Continuation of Treatment With Clozapine After an Episode of Neutropenia

Abstract

BackgroundClozapine is the most effective in treatment-resistant schizophrenia. Neutropenia is an adverse effect of the drug requiring treatment discontinuation. This study related treatment continuation with little or no interruption after a neutropenia episode. The study contrasted from rechallenge studies after an extended treatment interruption.MethodsThis retrospective chart audit examined 37 patients with an episode of neutropenia. It described characteristics of patients continuing treatment with minimal interruption.FindingsThirty-one patients continued treatment after an initial treatment interruption for less than 3 days. A probable cause for neutropenia other than clozapine was identified in 14 patients. Twelve patients continued treatment with a change in the absolute neutrophil counts threshold to 1000/μL to determine treatment cessation. Most patients recovered from the index episode of neutropenia within 2 days. They also frequently presented with recurring benign episodes of low neutrophil cell counts during treatment than a comparative group.ImplicationsThe study recommends modifying clozapine treatment protocol absolute neutrophil count thresholds to less than 1000/μL to determine treatment cessation. Consideration of other probable causes for neutropenia, diurnal variations in cell counts, and laboratory errors reduced preemptive discontinuation of treatment. A risk-benefit approach supports continuing clozapine treatment after an episode of neutropenia.

Clozapine Rechallenge or Continuation Despite Neutropenia, an Extended Follow-up of a Consecutive Quebec Case Series

“…To our knowledge, 7 consecutive case series of clozapine rechallenge after neutropenia, with sample sizes varying from 14 to 53 (total = 181) have been published. 8,9,11,[16][17][18][19] In those 7 consecutive case series, the success rates of clozapine rechallenge after neutropenia reported varies from 62% to 100% with relatively short follow-up periods (median follow-up, 1.61 years; range, unreported to 7 years), limiting the assessment of the durability of these results, while the median follow-up period in this series was 4.8 years (range, 1.3-19.4 years). Two of those case series are not necessarily comparable with the others because one was carried out in a child psychiatric hospital and one was conducted in a high-security forensics hospital where the benefits of clozapine rechallenge for violent patients could more heavily outweigh the risks of such practice and justify a more venturesome approach.…”

“…Continuing clozapine despite a mild neutropenia event is an increasingly used strategy in clinical practice subsequently to the manufacturer's hematologist approval (depending on local clozapine legislation) 11 . In the continuers group, most patients had a neutropenia episode of mild severity and 7 of 8 patients could maintain clozapine treatment at the end of follow-up, suggesting continuation of clozapine with the local clozapine governance authorization, could be an interesting option for clozapine responders with mild initial neutropenia events.…”

“…Furthermore, national authorities should lower the neutrophil threshold warranting clozapine discontinuation to 1.0 Â 10 9 /L and remove white blood cells monitoring, similarly to the updated Food and Drugs Administration clozapine monitoring guidelines, to prevent unnecessary cessation of a potentially life-saving therapy with clozapine. 11,22 A shared decision-making approach with thorough risk-benefit assessment should be used with the patient and his close ones to decide on clozapine continuation despite neutropenia.…”

“…10 As an alternative to discontinuing clozapine after neutropenia, its continuation may also be considered, although this is generally only attempted in neutropenia of mild severity (ANC, 1.0-1.5 Â 10 9 /L) outside of the United States. 11,12 Although clozapine was shown to reduce risk of all-cause mortality, this strategy is seldom used as it is off labeled and the potential progression of neutropenia to agranulocytosis may be fatal. 6 To address these limitations, described herein is the first consecutive North American case series combining clozapine rechallenge/ continuation, an adult setting, a long follow-up period, and a systematic assessment of every alternate explanation of neutropenia using Naranjo Adverse Drug Reaction Scale.…”

“…Furthermore, solely one case series has systematically assessed every alternative explanation of neutropenia using a pharmacovigilance tool 10 . As an alternative to discontinuing clozapine after neutropenia, its continuation may also be considered, although this is generally only attempted in neutropenia of mild severity (ANC, 1.0–1.5 × 10 9 /L) outside of the United States 11,12 . Although clozapine was shown to reduce risk of all-cause mortality, this strategy is seldom used as it is off labeled and the potential progression of neutropenia to agranulocytosis may be fatal 6 …”