Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study

Oloyede, Ebenezer; Whiskey, Eromona; Casetta, Cecilia; Dzahini, Olubanke; Dunnett, Danielle; Gandhi, Sanyam; Gaughran, Fiona; Shergill, Sukhi; McGuire, Philip; MacCabe, James H.; Taylor, David

doi:10.1016/s2215-0366(22)00188-2

Cited by 22 publications

(34 citation statements)

References 29 publications

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“…This has not led to an increase in mortality secondary to clozapine-induced severe neutropenia (van der Klauw et al ., 1998; Schulte, 2006). Furthermore, in 2015 the US FDA updated its clozapine guidelines, decreasing the ANC cut-off for clozapine cessation to a lower threshold compared to many other countries (Sultan et al ., 2017; Oloyede et al ., 2022). In addition, the requirements for monitoring WCC were removed (Whiskey et al ., 2019) and patients with BEN were permitted to commence clozapine treatment under lower thresholds than in most countries.…”

Section: Discussionmentioning

confidence: 99%

Clozapine haematological monitoring for neutropenia: a global perspective

Oloyede

Blackman

Whiskey

et al. 2022

Epidemiol Psychiatr Sci

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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.

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Section: Discussionmentioning

confidence: 99%

Clozapine haematological monitoring for neutropenia: a global perspective

Oloyede

Blackman

Whiskey

et al. 2022

Epidemiol Psychiatr Sci

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“…Revisions include prescribing CLZ for patients with benign neutropenia and using algorithms and artificial intelligencebased tools for patients who benefited from atypical antipsychotic medications but had CIAG. Recently, a modeling study indicated that the CLZ rechallenging success after patients' hematological parameters falls below particular thresholds, namely, the CLZ central non-rechallenge database (CNRD); the success rates were similar between individuals who did not meet the CNRD registration criteria and those who did meet those criteria (Oloyede et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…However, if the white blood cell count (WBC) or absolute neutrophil count (ANC) decreases to <3,000/mm 3 or 1,500/mm 3 , CLZ treatment should be discontinued (rechallenging for patients with CIAG is also prohibited unless the CPMS committee gives permission based on the clinical course) at that moment. The relaxation of the criteria for the entry to the UK CLZ central non-rechallenge database has been modeled recently (Oloyede et al, 2022).…”

Section: Decision Analytic Model and Pgxguided Strategymentioning

confidence: 99%

Pharmacogenomic-guided clozapine administration based on HLA-DQB1, HLA-B and SLCO1B3-SLCO1B7 variants: an effectiveness and cost-effectiveness analysis

et al. 2022

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The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.

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“…Monitoring twice per week 91,151,[157][158][159]170  Eosinophilia > 3/nl: search for CIM, pancreatitis, DRESS syndrome, CIA  BEN: does not constitute a contraindication; consider expanding monitoring [167][168][169][170][171]  Most hematological changes are only transient 236 Qubad & Bittner -Clozapine treatment in schizophrenia 35 Sedation* 270,372,396  Regular clinical assessment  Most commonly transient in nature 270,372,396  Titration to lowest effective dose 16,270,372  Minimize day-time doses 270,372  Avoid concomitant sedating drugs 91,270,372 Qubad & Bittner -Clozapine treatment in schizophrenia 36 Myocarditis, cardiomyopathy 199,206  Highest risk during the first four weeks of treatment ULN 148,180,199,206  Cardioprotective treatment: ACEinhibitors and beta blockers 317  In severe cases transfer to intensive care unit 91,191  Symptoms improve within 5 days of treatment termination; most common course: restitutio ad integrum 91,180 , cardiomyopathy is a potential complication…”

Section: Cyp Inducers Cyp Inhibitorsmentioning

confidence: 99%

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

Qubad¹,

Bittner²

2022

Preprint

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Despite its continued relevance as the single most effective and important evidence-based treatment for schizophrenia, the degree of underutilization of clozapine across health systems remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to use clozapine due to its relatively large side-effect burden and its comparatively complex dosing and monitoring requirements. This underscores the necessity for continued education of clinicians in the intricacies of clozapine use and in the still growing case in favor of this vital treatment option. Consequently, this narrative review provides a comprehensive outline of all lines of evidence, which support clozapine’s wide-ranging superior efficacy, and of the current knowledge regarding the prevalence and diagnosis of treatment resistance. The distinct neurobiological and clinical characteristics of this condition makes the swift initiation of clozapine indispensable. Moreover, we review the extensive literature regarding clozapine’s side effect profile and current recommendations for optimal treatment and monitoring algorithms including for particularly vulnerable populations such as elderly patients and pregnant women and for potential re-challenges after myocarditis and neutropenia. We also discuss established approaches to increase treatment response as well as augmentation strategies for patients with partial or full clozapine resistance. We argue for a clear focus on early and consistent detection and management of side effects, which can ensure patient safety and reduce permanent all-cause discontinuation. This strategy needs to be combined with a long-term approach acknowledging the late onset of clozapine’s full advantageous effects, which – in cases like reduced mortality rates – even then may not be easily discernible. Our aim is to encourage a safer, more frequent, and timely use of clozapine to maximize patients’ short- and long-term benefits. Even now, the extent of these benefits as well as patient’s satisfaction with treatment still clearly set clozapine apart from all other available treatment options.

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Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study

Cited by 22 publications

References 29 publications

Clozapine haematological monitoring for neutropenia: a global perspective

Clozapine haematological monitoring for neutropenia: a global perspective

Pharmacogenomic-guided clozapine administration based on HLA-DQB1, HLA-B and SLCO1B3-SLCO1B7 variants: an effectiveness and cost-effectiveness analysis

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

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