion with clozapine-induced blood dyscrasia 2.…”

“…Clinicians need to be aware that concomitant treatment with other drugs that cause leucopenia may also increase the risk of agranulocytosis 1 10…”

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine

“…Interestingly enough, none of these authors mentioned that carbamazepine, via activation of 3A4, 19 can significantly decrease clozapine concentration and compromise therapeutic response. Some authors 9,10,14,33,40,41 recommend sodium valproate; others 10,14,[42][43][44][45] recommend sodium valproate, gabapentin, topiramate or lamotrigine.…”