Clozapine-associated Neutropenia Research Articles

The timing and severity of clozapine-associated neutropenia in the US: Is the risk overstated?

BackgroundConcern about clozapine-associated neutropenia contributes to clozapine's underutilization and racial disparities in access. People with African ancestry are more likely to have lower normative absolute neutrophil counts (ANC), associated with the Duffy null genetic polymorphism. Recent data on clozapine-associated neutropenia in the US are lacking. MethodsPatients prescribed clozapine in the Johns Hopkins Medicine electronic medical record (EMR) between 2013 and 2023 were identified. Duffy null Associated Neutrophil Count (DANC) was assigned if there were two ANC's < 2000 cells/μL, >30 days apart, before starting clozapine. Rates of neutropenia, timing of first neutropenia, and demographic differences were explored. Results974 received clozapine and had ANC's available, with 63.9 % male, 51.1 % White, and 39 % Black. 287 were presumed to start clozapine during the study period, and were 62.4 % male, 46 % White, and 44.9 % Black. No patients developed severe neutropenia. 59 (6.1 %) developed mild or moderate neutropenia. 19 (6.6 %) new starts had presumed DANC, and none developed neutropenia. 11 of 16 presumed new starts who developed neutropenia did so within eight months. No demographic differences were found between groups for presumed new starts. For non-new starts, where DANC assignment was not possible, Black patients were more likely than White patients to develop neutropenia (OR 3.48, 95 % CI [1.65, 7.73]). DiscussionTo our knowledge, this is the first observational study of clozapine-associated neutropenia in the US in the past decade, and it includes a substantial proportion of Black patients. ANC monitoring requirements may be too strict, contributing to clozapine underutilization.

Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study

Clozapine is associated with the risk of serious neutropenia. However, this risk might decrease over time, meaning that indefinite absolute neutrophil count (ANC) monitoring could be unnecessary. We aimed to determine the epidemiology and timing of clozapine-associated neutropenia outcomes, to investigate variables that might contribute to the odds of neutropenia, and to determine risk of competing neutropenic events during clozapine treatment. We performed a retrospective analysis of the Australian and New Zealand Viatris Pharmacovigilance system (one of two monitoring databases for these two countries) between June 6, 1990, and Oct 25, 2022. Patients were excluded from analysis if they commenced clozapine before 1990, did not have a haematology test within 2 weeks of commencement date, or had no follow-up. We measured minor neutropenia (ANC 1·0-1·5 × 109 per L) and serious neutropenia (ANC <1·0 × 109 per L) leading to cessation of clozapine within 6 weeks of the neutropenic event. We determined the rates of minor and serious neutropenia and calculated odds ratios (ORs) for the likelihood of neutropenia leading to cessation. For serious neutropenia leading to cessation, we used time-to-event to calculate rolling weekly averages and to perform competing risk analysis of outcomes using Cox proportional hazards models and a Fine-Gray subdistribution hazards regression model. For the subset of data where information on previous clozapine use was available, we did an analysis for participants who did and did not have previous clozapine exposure. We included 26 630 people, with 2·6 million ANC values. Within the total cohort, 17 585 people (66%) were male, 9025 (33·9%) female, and 20 (0·1%) other gender, and the mean age was 36·1 years (SD 13·7). We did not have data on race or ethnicity. Of the 26 630 people taking clozapine, 1146 (4·3%) had minor neutropenia, 313 (1·2%) had serious neutropenia leading to cessation, and 223 (0·8%) had serious neutropenia unrelated to clozapine without cessation. In people with no previous exposure to clozapine (n=15 973), the cumulative incidence of serious neutropenia leading to cessation was 0·9% at 18 weeks and 1·4% at 2 years; the weekly incidence rate for serious neutropenia leading to cessation peaked at 9 weeks (0·128%) and fell to a rolling average weekly incidence of 0·001% by 2 years. For minor neutropenia, the cumulative incidence was 1·7% at 18 weeks and 3·5% at 2 years; the weekly incidence rate peaked at 9 weeks (0·218%) and fell to a stable rolling average of 0·01%. The median time to a serious neutropenic event leading to cessation was 17 weeks (IQR 9·96-102). Previous clozapine exposure reduced the risk of serious neutropenia leading to cessation (OR 0·19, 95% CI 0·12-0·31; p <0·0001). Most serious neutropenia leading to clozapine cessation occurs within 18 weeks of treatment and becomes negligible after 2 years. Weekly haematological monitoring after the first 18 weeks could be safely reduced to once every 4 weeks and ceased after 2 years unless clinically indicated. Clozapine retrial after interruption with 2 cumulative years of unremarkable testing might not require further haematological monitoring. A serious neutropenia ANC threshold of ≤1·0 × 109 per L could be used in more jurisdictions. None.

Clozapine- and non-clozapine-associated neutropenia in patients with schizophrenia: a retrospective cohort study.

Introduction:The antipsychotic drug clozapine remains underutilized partly because of the risk of life-threatening adverse effects, such as neutropenia. Therefore, an extensive hematological monitoring program was set up to detect neutropenia.Methods:In this retrospective cohort study, we used registry-based data from the Capital Region of Denmark to investigate incidence rates of neutropenia among patients with a diagnosis of schizophrenia or other psychotic disorders and treated with clozapine for the first time. In a within-subject design, we compared rates of neutropenia in time periods where patients were exposed to clozapine versus time periods, where they were not exposed to clozapine. We also investigated whether the lengths of clozapine-associated neutropenia (CAN) were related to discontinuation of clozapine treatment.Results:Data from 520 clozapine users were included. The incidence rate of CAN was 3.2 cases per 100 person-years (95% confidence interval [CI]: 2.1–4.8) throughout the entire study. There was no significant difference in incidence rates of neutropenia during clozapine exposure and non-clozapine exposure, with an incidence rate ratio of 0.7 (95% CI: 0.4–1.3). One episode of severe neutropenia was detected. Episodes of CAN with only one sub-threshold neutrophil count were not associated with higher clozapine discontinuation (26%) than CAN episodes of more than one sub-threshold neutrophil count (28%).Conclusion:In the present study, we could not confirm that clozapine treatment was associated with neutropenia.

G-CSF mediated neutrophil augmentation in a unique case of comorbid idiopathic Parkinson’s disease and treatment-resistant schizophrenia on clozapine

Treatment of psychosis in Parkinson’s disease (PD) is challenging; pharmacological options are limited, with clozapine considered most effective. The risk of agranulocytosis restricts the use of clozapine, but, where this occurs, cautious re-challenge with granulocyte stimulating factor can be successful. We present a unique case of a patient who developed early-onset PD on a background of antecedent treatment-resistant schizophrenia, who had been treated effectively with clozapine for over 15 years with no adverse events. However, during a hospital admission intended to optimise her Parkinsonian medications, she developed persistent neutropenia necessitating clozapine discontinuation. Numerous attempts to re-challenge with clozapine failed until augmentation with lithium and G-CSF was trialled. Two doses of G-CSF led to a sustained increase in the neutrophil count, allowing the continuation of clozapine therapy in the 1 year of follow up. This illustrates the potential for G-CSF to be used to facilitate clozapine use in a patient population not described previously. Neutrophil augmentation allowed the sustained continuation of this effective therapy, treating her psychotic symptoms without detriment to her movement disorder. We suggest that G-CSF might be considered as a treatment option in other cases where clozapine-associated neutropenia obstructs its use.

Clozapine-associated neutropenia in Latin America: incidence report of 5380 Chilean users.

Systematic information about Latino clozapine users is still scarce. Our aim was to evaluate the risk of clozapine-associated neutropenia in a Chilean cohort using the last Food and Drug Administration's recommendations for clozapine monitoring. Findings should improve clinical practice and promote changes in clozapine guidelines in Latin America. We conducted a retrospective observational study of 5380 Chilean clozapine users that started clozapine treatment between 2003 and 2015. The absolute risk of severe neutropenia was 0.61% (33/5380) with an incidence of 0.086 cases per 100 person-years of follow-up. 87.9% of cases with severe neutropenia appeared during first 18 weeks. Cases of mild neutropenia were 3.9% of total sample and occurred almost constantly without a specific risk time. 77.5% of cases of moderate or severe neutropenia didn't present an event of mild neutropenia before. 22.8% of clozapine users (1227/5380) discontinued treatment for any cause and 4.2% (225/5380) due to neutropenia in any severity level. Clozapine-associated neutropenia risk in Latino users is similar than in the rest of the world. The evidence of a very low risk for severe neutropenia and the behaviour of mild neutropenia cases confirm the feasibility of changes in Latin American clozapine guidelines using current Food and Drug Administration's recommendations as a model.

Experts Brainstorm How to Expand Clozapine Use

Back to table of contents Previous article Next article Clinical & ResearchFull AccessExperts Brainstorm How to Expand Clozapine UseNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:2 Aug 2019https://doi.org/10.1176/appi.pn.2019.7a5AbstractMonthly blood tests are not the only hurdle keeping some psychiatrists from prescribing this proven treatment for treatment-resistant schizophrenia.The availability of quick, easy-to-use, point-of-care blood tests should help increase the use of clozapine, said a panel of experts at APA’s Annual Meeting in May. However, the rigorous blood monitoring required to check for clozapine-associated neutropenia is not the only reason this proven treatment for treatment-resistant schizophrenia remains underused, they noted. Psychiatrists’ hesitancy and lack of experience using clozapine are even greater barriers.iStock/angelpSpeaking to a packed house, investigators Dan Siskind, Ph.D., M.B.B.S., of the University of Queensland in Australia; Dan Cohen, M.D., Ph.D., of Mental Health Care North-Holland in the Netherlands; Henry Nasrallah, M.D., of St. Louis University School of Medicine; and Jonathan Meyer, M.D., of the University of California, San Diego, shared their experiences prescribing clozapine and discussed available resources for psychiatrists interested in learning more about the medication.Cohen touched on an issue that concerns many psychiatrists: Physicians who prescribe clozapine are expected to regularly monitor these patients’ blood to ensure they do not exhibit a rapid loss of white blood cells (neutropenia), which can endanger their health. Many clinics may be hesitant to prescribe clozapine because of costs and time involved in blood monitoring.There are blood tests that can simplify the collection process, Cohen explained. One option might be tabletop, point-of-care blood tests that use a finger prick to collect capillary blood (as opposed to venous blood draws) to quickly assess samples. Cohen conducted a survey study of 70 patients who reported that capillary blood drawing was more convenient and tolerable than traditional blood drawing. It’s also more cost effective, he noted. (His study involved a device developed by the Swedish company Hemocue, and the panel pointed out that U.S. company Athelas received FDA approval last year for a point-of-care, white blood cell test.)Another approach might be to use dried blood spot sampling, as is done to test for metabolic disorders in newborns. While dried blood spot sampling can assess clozapine drug levels only to determine whether the patient is in a therapeutic range, the test involves a pinprick and some filter paper to collect blood, which can then be sent to a laboratory for analysis.While the panelists noted that there are other rare side effects associated with clozapine, including myocarditis (inflammation of the heart muscle), constipation, and excess drooling, physicians’ limited experience with clozapine remains a key contributor to underuse.Siskind encouraged psychiatrists with clozapine experience to share their knowledge with others whenever possible and to get others—including nurses, other clinical staff, even patients—involved in the process as well. “If we can get current users to discuss their experiences, the good and the bad, it could help convince many others,” he said.As one example of a clozapine-users network, Nasrallah talked about the CURESZ (Comprehensive Understanding via Research and Education into Schizophrenia) Foundation. He established CURESZ in 2016 along with Bethany Yeiser, a patient of Nasrallah’s with schizophrenia who made a full recovery with the help of clozapine. In addition to providing educational lectures about schizophrenia to young adults across the nation, CURESZ has established an international panel of clozapine experts to help guide physicians and their patients. Any physician can access the CURESZ website to find the nearest expert for assistance and potential referral.Meyer then highlighted a book he recently co-authored that serves as a comprehensive clozapine therapy resource for physicians. “I felt the field needed this more than anything. For all the years clozapine has been used, there has only been one previous textbook on the subject,” he said. And, unfortunately, that previous book quickly became outdated as the clozapine blood-monitoring guidelines were changed right after it was published.“The clinical evidence is there,” Siskind said in conclusion of his talk. “Clozapine reduces hospitalizations, it reduces mortality, patients like to take it, and it saves hospitals money. We just need to convince providers to overcome their worries about lack of experience and give clozapine a shot.” ■CURESZ is posted here. ISSUES NewArchived

Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective.

Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.

Meta-analysis examining the epidemiology of clozapine-associated neutropenia.

Clozapine is associated with life-threatening neutropenia. There are no previous meta-analyses of the epidemiology of clozapine-associated neutropenia. To determine the cumulative incidence of mild, moderate and severe neutropenia, incidence of death related to severe neutropenia, case fatality rate of neutropenia and the longitudinal incidence of neutropenia following exposure to clozapine. A systematic search of Medline, EMBASE and PsycINFO using search terms [clozapine OR clopine OR zaponex OR clozaril] AND [neutropenia OR agranulocytosis]. Random effects meta-analysis to determine event rates and longitudinal incidence of events per 100 person-years of exposure. A total of 108 studies were included. The incidence of clozapine-associated neutropenia was 3.8% (95% CI: 2.7-5.2%) and severe neutropenia 0.9% (95% CI: 0.7-1.1%). The incidence of death related to neutropenia following prescription of clozapine was 0.013% (95% CI: 0.01-0.017%). The case fatality rate of severe neutropenia was 2.1% (95% CI: 1.6-2.8%). The peak incidence of severe neutropenia occurred at one month of exposure and declined to negligible levels after one year of treatment. 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.

Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor

Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis. We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis. We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count < 0.5 × 10 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred. Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

New Genetic Link May Identify Mechanism Behind Clozapine Agranulocytosis

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessNew Genetic Link May Identify Mechanism Behind Clozapine AgranulocytosisNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:18 Aug 2016https://doi.org/10.1176/appi.pn.2016.8a29AbstractA genome-wide scan of over 5,000 schizophrenia patients identifies a potential role for a liver transporter linked with a similar white blood cell problem induced by the chemotherapy drug docetaxel.Agranulocytosis is a rare but potentially fatal problem in which the levels of white blood cells in the blood drop rapidly. Unfortunately, agranulocytosis is one of the potential side effects of taking clozapine, which has limited the use of the antipsychotic despite its proven benefits. Two years ago, an analysis of the genetic data from over 160 people who experienced clozapine-induced agranulocytosis (CIAG) by an international research consortium revealed two genes associated with an increased risk of this adverse effect—a finding that could one day help to develop a predictive screen for the disorder (Psychiatric News, October 3, 2014).Researchers in the United Kingdom recently analyzed the genomes of nearly 5,500 schizophrenia patients taking clozapine, which included 66 patients whose blood cell counts dropped below normal levels. This analysis also identified several potential genetic variants linked with an increased risk of white blood cell loss following clozapine use, including one near HLA-DBQ—a critical immune-related gene that was identified in the 2014 study. The findings were published July 12 in Molecular Psychiatry.Fred Jarskog, M.D., a professor of psychiatry at the University of North Carolina School of Medicine and one of the members of the consortium behind the 2014 study, told Psychiatric News that these latest findings validate the association between HLA-DBQ and CIAG. “In some ways, though, the more exciting news emerged after the U.K. group reached out to our team [led by Patrick Sullivan, M.D., the director of UNC’s Psychiatric Genetics program] to discuss pooling our respective data,” Jarskog said. When all 239 cases were compared with controls, a new variant associated with clozapine-associated white blood cell loss emerged, in between a pair of genes called SLCO1B1 and SLCO1B3. Both these genes encode transport proteins that help the liver absorb a wide variety of compounds, including drugs, for subsequent metabolism. While neither of these genes has previously been linked with clozapine responses, they both have strong connections to adverse events brought on by other medications; SLCO1B1 variants are associated with the risk of muscle problems in statin users, while SLCO1B3 variants are interestingly linked to the loss of white blood cells in patients taking the chemotherapy drug docetaxel.“In the case of docetaxel, the evidence points to a dose-related phenomenon, where higher drug concentrations in the blood lead to worse cell loss,” Jarskog told Psychiatric News. Jarskog said it would be worthwhile to see whether a similar dose-dependent profile exists for CIAG, thus confirming some metabolic influence on this disorder. However, he noted that determining whether such a relationship exists could prove challenging given the rarity of CIAG compared with docetaxel-induced white blood cell loss.“For our samples, we have the information on the clozapine dosage for each patient, but not how the drug was being metabolized in the body,” he said. “It took a major international effort to reach the point of having data for over 200 cases of this disorder,” he continued. “For the time being we have to work with what we got.”The fact that clozapine-associated white blood cell loss is relatively rare also means that even with this new genetic information, it will likely be some time before researchers achieve the ultimate clinical goal of developing a screen that can identify patients who are susceptible to this side effect of the medication. The authors of the Molecular Psychiatry report calculated that a genomic test incorporating the HLA and SLCO1B variants would be about only 10 percent accurate at detecting whether a person might develop significant white blood cell loss while taking clozapine, as a majority of people who develop this side effect do not carry any of the currently identified risk alleles.This study was funded by grants from the Medical Research Council. ■“Genome-Wide Common and Rare Variant Analysis Provides Novel Insights Into Clozapine-Associated Neutropenia” can be accessed here. ISSUES NewArchived

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Clozapine-associated neutropenia and agranulocytosis in Argentina (2007-2012).

The risks of severe leukopenia and agranulocytosis have varied over time and among geographical regions and cultures, with little information available on South American populations. Accordingly, we reviewed and analyzed data from a 6-year experience monitored by an Argentine national registry to which reporting of adverse events reports is required. We analyzed data for 2007-2012 from the pharmacovigilance program of the Argentine drug-regulatory agency (ANMAT) using standard bivariate and multivariate statistical methods and survival analysis. We identified 378 cases of adverse hematological events over 6 years among an average of 12 305 individuals/year treated with clozapine (308±133 mg/day) to estimate the mean annualized rates of leukopenia [0.19 (95% confidence interval [CI] 0.11-0.27)], neutropenia [0.38 (95% CI 0.34-0.43)], and agranulocytosis [0.05 (95% CI 0.02-0.08)] % per year [median latency 2 (95% CI 1.3-2.1) months]; fatalities related to agranulocytosis averaged 4.2 (95% CI 0.0-9.2) per 100 000 treated individuals/year. Factors associated significantly and independently with agranulocytosis were female sex, older age, and use of other drugs in addition to clozapine. With monitoring by international standards, recent risks of clozapine-associated agranulocytosis in Argentina were lower, but fatality rates were higher than that in other regions of the world. Risk factors include the use of multiple psychotropic drugs, female sex, and older age.

Incidence and risk for neutropenia/agranulocytosis among clozapine users: A retrospective cohort study

Objective. To estimate the incidence and the risk of neutropenia or agranulocytosis (the outcome) associated with clozapine use (the exposure), and to identify risk factors. Methods. All data were derived from the computerized hospital database. Adult psychiatric patients were identified, and 95 incident clozapine users and 884 non-clozapine users were included. Cox proportional hazards regression was used to estimate the hazards ratio (HR) of developing the outcome after clozapine use adjusted for confounders. The interaction between clozapine and valproic acid was assessed a posteriori. Results. Throughout the 24-month follow-up, the incidence of neutropenia was 6.3% in the clozapine group and 5.8% in the non-clozapine group. One agranulocytosis was found in the non-clozapine group. The HR (95% CI) for neutropenia were: clozapine 1.33 (0.54–3.25) and age . 45 years 2.99 (1.63–5.48). Lithium, as an independent protective factor, reduced the risk for neutropenia by 85% compared with patients who did not receive lithium, HR 0.15 (95% CI 0.02–1.09). Valproic acid might potentiate the clozapine-associated neutropenia (HR 5.10, 95% CI 0.70–37.12). Conclusion. Clozapine might slightly increase the risk of neutropenia in psychiatric patients. Concerning clozapine-associated neutropenia, older patients are at increased risk and use of valproic acid concurrently with clozapine should be avoided.

Clinical experience of clozapine-induced neutropenia in the UK. Laboratory investigation using liquid culture systems and immunofluorocytometry.

An incidence of drug-induced neutropenia of 2.5% has been found in the first 1000 patients to be treated with clozapine in the UK. The majority of affected patients experienced mild neutropenia (n = 22) with only 3 patients developing agranulocytosis. Data collected from these 25 patients suggest that the mechanism of neutropenia may be multifactorial. Laboratory investigation using liquid culture systems and immunofluorocytometry has identified clozapine and its major metabolite N-desmethyl clozapine as exhibiting toxic effects against myeloid maturation and myeloid mitotic compartments, respectively. Increased susceptibility to the toxic effects of clozapine was shown in 1 patient who had previously developed clozapine-associated neutropenia. No clinical or laboratory evidence of drug-induced antineutrophil or antimyeloid precursor antibodies was found.