Reduced Blood Monitoring and Hematological Abnormalities in Clozapine-Treated Patients

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Case Vignette

“Mr Green” is a 46-year-old Caucasian male with a 30-year history of schizophrenia and metabolic syndrome. His illness has been stable for over 10 years on clozapine, with no history of neutropenia or other adverse hematologic effects of the medication. He was fully vaccinated against COVID-19. However, Mr Green had significant anxiety about blood monitoring during the COVID-19 pandemic, due to intense fears about contracting the virus. As a result, he refused multiple monthly blood draws. Although his psychiatrist encouraged him to go to the laboratory for blood monitoring, the provider often used the “Patient refused/Clinical Discretion” option in the New Clozapine REMS registry, so that Mr Green could continue to receive his medication. Eventually, he returned to regular monthly monitoring, again without evidence of hematologic abnormalities.

Clozapine is “gold-standard” most effective antipsychotic for treatment-resistant schizophrenia.¹ A major barrier to the use of clozapine is the required stringent blood monitoring protocol due to an approximately 1% risk of severe neutropenia/agranulocytosis.² Recent research has found that the risk of agranulocytosis with clozapine is 0.3% to 0.8%, intensifying debate about this protocol,³ given that other medications with comparable rates do not have monitoring requirements. Blood monitoring frequency varies internationally, despite evidence for no difference in rates of severe clozapine-induced neutropenia across 5 continents.⁴ Therefore, there is need to balance the benefits of blood monitoring for clozapine with the risks of delimiting access to treatment.

The Current Study

During the COVID-19 pandemic, although patients were advised to continue with their scheduled hematologic monitoring, Health Canada advised physicians to use their best clinical judgment regarding continuing clozapine in the absence of regular blood testing.⁵ Thai et al performed a chart review study using the Clozaril Support and Assistance Network (CSAN) to assess the impact of reduced hematological monitoring frequency during the COVID-19 pandemic.⁶

The authors obtained data from the Royal Ottawa Mental Health Centre and electronic health record (EHR). They included patients aged 16 or older, regardless of clinical status, prescribed clozapine for at least 1 year since March 17, 2019. Hematological variables were extracted from the monitoring database from March 2019 to March 2021. “Yellow” results were fined as WBC 2.0-3.5 (x109/L) and absolute neutrophil count (ANC) 1.5-2.0. “Red” results were fined as WBC <2.0 and ANC <1.5. Agranulocytosis was defined as ANC <0.5. Mild-to-moderate leukopenia was defined as WBC 2.0-3.5 and severe leukopenia WBC 1.0-2.0. “Hematological abnormalities” encompassed any results categorized as yellow, red, leukopenia, or neutropenia. Clinical decision-making determined whether a patient was on a normal (every month) or extended (every 1 to 3 months) blood monitoring schedule.

Clinical and demographic data were extracted, including psychiatric diagnoses, clozapine dose, hospitalization days, medical comorbidities, smoking status, adverse effects, and other psychotropic medications. Differences in these variables were compared for subjects undergoing normal vs extended monitoring. Relationships between extended bloodwork and hematological abnormalities were analyzed using binomial logistic regression and zero-inflated negative binomial regression.

Investigators evaluated 621 patients, mean age 47, 68% male, in the study. Approximately 97% were diagnosed with schizophrenia or schizoaffective disorder. Patients on extended monitoring were significantly younger and more likely to be obese, and more likely to be diagnosed with schizoaffective disorder (vs schizophrenia). The average frequency of blood tests was significantly higher before than during the pandemic. The proportion of patients with any hematological abnormalities during the pandemic was 3.8% for the normal group and 3.4% for the extended group. One patient in the normal group and none in the extended group had agranulocytosis. In logistic regression, there was no significant difference in the detection of hematological events during the pandemic between the standard and extended monitoring groups, after controlling for potential confounders (OR=0.83, 95% CI 0.44-1.53, P=0.54). The total number of blood tests performed during the pandemic was a significant predictor of detecting at least 1 blood abnormality (OR=1.07, 95% CI 1.04-1.11, P<0.001). The pattern of findings was similar in the subgroup of 332 patients with obesity and diabetes.

Study Conclusions

The authors found no significant difference in the likelihood of detecting hematological abnormalities between Canda’s standard clozapine blood monitoring protocol and an extended protocol during the COVID-19 pandemic. Study limitations include the retrospective, naturalistic design, which relies on the accuracy, quality, and completeness of EHR data. The authors also noted a lack of information in the EHR regarding comorbidities, such as benign ethnic neutropenia, and prior hematological history. Within-patient analyses comparing hematological adverse events in patients who transitioned from standard to extended monitoring frequencies between the two periods were not performed.

The Bottom Line

Extended hematological monitoring did not adversely affect the detection of hematological abnormalities in patients taking clozapine during the COVID-19 pandemic. Findings may support consensus statement recommendations that for patients on clozapine for longer than 1 year with no history of ANC <2.0, blood monitoring can be less frequent than monthly without increasing the risk of severe neutropenia.⁵

Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times. The author reports that he receives research support from Augusta University.

References

1. Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209(5):385-392.

2. Alessi-Severini S, Biscontri RG, Collins DM, et al. Utilization and costs of antipsychotic agents: a Canadian population-based study, 1996–2006. Psychiatr Serv. 2008;59(5):547-553.

3. Myles N, Myles H, Xia S, et al. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand. 2018;138(2):101-109.

4. Oloyede E, Blackman G, Whiskey E, et al. Clozapine haem­atological monitoring for neutropenia: a global perspective. Epidemiol Psychiatr Sci. 2022;31:e83.

5. CSAN® Clozaril Support and Assistance Network. CLOZARIL® (Clozapine) – COVID-19, Update Health Canada Guidance. 2022. Accessed September 24, 2024. https://clozaril.ca/wp-content/uploads/2022/10/2022-10-Cov19-HLS-Letter_EN.pdf

6. Thai H, Preobrazenski N, Hsieh T, et al. Evaluating reduced blood monitoring frequency and the detection of hematological abnormalities in clozapine-treated patients with schizophrenia: a chart review study from the COVID-19 pandemic. Schizophr Bull. 2024:sbae113.