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Background: Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term.
Methods: We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan-Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case-control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study.
Findings: We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44-57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58-3·16) on clozapine and 0·13% (0·04-0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79-77·22) for less than 6 months on clozapine to 4·38 (1·86-10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis.
Interpretation: The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis.
Funding: Northwell Health and Sigrid Jusèlius Foundation.
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http://dx.doi.org/10.1016/S2215-0366(24)00097-X | DOI Listing |
Schizophr Bull
December 2024
Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, 980-8574, Japan.
Background And Hypothesis: Eosinophilia has not been highlighted in clozapine-induced adverse inflammatory events, as it is often asymptomatic and self-limiting, while drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome occurs rarely. This study aimed to reveal the temporal relationships between eosinophilia and other inflammatory events during clozapine initiation.
Study Design: The temporal relationships between eosinophilia and other inflammatory events were evaluated among 241 patients with schizophrenia treated with clozapine for the first time at 7 hospitals.
Eur Child Adolesc Psychiatry
December 2024
Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA.
Patient Prefer Adherence
November 2024
Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA.
Purpose: Clozapine is an antipsychotic which was approved in 1989 for treatment-resistant schizophrenia in the United States (US). There were few randomized trials before its approval and potentially lethal clozapine adverse drug reactions (ADRs), such as agranulocytosis and myocarditis were identified by pharmacovigilance. VigiBase, the WHO global database, is a cornerstone of international pharmacovigilance efforts for ADR identification during post-marketing surveillance.
View Article and Find Full Text PDFBr J Psychiatry
October 2024
Department of Psychiatry, University of Oxford, Oxford, Oxford Health NHS Foundation Trust, Oxford and Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
Oloyede and colleagues advocate for updating haematological monitoring requirements for clozapine, arguing that current protocols overestimate the risk of clozapine-induced agranulocytosis. Their research suggests that stringent monitoring may unnecessarily limit access to clozapine, a crucial treatment for resistant schizophrenia. The editorial supports calls for international consensus to carefully weigh the pros and cons of relaxing monitoring guidelines while ensuring comprehensive care for patients.
View Article and Find Full Text PDFPharmacy (Basel)
September 2024
Surrey and Borders Partnership NHS Foundation Trust, Leatherhead KT22 7AD, UK.
Clozapine is the only approved antipsychotic for refractory schizophrenia to date. It can cause a range of serious and fatal adverse effects, including Clozapine-Induced Gastrointestinal Hypomotility (CIGH). While guidance is readily available to help manage CIGH effectively in hospital inpatients, practical recommendations applicable to the community (outpatient) setting are lacking.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!