Clozapine haematological monitoring for neutropenia: a global perspective

Abstract

Aims Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates. Method We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons. Results One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita. Conclusions Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

International Variation in Clozapine Hematologic Monitoring—A Call for Action

“…Shortly after the aforementioned Finnish Epidemic, a clozapine manufacturer–sponsored article put forward the concept of weekly monitoring for the first 18 weeks of treatment . This was remarkably similar to earlier recommendations for chlorpromazine in the 1950s . Here, we are reminded that a negative association between antipsychotics and agranulocytosis predated widespread clozapine use.…”

“…Treatment-resistant psychosis, defined as the persistence of psychotic symptoms despite sequential antipsychotic treatment, is a major cause of disability and functional impairment worldwide . Within the past decade, there has been a commitment among health institutions to address clozapine underuse . This commitment reflects the evidence demonstrating superior clinical benefits of clozapine compared with other licensed antipsychotics.…”

“…These monitoring schemes are not without controversies and limitations; the hematologic thresholds for treatment discontinuation are somewhat arbitrary, and the indefinite nature of hematologic monitoring is without evidential foundation. Concerning the first of these, while the patent holders suggested in earlier discussions that clozapine discontinuation thresholds had been set with a margin of safety, use of thresholds takes little or no consideration for the pattern of neutrophil count changes . Even if monitoring by threshold is accepted, the thresholds themselves are subject to debate.…”

“…In addition to this, patients with BEN, the hematologic phenotype with a relatively low ANC less than 1500/μL without increased risk of infection, were permitted to receive clozapine under still lower thresholds. Though these changes represent a positive step toward improved clozapine access, similar changes by regulatory agencies on an international scale have been slow to emerge, and thresholds differ markedly from one country to another …”

The ever-growing case for clozapine in the treatment of schizophrenia: an obligation for psychiatrists and psychiatry

“…Point-of-care devices for full blood cell counts and TDM have the potential to greatly simplify monitoring requirements 50*,52,55,74 . Responsibly easing policies such as restrictions for re-challenging patients after mild forms of neutropenia 38 and blood monitoring requirements after the initial year of treatment 77 should also increase clozapine use.…”