To the Editors
Clozapine (CLZ) not only is effective in 30% to 60% of patients with treatment-resistant schizophrenia (TRS)1 but also carries the risk of adverse drug reactions.2 Because neutropenia associated with CLZ is reported in 3.8% of patients and agranulocytosis is estimated to be 0.4%, absolute neutrophil count (ANC) monitoring is required during continuous administration of CLZ.3,4 The coronavirus disease 2019 (COVID-19) pandemic raises concerns about the continued administration of CLZ in TRS patients with COVID-19.5 Although patients with COVID-19 infection frequently experience lymphopenia but not neutropenia,6,7 transitory drops in neutrophil counts in TRS patients were reported recently.8,9 COVID-19 vaccinations are administered worldwide and effective for the prevention of COVID-19 infection,10 but there is no report about the relationship between neutropenia after COVID-19 vaccination during CLZ treatment. We experienced a TRS patient with 5 years' CLZ administration who showed a transient decrease of the absolute white blood cell (WBC) count and ANC after administration of COVID-19 vaccinations (Pfizer/BioNTech).
CASE PRESENTATION
A 45-year-old woman first experienced auditory hallucination and persecutory delusion at 20 years old. She had a 25-year history of schizophrenia (International Classification of Diseases, Tenth Revision) characterized by auditory hallucinations and persecutory delusions that had resulted in disruption to her education, family life, and employment. Haloperidol and risperidone were partially effective at first, but she stopped them. Her symptoms became worse, and she made several attempts at suicide. Treatment with 16 mg blonanserin for 8 weeks, 20 mg olanzapine for 12 weeks, 6 mg risperidone for 12 weeks, and 24 mg aripiprazole for 16 weeks was ineffective, and a regimen of 112.5 mg/day CLZ with 200 mg/d lithium carbonate was initiated when she was 41 years old. This decreased her hallucinations and delusions, and her suicidal thoughts disappeared. She continued her part-time job for the next 4 years. Her absolute WBC count every 2 weeks was usually from 3.86 to 7.42 × 109/L, and her ANC was from 2.20 to 3.86 × 109/L. She did not have a history of COVID-19 infection or allergy.
Table 1 shows the changes in her WBC count and ANC. When the first COVID-19 vaccination (0.5 mL; Pfizer/BioNTech) was administered, her only subjective adverse effect was arm pain for 3 days. Three days after the COVID-19 vaccination, her absolute WBC suddenly dropped to 3.16 × 109/L, and her ANC also dropped to 1.90 × 109/L. At 7 days after the first vaccination, these values had returned to the normal range. A second COVID-19 vaccination of 0.5 mL was administered 3 weeks after the first vaccination. The WBC suddenly dropped to 3.03 × 109/L and neutrophils to 1.92 × 109/L 3 days after the second vaccination. Seven days after the second vaccination, they had returned to the normal range. There was no fever, flu-like symptoms, sweating, or tachycardia, which are suggestive of infection, and the CLZ regimen was stable before and after the vaccination. Following the regulations of the Clozaril Patient Monitoring Service Japan, because her ANC dropped from green (>2.00 × 109/L ANC) to dark amber (from 1.99 to 1.50 × 109/L ANC), she required blood tests twice as frequently for 26 weeks. She gave written consent to publish the case report.
TABLE 1.
Change of Absolute WBC and Neutrophil Count After First or Second COVID-19 Vaccination (×109/L)
| Before | First Vaccination | Second (Day 21) | ||||
|---|---|---|---|---|---|---|
| (Day 0) | Day 3 | Day 7 | Day 10 | Day 24 | Day 28 | |
| Absolute WBC | 3.86–7.42 | 3.16 | 3.83 | 4.24 | 3.03 | 4.37 |
| Absolute neutrophil | 2.20–3.86 | 1.90 | 2.69 | 3.14 | 1.92 | 2.97 |
There were 5 cases of leukopenia (1 fatal) and 36 cases of neutropenia after COVID-19 vaccinations (Pfizer/BioNTech) in the United Kingdom spontaneous reports received between August 12, 2020, and January 9, 2021 for the mRNA Pfizer/BioNTech vaccine. In our patient, neutropenia was transient without developing agranulocytosis.
International regulations regarding the use of CLZ vary significantly. The Japanese regulations are among the most stringent, requiring an absolute WBC 4.00 × 109/L, ANC 2.00 × 109/L, and hospitalization at initiation.11 The United Kingdom, Canada, and Australia require an absolute WBC 3.50 × 109/L and ANC 2.00 × 109/L.11 In the United States, absolute WBC monitoring is not required, and an ANC 1.50 × 109/L is acceptable. In the United States, the criteria of the CLZ Risk Evaluation and Mitigation Strategy are the lowest of most countries: with mild neutropenia (1.00–1.49 × 109/L), patients continue treatment with blood tests 3 times weekly until ANC ≥ 1.50 × 109/L. Once ANC ≥ 1.50 × 109/L, the patient is returned to the last “normal range” ANC monitoring interval. Community initiation of CLZ in these countries is also possible.11 In Japan, when the absolute WBC count is less than 4.00 × 109/L or ANC is less than 2.00 × 109/L (medium amber), patients are required to take blood tests 2 times a week until returning to the normal range. At less than absolute WBC 3.50 × 109/L or ANC 2.00 × 109/L (dark amber), they continue to take blood tests every week for 26 weeks even after returning to the normal range. In addition, at less than WBC 3.00 × 109/L or ANC 1.50 × 109/L, CLZ is withdrawn.
The risk of stopping CLZ may be greater than the risk of agranulocytosis, especially if CLZ has been used for at least 6 months to a year.12 In Japan, very restrictive cutoffs including those for absolute WBC and ANC monitoring and the requirement to initiate CLZ in a hospital are used. However, the regulation by the Clozaril Patient Monitoring Service should be flexible in the case of vaccination. Clinicians should be able to decide in consultation with the patient whether national rules about WBC constraints and cessation of CLZ are too stringent and should be followed or not. If the decision is to disregard the regulations, the patient should be informed that this is off-label use.
Manabu Takaki, MD, PhD
Department of Neuropsychiatry
Okayama University Graduate School of Medicine
Dentistry and Pharmaceutical Sciences
Okayama, Japan manabuta@cc.okayama-u.ac.jp
Yuji Yada, MD, PhD
Okayama Psychiatric Medical Center
Okayama, Japan
Shinji Sakamoto, MD, PhD
Masaki Fujiwara, MD, PhD
Yuko Okahisa, MD, PhD
Norihito Yamada, MD, PhD
Department of Neuropsychiatry Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences
Okayama, Japan
ACKNOWLEDGMENTS
The authors would like to thank the Zikei Institute of Psychiatry (Okayama, Japan) for support.
AUTHOR DISCLOSURE INFORMATION
The authors declare no conflicts of interest.
There is no source of funding in this work.
Contributor Information
Yuji Yada, Email: navyflag1234@gmail.com.
Shinji Sakamoto, Email: shinjisakamoto1202@gmail.com.
Masaki Fujiwara, Email: fujiwara761222@gmail.com.
Yuko Okahisa, Email: okahis-y@cc.okayama-u.ac.jp.
Norihito Yamada, Email: nyamada@okayama-u.ac.jp.
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