Clozapine-associated neutropenia prevalence in a large, integrated health care system

Purpose : Clozapine, a highly effective antipsychotic medication, is associated with rare but potentially life-threatening neutropenia. In February 2025, the US Food & Drug Administration (FDA) eliminated its clozapine Risk Evaluation and Mitigation Strategies (REMS) program, which required documented absolute neutrophil count (ANC) lab results prior to clozapine dispensation. Considering the FDA decision, the purpose of this study was to examine the prevalence and patient-level factors associated with clozapine-associated neutropenia in a large, diverse, US-based integrated health system. Methods : This was a retrospective cohort study of adult Kaiser Permanente Northern California members who initiated clozapine therapy between January 2021 and December 2022. Data were extracted from KPNC’s electronic health record, including sociodemographic and clinical characteristics, medication fills, and ANC values. The main outcome was any neutropenic event within two years of clozapine initiation, classified as mild (ANC=1000-1499/µL) or severe (ANC<1000/µL). Results : Among 402 patients, 10 (2.5%) experienced neutropenia within 24 months of starting clozapine. Eight cases were mild, and two were severe, with one resulting in death. Race differed significantly between those who experienced neutropenia and those who did not (p=0.038). The mean clozapine dose at the time of neutropenia was 192.5 mg, with significant differences between mild and severe cases (p=0.015). Logistic regression analyses showed no significant associations between neutropenia and patient-level sociodemographic or clinical characteristics. Conclusion : Clozapine-related neutropenia was rare and typically transient, but it can be life-threatening. Continued adherence to the manufacturer’s recommendations for ANC monitoring is warranted to ensure patient safety. Pharmacoepidemiology and Drug Safety Brief Report: Clozapine-associated neutropenia prevalence in a large, integrated health care system Running title : Clozapine-associated neutropenia Jill L. Nofziger, PharmD, BCPS, BCPP 1 ; Andrea H. Kline-Simon, MS 2 ; Leah M. Arnbrecht, PharmD, BCPP 3 ; Cimone Durojaiye, MPH 2 ; Matthew E. Hirschtritt, MD, MPH 2,4,5,6 1 Regional Clinical Pharmacy Operations, Kaiser Permanente Northern California; Livermore, CA, USA 2 Division of Research, Kaiser Permanente Northern California; Pleasanton, CA, USA 3 Clinical Pharmacy Operations, Kaiser Permanente Greater San Jose Area; San Jose, CA, USA 4 Department of Psychiatry, Kaiser Permanente Oakland Medical Center; Oakland, CA, USA 5 Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA 6 Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine Corresponding author: Jill L. Nofziger, PharmD, BCPS, BCPP; [email protected] Funding: This work was supported by the Delivery Science and Applied Research Program (The Permanente Medical Group, Inc.). Ethics statement: This study was approved as exempt by the Kaiser Permanente Northern California Institutional Review Board. Conflicts of Interest: The authors have no conflicts of interest to report. Data availability statement: This study used patient-level data; given the risk of identification of the individuals included in these analyses, the data are not available for sharing beyond the study team. However, the SAS syntax used to extract the data is available upon request from the corresponding author.

Purpose : Clozapine, a highly effective antipsychotic medication, is associated with rare but potentially life-threatening neutropenia. In February 2025, the US Food & Drug Administration (FDA) eliminated its clozapine Risk Evaluation and Mitigation Strategies (REMS) program, which required documented absolute neutrophil count (ANC) lab results prior to clozapine dispensation. Considering the FDA decision, the purpose of this study was to examine the prevalence and patient-level factors associated with clozapine-associated neutropenia in a large, diverse, US-based integrated health system.

This was a retrospective cohort study of adult Kaiser Permanente Northern California members who initiated clozapine therapy between January 2021 and December 2022. Data were extracted from KPNC’s electronic health record, including sociodemographic and clinical characteristics, medication fills, and ANC values. The main outcome was any neutropenic event within two years of clozapine initiation, classified as mild (ANC=1000-1499/µL) or severe (ANC<1000/µL).

Among 402 patients, 10 (2.5%) experienced neutropenia within 24 months of starting clozapine. Eight cases were mild, and two were severe, with one resulting in death. Race differed significantly between those who experienced neutropenia and those who did not (p=0.038). The mean clozapine dose at the time of neutropenia was 192.5 mg, with significant differences between mild and severe cases (p=0.015). Logistic regression analyses showed no significant associations between neutropenia and patient-level sociodemographic or clinical characteristics.

Clozapine-related neutropenia was rare and typically transient, but it can be life-threatening. Continued adherence to the manufacturer’s recommendations for ANC monitoring is warranted to ensure patient safety.

absolute neutrophil count; adverse drug reactions; agranulocytosis; antipsychotic; mental health; pharmacovigilance; REMS Key Points: • Clozapine is a highly effective antipsychotic medication that carries a rare but potentially life-threatening risk of neutropenia (absolute neutrophil count [ANC]<1500/µL). This study explored the prevalence of and patient characteristics associated with neutropenia among adults prescribed clozapine in a community-based integrated health system. • Among 402 adults with new clozapine fills in a 2-year period, eight experienced mild neutropenia and two severe neutropenia, one of which resulted in death. • Mild neutropenic events were transient, and clozapine was continued without further neutropenic events. • Severe clozapine-associated neutropenia was serious and life-threatening, warranting continued adherence to manufacturer’s ANC-monitoring guidelines. Plain Language Summary: Clozapine is an effective medication used to treat severe mental health conditions, but it requires frequent blood tests because it can cause a dangerous drop in one type of white blood cells, known as neutropenia. In February 2025, the US Food & Drug Administration decided to end its mandatory monitoring program for clozapine. This study aimed to understand how often neutropenia occurred in patients taking clozapine and what factors might be linked to it. We reviewed medical records of adult Kaiser Permanente Northern California members who started clozapine between January 2021 and December 2022. Among 402 patients, 10 (2.5%) developed neutropenia within two years of starting clozapine. Most cases were mild, but two were severe, and one resulted in death. There were no significant differences in patient characteristics or clinical factors among those who developed neutropenia. Our findings suggest that clozapine-related neutropenia is rare and often mild, but it can be life-threatening. Therefore, it is important to continue following the manufacturer’s recommendations for monitoring white blood cell counts, specifically the absolute neutrophil count. Purpose In February 2025, the US Food and Drug Administration (FDA) announced it was eliminating the clozapine risk evaluation and mitigation strategies (REMS) program. 1 This national monitoring program mandated that pharmacies only dispense clozapine – a highly effective antipsychotic medication – following receipt of normal absolute neutrophil counts (ANCs) every seven days for the first 6 months of therapy; every 14 days for the following 6 months; and every 30 days thereafter. Since the initial reports of life-threatening clozapine-associated neutropenia in the mid-1970s, its relative risk has been questioned; furthermore, the burden of frequent, mandatory blood draws and reporting has been cited as a major factor impeding its widespread use. 2–4 There is substantial evidence that among antipsychotic medications, clozapine demonstrates superiority in clinical efficacy (e.g., reduction of positive psychotic symptoms and suicidality) and has a comparatively lower risk of extrapyramidal side effects and tardive dyskinesia. 5,6 These sentiments regarding the burden and negative impacts of the clozapine REMS culminated in the convening of an FDA advisory committee in November 2024 to revisit the utility and continued existence of the program. The committee ultimately voted 14-1 to eliminate the REMS program. Presenters highlighted multiple international studies that demonstrated exceedingly low rates and transient nature of severe neutropenia among adults using clozapine. 7–9 Adding to these data, affected individuals, family members, and clinicians testified to the severe negative impacts of the restrictive REMS in accessing clozapine. In light of the FDA’s decision to eliminate the clozapine REMS program, we undertook a retrospective cohort study within the adult membership of a large, diverse, US-based integrated health system to examine the prevalence and patient-level factors associated with clozapine-associated neutropenia. Sample This was a data-only, retrospective cohort study of adult (age ≥18) Kaiser Permanente Northern California (KPNC) members who initiated clozapine between January 1, 2021 and December 31, 2022. This study was approved by the Kaiser Permanente Division of Research Institutional Review Board (including a waiver of informed consent). Members were identified as initiating clozapine when they had a new clozapine prescription fill without any fills in the year prior. Individuals were also required to have continuous KPNC membership for ≥12 months prior to initiation of clozapine with allowances for brief lapses ≤30 days. Measures Data were extracted from KPNC’s electronic health record. Sociodemographic data included age, sex, race/ethnicity, insurance type, and neighborhood deprivation index (NDI). Clinical characteristics included ICD-10 diagnoses for history of non-clozapine neutropenia and psychotic spectrum disorder (PSD) diagnoses in the year prior to the clozapine fill. The Charlson comorbidity score was calculated based on prior-year data. Medication fills and ANC lab results were also extracted. The main outcome was any neutropenic event in the two years after clozapine initiation. A “mild” neutropenic event was defined as an ANC between 1000-1499/µL; a serious neutropenic event was defined as an ANC six weeks of the lab result. 10 Chart reviews were conducted for patients with neutropenia to verify that patients developed neutropenia due to clozapine; to determine whether clozapine was continued, discontinued, or if the dose was changed; and any other complicating factors (e.g., concurrent medications). Analysis Summary statistics for sociodemographic and clinical characteristics were reported for the full sample by presence of neutropenia (any neutropenia [ANC<1500/µL] vs. none) and by severity level among those who had a neutropenic event (mild vs. severe). Differences in sociodemographic and clinical characteristics by the outcomes were assessed using appropriate methods (e.g., ANOVA, t-tests, Pearson chi-square tests). Logistic regression analyses examined associations between having any neutropenia (mild or severe) and patient and clinical characteristics. Statistical significance was defined as α<0.05 (two-tailed).

Cohort characteristics Among the 402 identified patients, approximately half (50.5%) had previously used clozapine >12 months prior ( Table 1 ) . Most of the cohort was male (56.5%) and White (56.7%) with a mean age of 43.1 years. The distribution of patients across different NDI quartiles was spread similarly, with more of the study population having a score of 1 (least deprived). The mean Charlson score was 1.05 (low burden of comorbid conditions). The most common PSD associated with clozapine was schizophrenia (54.5%) followed by schizoaffective disorder (34.8%). Two patients had a history of non-clozapine drug associated neutropenia, and one had benign ethnic neutropenia; neither experienced neutropenia while on clozapine during the observation period. Neutropenia prevalence and characteristics Within 24 months of starting clozapine, 10 patients (2.5%) experienced neutropenia ( Supplemental Table 1 ). The majority of those who experienced neutropenia were male (60%) and predominantly Asian/Native Hawaiian/Pacific Islander (50.0%) or White (40.0%). Race differed significantly between those who experienced neutropenia and those who did not (p=0.038), while no differences were observed in sex, age, NDI quartile, Medicaid coverage, Charlson score, prior clozapine use, or PSD. Among the 10 patients with neutropenia, eight had mild and two had severe neutropenia. The mean (SD) clozapine dose at the time of neutropenia was 192.5mg (148.2mg), with significant differences between mild and severe cases (140.6±80.1mg and 400.0±212.1mg, respectively; p=0.015). Time to neutropenia after initiating clozapine did not differ significantly between mild and severe cases, nor did sex, race, age, NDI quartile, Medicaid coverage, Charlson score, prior clozapine use, or PSD. Among the eight patients with mild neutropenia, six patients continued clozapine therapy uninterrupted, without recurrent neutropenia for the remainder of the study (approximately 0-8 months). Two discontinued clozapine for reasons unrelated to neutropenia, such as inefficacy, other side effects, and nonadherence. In the two cases of severe neutropenia, clozapine was discontinued. One patient had been on clozapine for ≥1 year without previous neutropenia, was on a stable dose for approximately three months, and began a 7-day antibiotic course with trimethoprim-sulfamethoxazole. Three days after starting the antibiotic, the ANC dropped to zero, returning to normal limits approximately seven weeks later. The other patient had been newly taking clozapine for six weeks before presenting to the emergency department with fever and an ANC=0/µL. This patient was admitted and subsequently died from neutropenic sepsis. Logistic regression model The adjusted odds ratios associated with neutropenia within 24 months of starting clozapine were nonsignificant for all covariates in the model ( Supplemental Table 2 ).

In this retrospective cohort study among 402 adults who filled prescriptions for clozapine, we identified two serious cases with an ANC=0/µL, indicating life-threatening neutropenia, both possibly clozapine related. In the other eight cases of mild neutropenia identified, the causes were unknown but possibly laboratory errors or transient clozapine-associated effects. These findings align with previous research showing clozapine-related neutropenia to be rare and often transient, reinforcing that while clozapine can cause significant hematologic adverse effects, these are infrequent. 9 In the mild neutropenia cases, clozapine was never stopped or held. The ANC returned to normal limits within days, and clozapine was continued either at its current dose, increased, or stopped for reasons unrelated to neutropenia. Neutropenia did not recur throughout the cohort period in all cases where clozapine was continued, illustrating that the effect may often be transient and non-life threatening. These results confirm that the risk of clozapine-related neutropenia is low, usually mild, and resolves quickly without change to clozapine therapy, reinforcing that a clozapine REMS program is unnecessary for safe monitoring and may be more obstructive than useful. In one severe neutropenia case, neutropenia occurred shortly after initiation of antibiotic therapy with trimethoprim-sulfamethoxazole, another drug linked to agranulocytosis, although rare. A previous case report similarly documented severe neutropenia associated with the coadministration of clozapine and trimethoprim-sulfamethoxazole, which resolved after discontinuing the antibiotic. 11 This suggests additive effects of drugs associated with neutropenia when co-administered with clozapine. In the other severe case, neutropenia was likely clozapine-related and resulted in death. Neutropenia occurred within the first six weeks of therapy, a period identified in previous studies as high-risk. 7 This case highlights the potential severity of clozapine-related neutropenia and should alert clinicians to the need for vigilant ANC monitoring during the first two years of clozapine therapy. Clinicians should also consider additive drug effects and other factors contributing to neutropenia when evaluating clozapine-associated neutropenia cases. Our study has several limitations. Despite KPNC’s large membership (>4.4 million members), we only identified 402 patients with a clozapine fill over 24 months, perhaps reflecting in part the burden of frequent blood draws. This small sample size may affect the generalizability of our findings. Additionally, the retrospective design prevents definitive conclusions about clozapine as the direct cause of neutropenia in all cases, with unmeasured confounding factors such as concomitant medications or underlying health conditions potentially impacting the results. Last, the observation period was restricted to 24 months following clozapine initiation based on literature indicating the highest risk within the first two years of clozapine therapy. 7 Longer follow-up periods might provide a more comprehensive understanding of the long-term risks of neutropenia associated with clozapine use.

This small retrospective study found that clozapine-related neutropenia is rare and usually transient. However, its occurrence can be life threatening, warranting continued adherence to the manufacturer’s recommendations for ANC monitoring even in the absence of mandatory reporting.

1. Duerr HA. FDA Officially Removes REMS Requirement for Clozapine. Psychiatric Times. February 25, 2025. Accessed April 18, 2025. https://www.psychiatrictimes.com/view/fda-officially-removes-rems-requirement-for-clozapine2. Ingimarsson O, MacCabe JH, Haraldsson M, Jónsdóttir H, Sigurdsson E. Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland. BMC Psychiatry . 2016;16(1):441. doi:10.1186/s12888-016-1167-03. Myles N, Myles H, Xia S, et al. A meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia. Aust N Z J Psychiatry . 2019;53(5):403-412. doi:10.1177/00048674198331664. Farooq S, Choudry A, Cohen D, Naeem F, Ayub M. Barriers to using clozapine in treatment-resistant schizophrenia: systematic review. BJPsych Bull . 2019;43(1):8-16. doi:10.1192/bjb.2018.675. Efthimiou O, Taipale H, Radua J, et al. 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Patient and Clinical Characteristics by Incidence of Neutropenia within 24 months of Starting Clozapine | Patient Characteristics | |||| | Sex, n (%) | 0.820 | ||| | Female | 175 (43.5) | 4 (40.0) | 171 (43.6) | | | Male | 227 (56.5) | 6 (60.0) | 221 (56.4) | | | Race, n (%) | 0.038 | ||| | Asian/Native Hawaiian/Pacific Islander | 57 (14.2) | 5 (50.0) | 52 (13.4) | | | Black/African American | 39 (9.7) | 1 (10.0) | 38 (9.7) | | | White | 228 (56.7) | 4 (40.0) | 224 (57.2) | | | Hispanic/Latino | 59 (14.7) | 0 (0) | 59 (15.1) | | | American Indian/Alaska Native | 6 (1.5) | 0 (0) | 6 (1.5) | | | Other/Unknown | 13 (3.2) | 0 (0) | 13 (3.4) | | | Age, mean (SD) | 43.1 (15.4) | 43.1 (20.5) | 43.1 (15.3) | 0.995 | | Neighborhood Deprivation Index (NDI) Quartiles, n (%) | |||| | 1 - least deprived, indicating higher socioeconomic status | 121 (30.1) | 3 (30.0) | 118 (30.1) | 0.977 | | 2 - moderately deprived | 98 (24.4) | 2 (20.0) | 96 (24.5) | | | 3 - more deprived | 99 (24.6) | 3 (30.0) | 96 (24.5) | | | 4 - most deprived, indicating lower socioeconomic status | 84 (20.9) | 2 (20.0) | 82 (20.9) | | | Medicaid coverage in year prior, n (%) | 111 (27.6) | 2 (20.0) | 109 (27.8) | 0.598 | | Clinical Characteristics | |||| | Charlson score, mean (SD) | 1.05 (1.61) | 1.10 (1.59) | 1.05 (1.62) | 0.921 | | History of non-clozapine drug associated neutropenia 2 | 2 (0.5) | 0 (0) | 2 (0.5) | 0.788 | | Benign ethnic neutropenia 2 | 1 (0.3) | 0 (0) | 1 (0.3) | 0.849 | | Prior use of clozapine, n (%) 3 | 203 (50.5) | 3 (30.0) | 200 (51.0) | 0.189 | | Psychotic-spectrum diagnosis in year prior to clozapine prescription, n (%) | 0.723 | ||| | Schizophrenia [ICD-10-CM code F20*] | 219 (54.5) | 6 (60.0) | 213 (54.3) | | | Schizoaffective disorder [F25*] | 140 (34.8) | 2 (20.0) | 138 (35.2) | | | Delusional disorder [F22*] | 4 (1.0) | 0 (0) | 4 (1.0) | | | Specified or other unspecified psychotic disorder [F28* orF29*] | 16 (4.0) | 1 (10.0) | 15 (3.8) | | | Other 4 | 23 (8.2) | 1 (10.0) | 22 (5.6) | 1 Any neutropenia event defined as any ANC lab tests with values <1500/µL during the 24-month period; 2 History of non-clozapine drug-associated neutropenia (ICD-10 code D70*, excluding D70.8); benign ethnic neutropenia (ICD-10 code D70.8); 3 Prior use defined as any clozapine prescription prior to the 1-year clear period; 4 Other indications for clozapine included affective disorders with psychotic features, treatment-refractory affective disorders, and aggression associated with autism spectrum disorder. 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Authors Metrics & Citations Metrics Article Usage 341views 272downloads Citations Download citation Jill L. Nofziger, Andrea H. Kline-Simon, Leah M. Arnbrecht, et al. Clozapine-associated neutropenia prevalence in a large, integrated health care system. Authorea. 09 May 2025. DOI: https://doi.org/10.22541/au.174677767.78063497/v1 DOI: https://doi.org/10.22541/au.174677767.78063497/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.