Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland

Abstract

BackgroundData on the haematological outcomes of patients who continue clozapine treatment following neutropenia are very rare as even mild neutropenia results in mandatory discontinuation of clozapine in most countries. However, in Iceland where clozapine monitoring is less stringent allows an observational study to be done on the risk of agranulocytosis and neutropenia during treatment with clozapine compared with other antipsychotics among patients with schizophrenia.MethodsThe present study is a part of a wider ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never been on clozapine by searching the electronic health records of Landspitali, the National University Hospital. Neutrophil counts were searched in electronic databases to identify patients who developed neutropenia/agranulocytosis and the frequency of neutrophil measurements was examined as well.ResultsThe median number of days between neutrophil measurements during the first 18 weeks of clozapine treatment was 25 days but after the first 18 weeks on the drug the median became 124 days. Thirty four cases of neutropenia were identified during clozapine treatment with an average follow up time of 9.2 years. The majority, 24 individuals developed mild neutropenia (1500–1900 neutrophils/mm3). None of these progressed to agranulocytosis. The remaining 10 patients developed neutropenia in the range 500–1400 /mm3 of whom one developed agranulocytosis, three stopped clozapine use and 6 patients continued on clozapine for at least a year without developing agranulocytosis. Unexpectedly, schizophrenia patients on other antipsychotics had an equal risk of developing neutropenia as those on clozapine.ConclusionsNeutropenia is common both in patients with schizophrenia on clozapine treatment and in those never on clozapine. Therefore a large part of neutropenia during clozapine treatment is probably not caused by clozapine. These findings have implications in assessing the balance between the risk of progression from neutropenia to agranulocytosis against the morbidity resulting from the premature discontinuation of clozapine under the current monitoring regulations in the US and in most of Europe.

Delegating Clozapine Monitoring to Advanced Nurse Practitioners: An Exploratory, Randomized Study to Assess the Effect on Prescription and Its Safety

“…It is the responsibility of the physician to organise these weekly laboratory investigations. To our knowledge, only one other study reported the frequency of neutrophil measurements after the initiation of clozapine, with measurements being performed during the first 18 weeks at a mean interval of 25 days (Ingimarsson et al 2016). This is less often than in our study.…”

Need to bleed? Clozapine haematological monitoring approaches a time for change

“…In a study of patients with schizophrenia comparing those on long-term clozapine treatment versus non-clozapine antipsychotics, mild neutropenia (1.5-1.9 x10 9 /l) was significantly associated with clozapine compared with non-clozapine drugs (hazard ratio of 1.86). Moderate to severe neutropenia (0-1.4 x10 9 /l) on the other hand was more common in patients who had never been on clozapine despite having blood counts half as frequently as those on clozapine (Ingimarsson et al, 2016). The Iceland data suggest that many instances of neutropenia are probably unrelated to clozapine and very rarely progress to the more severe agranulocytosis.…”

Neutrophil-to-lymphocyte ratio exhibits the different correlation with psychiatric symptoms in the different status of antipsychotic therapy in schizophrenia: a large-scale retrospective cross-sectional study.

“…37 Clozapine-induced neutropenia occurs in ∼1% of patients. In recent decades, it was found that patients with schizophrenia who take other antipsychotics had an equal risk of developing neutropenia as those taking clozapine [38]. Notable, neutrophils are mainly known for their proinflammatory role in anti-bacteria.…”