Repurposing clozapine in psychosis
<p>Treatment resistant schizophrenia (TRS), affecting approximately 20-30% of patients diagnosed with schizophrenia, has a high burden for patients, family members and the healthcare system. Clozapine is the most effective antipsychotic available and the only licensed treatment for TRS. Despit...
| Main Author: | |
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2024
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| Subjects: |
| _version_ | 1811139298758492160 |
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| author | Oloyede, E |
| author2 | Blackman, G |
| author_facet | Blackman, G Oloyede, E |
| author_sort | Oloyede, E |
| collection | OXFORD |
| description | <p>Treatment resistant schizophrenia (TRS), affecting approximately 20-30% of patients diagnosed with schizophrenia, has a high burden for patients, family members and the healthcare system. Clozapine is the most effective antipsychotic available and the only licensed treatment for TRS. Despite this, clozapine is vastly under prescribed in the United Kingdom (UK) and most countries worldwide. In addition, clozapine initiation is frequently delayed despite individuals meeting consensus criteria for TRS. Reasons for clozapine’s underuse are multifaceted but include restrictive regulations and clinician attitudes.</p>
<p>The timely initiation of clozapine is important for maximising long-term treatment benefits. Accordingly, there is increasing interest amongst academics and public health bodies to address clozapine underuse in TRS. The literature has appropriately explored and identified potential facilitators for improved clozapine use in TRS, which include regulatory changes. However, much of the evidence underpinning these recommendations are limited. In this thesis, I aimed to investigate epidemiological characteristics and trends of clozapine prescribing, as a basis to provide evidence-based recommendations for the early initiation and continued maintenance of clozapine in TRS.</p>
<p>Chapter two provides an overview of national guidelines for haematological monitoring internationally. I compared national standards for haematological monitoring, treatment discontinuation, rechallenge following suspected neutropenia and monitoring criteria for benign ethnic neutropenia (BEN). Furthermore, I developed a Stringency Index (SI) to analyse the impact of haematological monitoring standards on clozapine utilisation rates and healthcare expenditure. Between 102 countries, chapter two found marked differences in haematological monitoring guidelines, despite the same evidence base. There was a positive association between a country’s SI and health expenditure per capita and a negative association between a country’s SI and prescription rates.</p>
<p>In chapter two, I discussed the United States (US) Food and Drug Administration (FDA) modified clozapine monitoring criteria to improve clozapine use. This included lowering neutrophil thresholds for clozapine cessation by 0.5x109/L (500/μL). There was also removal of a previous requirement for white cell count (WCC) monitoring, and the use of a clozapine non-rechallenge database (CNRD), which had been designed to safeguard patients from being inadvertently re-exposed to clozapine after suspected agranulocytosis. However, I also showed that only a few countries (Chile, Israel, Lebanon, South Africa) have adopted these FDA changes.</p>
<p>Using a national cohort of patients in the UK who were placed on the UK CNRD, chapter three found that only 15% of patients would have discontinued clozapine had the US FDA criteria been applied. My thesis also showed that most patients were placed on the UK CNRD beyond the highestrisk period for CIA. In addition, the results of chapter two demonstrate that many patients can be safely re-exposed to clozapine after suspected clozapine-induced neutropenia. This suggests that current haematological monitoring criteria for identifying clozapine-induced agranulocytosis (CIA) has a high false positive rate.</p>
<p>Chapter four investigated the clinical impact of extended haematological monitoring using a controlled one-year mirror-image design in patients who being treated with clozapine. I found that there was no increased risk of haematological events in patients receiving extended (3 monthly) compared to standard (monthly) monitoring, and no difference in clinical outcomes, defined in terms of hospitalisation and psychotropic use. These results suggest that extended monitoring can safely be implemented in some patients.</p>
<p>In Chapter five, I used a large cohort of patients treated with clozapine to examine the prevalence of BEN and the potential impact of unidentified BEN on the maintenance of clozapine treatment. I found that BEN remains an uncommonly recognised haematological phenotype, and that registration with BEN occurred predominantly after a previous haematological aberration or on clozapine rechallenge. I also showed that there are patients who are prohibited from receiving clozapine due to unidentified BEN, as opposed to suspected CIA. the results of this chapter thus suggest that improved identification of BEN would reduce inequalities in clozapine access and maintenance.</p>
<p>Chapter six presents the results of a literature review of clozapine-induced withdrawal symptoms. This revealed that clozapine can cause an array of withdrawal symptoms on discontinuation, broadly divided into symptoms of rebound psychosis, cholinergic rebound, catatonia and serotonergic discontinuation. I then provided evidence-based recommendations for reducing the risk of withdrawal symptoms and relapse following clozapine discontinuation.</p>
<p>Finally, in chapter seven, I draw together the findings across chapters. Together, the results indicate that current regulations around clozapine use are overly stringent and create barriers to increased clozapine use. Whilst acknowledging the methodological limitations of the studies, the thesis provides recommendations for the earlier initiation of clozapine in TRS. Namely, revising haematological monitoring requirements, including routine inclusion of modified monitoring criteria for individuals with BEN and limiting monitoring for CIA to the highest risk period.</p> |
| first_indexed | 2024-09-25T04:03:52Z |
| format | Thesis |
| id | oxford-uuid:a13ccae6-3c23-4b7f-aa5a-e0625938b450 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:03:52Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:a13ccae6-3c23-4b7f-aa5a-e0625938b4502024-05-07T16:36:13ZRepurposing clozapine in psychosisThesishttp://purl.org/coar/resource_type/c_db06uuid:a13ccae6-3c23-4b7f-aa5a-e0625938b450PsychiatryEnglishHyrax Deposit2024Oloyede, EBlackman, GMcGuire, P<p>Treatment resistant schizophrenia (TRS), affecting approximately 20-30% of patients diagnosed with schizophrenia, has a high burden for patients, family members and the healthcare system. Clozapine is the most effective antipsychotic available and the only licensed treatment for TRS. Despite this, clozapine is vastly under prescribed in the United Kingdom (UK) and most countries worldwide. In addition, clozapine initiation is frequently delayed despite individuals meeting consensus criteria for TRS. Reasons for clozapine’s underuse are multifaceted but include restrictive regulations and clinician attitudes.</p> <p>The timely initiation of clozapine is important for maximising long-term treatment benefits. Accordingly, there is increasing interest amongst academics and public health bodies to address clozapine underuse in TRS. The literature has appropriately explored and identified potential facilitators for improved clozapine use in TRS, which include regulatory changes. However, much of the evidence underpinning these recommendations are limited. In this thesis, I aimed to investigate epidemiological characteristics and trends of clozapine prescribing, as a basis to provide evidence-based recommendations for the early initiation and continued maintenance of clozapine in TRS.</p> <p>Chapter two provides an overview of national guidelines for haematological monitoring internationally. I compared national standards for haematological monitoring, treatment discontinuation, rechallenge following suspected neutropenia and monitoring criteria for benign ethnic neutropenia (BEN). Furthermore, I developed a Stringency Index (SI) to analyse the impact of haematological monitoring standards on clozapine utilisation rates and healthcare expenditure. Between 102 countries, chapter two found marked differences in haematological monitoring guidelines, despite the same evidence base. There was a positive association between a country’s SI and health expenditure per capita and a negative association between a country’s SI and prescription rates.</p> <p>In chapter two, I discussed the United States (US) Food and Drug Administration (FDA) modified clozapine monitoring criteria to improve clozapine use. This included lowering neutrophil thresholds for clozapine cessation by 0.5x109/L (500/μL). There was also removal of a previous requirement for white cell count (WCC) monitoring, and the use of a clozapine non-rechallenge database (CNRD), which had been designed to safeguard patients from being inadvertently re-exposed to clozapine after suspected agranulocytosis. However, I also showed that only a few countries (Chile, Israel, Lebanon, South Africa) have adopted these FDA changes.</p> <p>Using a national cohort of patients in the UK who were placed on the UK CNRD, chapter three found that only 15% of patients would have discontinued clozapine had the US FDA criteria been applied. My thesis also showed that most patients were placed on the UK CNRD beyond the highestrisk period for CIA. In addition, the results of chapter two demonstrate that many patients can be safely re-exposed to clozapine after suspected clozapine-induced neutropenia. This suggests that current haematological monitoring criteria for identifying clozapine-induced agranulocytosis (CIA) has a high false positive rate.</p> <p>Chapter four investigated the clinical impact of extended haematological monitoring using a controlled one-year mirror-image design in patients who being treated with clozapine. I found that there was no increased risk of haematological events in patients receiving extended (3 monthly) compared to standard (monthly) monitoring, and no difference in clinical outcomes, defined in terms of hospitalisation and psychotropic use. These results suggest that extended monitoring can safely be implemented in some patients.</p> <p>In Chapter five, I used a large cohort of patients treated with clozapine to examine the prevalence of BEN and the potential impact of unidentified BEN on the maintenance of clozapine treatment. I found that BEN remains an uncommonly recognised haematological phenotype, and that registration with BEN occurred predominantly after a previous haematological aberration or on clozapine rechallenge. I also showed that there are patients who are prohibited from receiving clozapine due to unidentified BEN, as opposed to suspected CIA. the results of this chapter thus suggest that improved identification of BEN would reduce inequalities in clozapine access and maintenance.</p> <p>Chapter six presents the results of a literature review of clozapine-induced withdrawal symptoms. This revealed that clozapine can cause an array of withdrawal symptoms on discontinuation, broadly divided into symptoms of rebound psychosis, cholinergic rebound, catatonia and serotonergic discontinuation. I then provided evidence-based recommendations for reducing the risk of withdrawal symptoms and relapse following clozapine discontinuation.</p> <p>Finally, in chapter seven, I draw together the findings across chapters. Together, the results indicate that current regulations around clozapine use are overly stringent and create barriers to increased clozapine use. Whilst acknowledging the methodological limitations of the studies, the thesis provides recommendations for the earlier initiation of clozapine in TRS. Namely, revising haematological monitoring requirements, including routine inclusion of modified monitoring criteria for individuals with BEN and limiting monitoring for CIA to the highest risk period.</p> |
| spellingShingle | Psychiatry Oloyede, E Repurposing clozapine in psychosis |
| title | Repurposing clozapine in psychosis |
| title_full | Repurposing clozapine in psychosis |
| title_fullStr | Repurposing clozapine in psychosis |
| title_full_unstemmed | Repurposing clozapine in psychosis |
| title_short | Repurposing clozapine in psychosis |
| title_sort | repurposing clozapine in psychosis |
| topic | Psychiatry |
| work_keys_str_mv | AT oloyedee repurposingclozapineinpsychosis |