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Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis.

ABSTRACT: The wider use of clozapine is limited by the risk of agranulocytosis and the associated requirement for monitoring of neutrophil counts. We searched local electronic patient records for cases of agranulocytosis occurring during clozapine treatment during the period 2007-2020. We found 23 episodes recorded as agranulocytosis in clozapine patients. Of these, nine met pre-defined criteria and were considered episodes of life-threatening agranulocytosis (LTA). These episodes of clozapine-induced LTA exhibited a distinct pattern of continuous and rapid neutrophil count decline to zero or near zero. Mean time for neutrophils to fall from ANC > 2 to ANC <0.5 × 10⁹/L was 8.4 days (range 2-15 days). Each event was also characterised by a prolonged nadir and delayed recovery (range 4-16 days). Non-LTA episodes were, in contrast, brief and benign. We conclude that an important proportion of cases of agranulocytosis identified in people prescribed clozapine are not life-threatening and may not even be clozapine-related. Monitoring schemes should aim to identify true clozapine-induced LTA as opposed to threshold-defined nominal agranulocytosis. Genetics studies might benefit from examining associations with clozapine-induced LTA rather than with recorded cases of agranulocytosis or neutropenia.

SUBMITTER: Taylor D

PROVIDER: S-EPMC8920060 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

Project description:BackgroundThis is an update of the section on complications that are associated with coughing in the 2006 CHEST cough guidelines that addresses two aims: (1) to systematically identify and thematically categorize the diverse complications of cough by providing a guide for future studies and (2) to identify gaps in the literature for future research.Research questionWhat are the potential complications that are associated with the act of coughing that have been reported in infants, children, adolescents, and adults?Study design and methodsA scoping review was performed with the use of PubMed and SCOPUS databases that were searched from their beginning until September 6, 2019.ResultsTwo hundred forty-seven publications met our inclusion criteria. To these, we added 38 articles from the 2006 complications paper that were not identified in the literature search plus the paper itself for a final total of 286 publications that formed the basis of this review. Since 2006, three new categories of complications have been reported: ear, nose and throat; disease transmission; and laboratory testing. Multiple additional complications that fall outside of these three categories have also been identified and included in the following categories: cardiovascular, constitutional symptoms, dermatologic, GI, genitourinary, musculoskeletal, neurologic, ophthalmologic, psychosocial/quality of life, and respiratory. Not previously highlighted is that some of the complications led to serious morbidity that included death, especially in patients with comorbid conditions, and potentially resulted in harm to others when cough resulted in a motor vehicle accident.InterpretationOur work identified a large number of cough complications that we thematically categorized primarily by organ system so that future studies of each system or each complication can be conducted. The gap in the literature that future studies should address is to identify the frequency of the complications and the strength of their association with cough. Only then will one be able to describe the findings in a manner that allows specific recommendations for avoiding these complications. In the meantime, patients with cough should be evaluated and treated according to evidence-based guidelines to mitigate or prevent the myriad of potential complications that are associated with coughing.

Project description:ObjectivesRechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs.MethodsMEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis.ResultsEight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively, p-value = 0.065). Two administration strategies were identified, "as-needed" and prophylactic, both yielding similar success rates (81% and 80%, respectively). Only mild and transient adverse events were documented.ConclusionsAlthough limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.

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Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis.

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