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Does clozapine increase the risk of severe COVID-19 infection? Researchers performed a larger register-based cohort study of this association.
“Mr Brown” is a 55-year-old Caucasian male with a 30-year history of schizophrenia, hypertension, and hyperlipidemia. His illness has been stable for over 25 years on clozapine. He was fully vaccinated against COVID-19 5 months ago. However, 1 month ago, he tested positive for COVID-19. Although he had no known infected contacts, his teenaged son had fatigue and rhinorrhea the preceding week. Mr Brown’s primary symptoms included loss of taste and smell, fatigue, and an occasional dry cough, which resolved within 7 days. He did not have any fever or shortness of breath, nor did he require emergency department or inpatient services. He continued taking clozapine under the advisement of his psychiatrist without complication. Other than over-the-counter analgesics and antitussives, he did not take any medications for COVID-19. Mr Brown quarantined for 10 days, and then resumed his usual activities without further sequelae.
Clozapine, the “gold-standard” antipsychotic for treatment-resistant schizophrenia, may affect the innate immune system and is associated with increased risk of neutropenia and agranulocytosis.1 Clozapine may also affect the adaptive immune system, given associations with reduced levels of immunoglobulins.2 There is evidence for an increased risk of infections, including viral infections pneumonia, in patients treated with clozapine versus other antipsychotics.3 Severe COVID-19 infection can cause pneumonia, acute respiratory distress syndrome, and death. Furthermore, several risk factors for severe COVID-19 infection, including older age, diabetes, and cardiovascular disease, are more prevalent in patients treated with clozapine.4
The Current Study
Accordingly, Ohlis and colleagues5 investigated whether patients treated with clozapine are at increased risk of more severe COVID-19 infection, as indexed by inpatient treatment, intensive care unit (ICU) care, or death, compared to other antipsychotics, using a regional health care register. They included all residents in the Stockholm, Sweden region (approximately 2 million total inhabitants) aged 18 or older by March 1, 2020, who had: 1) a diagnosis of a psychotic disorder (in the preceding 14 months), and 2) been prescribed and dispensed antipsychotic medication during 2020. Exposure was defined as clozapine treatment, and those prescribed other antipsychotics were unexposed. The primary outcomes were inpatient or ICU care or death due to COVID-19 between March 1, 2020, and January 14, 2021. Data were analyzed using Cox proportional hazard ratios, controlling for effects of age, sex, residence, country of birth, socioeconomic status, number of care visits, and comorbid medical illness.
A total of 8233 persons in Stockholm County met study inclusion/exclusion criteria, of whom 966 (12%) had received clozapine treatment. The mean subject age was 51, and 53% of subjects were male. Overall, 1.9% of clozapine-treated patients and 2.7% of other antipsychotic-treated patients experienced COVID-19-related inpatient care, ICU, or death during the study period. After controlling for potential confounding factors, the hazard ratios (HRs) for inpatient care (HR=0.96, 95% CI 0.54-1.70), ICU care (HR=1.69, 95% CI 0.48-5.93), and death (HR=0.86, 95% CI 0.26-2.8) were not significantly different for patients treated with clozapine versus other antipsychotics.
The authors found no indications that clozapine treatment was associated with a more severe course of COVID-19 infection. Findings are consistent with other case series that did not find an association between COVID-19 infection and reduced neutrophil counts in patients treated with clozapine. Study strengths included the use of register data with comprehensive measures of many potential risks for severe illness. However, results should be interpreted with caution, given the small number of severe cases, which raises the possibility of inadequate study power. Data on length of antipsychotic treatment, and whether antipsychotics were withheld upon diagnosis of COVID-19, were also not available.
The Bottom Line
Findings support existing recommendations for sustained treatment with clozapine during the COVID-19 pandemic. Adverse psychiatric risks of discontinuing clozapine treatment likely outweigh the risks of continued treatment with careful monitoring.
Dr Miller is a 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 TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. Li XH, Zhong XM, Lu L, et al. The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies. Psychol Med. 2020;50(4):583-594.
2. Ponsford MJ, Steven R, Bramhall K, et al. Clinical and laboratory characteristics of clozapine-treated patients with schizophrenia referred to a national immunodeficiency clinic reveals a B-cell signature resembling common variable immunodeficiency (CVID). J Clin Pathol. 2020;73(9):587-592.
3. Kuo CJ, Yang SY, Liao YT, et al. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull. 2013;39(3):648-657.
4. Gee S, Gaughran F, MacCabe J, et al. Management of clozapine treatment during the COVID-19 pandemic. Ther Adv Psychopharmacol. 2020;10:2045125320928167.
5. Ohlis A, Wallin AS, Sarafis A, et al. Clozapine treatment and risk of severe COVID-19 infection. Acta Psychiatr Scand. 2021. Online ahead of print.