Meta‐analysis examining the epidemiology of clozapine‐associated neutropenia

Myles, Hannah; Xia, Shelley; Large, Matthew; Kisely, Steve; Galletly, Cherrie; Bird, Robert; Siskind, Dan

doi:10.1111/acps.12898

Cited by 170 publications

(147 citation statements)

References 20 publications

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“…It is the most effective antipsychotic medication for reducing positive symptoms 165 and hospitalisations 166 . However, clozapine is associated with severe neutropenia/agranulocytosis (incidence 0.9% 95% CI: 0.7-1.1%) usually in the first month following commencement, rarely leading to death (incidence 0.013% 95% CI: 0.01-0.017%) 167 . Cardiac ADRs can be life-threatening and include myocarditis (incidence 0.03%-1%, usually within first month) 168,169 and cardiomyopathy (incidence 0.06-0.12%, usually after the first year) 168,170 .…”

Section: Clozapinementioning

confidence: 99%

The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness

Firth

Siddiqi

Koyanagi

et al. 2019

The Lancet Psychiatry

1,040

1,093

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Executive SummaryThe poor physical health of people with mental illness is a multi-faceted, transdiagnostic, and global problem. Physical health disparities are observed across the entire spectrum of mental illnesses, in low, middle-and high-income countries. This stems from both a heightened risk of physical diseases in people with mental illness, along with their reduced access to adequate healthcare. The high rates of physical comorbidities (and typically-poor clinical management of this) drastically reduces life expectancy, and also increases the personal, social and economic burden of illness across the lifespan.This Commission has brought together an international team of researchers, clinicians, and key stakeholders from various backgrounds and professionally / personally-relevant experience, in order to summarize advances in understanding on this topic, and present clear directions for health promotion, clinical care and future research. The breadth and multifactorial nature of physical health disparities across the range of mental health diagnoses poses an almost limitless number of potential considerations. Therefore, rather than attempting to cover all of the different possible combinations of physical-mental comorbidities individually, the aim of this Commission was to: (i) establish highlypertinent aspects of physical health-related morbidity and mortality which apply transdiagnostically, (ii) highlight the common modifiable factors driving these disparities, (iii) present actions and initiatives for health policy and clinical services to address these issues, and (iv) identify promising areas for future research towards discovering novel solutions. This was addressed across 5 different Parts of the Commission: Parts 1 and 2 determined the scope, priorities and key targets for physical health improvement across multiple mental illnesses. Parts 3, 4 and 5 discussed emerging strategies and produced recommendations for improving physical health outcomes in people with mental illness. Leaders and contributors for each Part are shown in the Appendix (pg.1) . Part 1: 'Its more than premature mortality'Part 1 identified almost 100 systematic reviews/meta-analyses examining the prevalence of physical comorbidities in mental illness. Around 70% of the meta-research focused on cardiometabolic diseases; consistently reporting that mental illnesses were associated with 1.4-to 2-fold increased risk for obesity, diabetes and cardiovascular diseases compared to the general population. Although mostly studied in 'severe mental illness' ('SMI', and particularly psychotic disorders), the prevalence of cardiometabolic diseases was similarly elevated across a broad range of other diagnoses, including substance use disorders (SUDs), and 'common mental disorders' ('CMDs', such as depression and anxiety). Part 2: Key modifiable factors in health behaviours and health servicesPart 2 built on the findings of Part 1 with a hierarchal evidence synthesis of modifiable risk factors for physical diseases in mental illness. The bu...

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Section: Clozapinementioning

confidence: 99%

The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness

Firth

Siddiqi

Koyanagi

et al. 2019

The Lancet Psychiatry

1,040

1,093

View full text Add to dashboard Cite

show abstract

“…However, severe neutropenia (ANC < 500/µL) is rare (9/1000 people started on clozapine), with a case fatality rate of 2.1%. 4 Importantly, severe neutropenia has its peak incidence in the first months after clozapine commencement and declines to negligible levels after 1 year. 4…”

Section: Recommendationmentioning

confidence: 99%

“…[1][2][3] Owing to the risk of clozapine-associated severe neutropenia, absolute neutrophil count (ANC) monitoring programs are a prerequisite for clozapine dispensation in most jurisdictions globally. 4,5 Regionspecific limits on outings and clinical resource constraints during the COVID-19 pandemic may create challenges for patients to access routine clozapine-associated care, including ANC testing required for dispensing. Discontinuing clozapine, especially abruptly, creates significant risk of relapse or exacerbation of severity of illness and needs to be avoided.…”

mentioning

confidence: 99%

Consensus statement on the use of clozapine during the COVID-19 pandemic

Siskind

Honer

Clark

et al. 2020

jpn

128

130

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“…The peak incidence occurs at 1 month of exposure and declines to negligible levels after 1 year of treatment. 21 A recent meta-analysis provided a prevalence of agranulocytosis of 0.4% (95% CI: 0.3% to 0.6%); deaths caused by agranulocytosis were 0.05% (CI: 0.03% to 0.09%). 22 This widespread awareness by clinicians is reflected in the almost 35 000 reports of neutropenia in VigiBase with the number of fatal outcomes only in the 500s (2% relative lethality).…”

Section: Inflammation Can Increase Clozapine Levelsmentioning

confidence: 99%

Clozapine is strongly associated with the risk of pneumonia and inflammation

et al. 2020

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Clinicians need to remember that (1) systemic inflammations can increase clozapine level; (2) clozapine, by itself, can cause inflammation, particularly during titration that is too rapid for that patient; (3) clozapine may increase the risk of infection; and (4) more specifically, clozapine may be particularly strongly associated with the risk of pneumonia. Pneumonia appears to be associated with high mortality in clozapine patients around the world. Clinicians who are alert to the risk of pneumonia in clozapine patients may significantly decrease mortality in clozapine patients. There is no data on COVID-19 infections in clozapine patients, but based on what we know about clozapine pharmacology, we can hypothesise that clozapine, possibly by impairing immunological mechanisms, may increase the risk of pneumonia in infected patients. More importantly, once fever and/or pneumonia develops, the clozapine dose should be cut in half to decrease the risk of clozapine intoxication. If there is any doubt that in spite of halving the dose there are still signs of clozapine intoxication, completely stopping clozapine may be indicated. Once the signs of inflammation and fever have disappeared, the clozapine dose can be increased to the prior dosage level.

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Meta‐analysis examining the epidemiology of clozapine‐associated neutropenia

Abstract: Severe neutropenia associated with clozapine is a rare event and occurs early with a substantial decline in risk after one year of exposure. Death from clozapine-associated neutropenia is extremely rare. Implications for haematological monitoring are discussed.

Cited by 170 publications

References 20 publications

The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness

The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness

Consensus statement on the use of clozapine during the COVID-19 pandemic

Clozapine is strongly associated with the risk of pneumonia and inflammation

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