COVID-19: Risks, Complications, and Monitoring in Patients on Clozapine

Abstract

The Dutch Clozapine Collaboration Group is frequently asked for advice about the management of clozapine-treated patients when infected with or vaccinated against SARS-CoV-2. We provide state of the art information about the risks of SARS-CoV-2 infection for patients on clozapine and we give advice on measures to be taken, especially in regard to the monitoring of clozapine plasma levels, WBC count and differentiation during COVID-19 and after vaccination. We present an overview of relevant editorials, observational studies, and case studies, in which COVID-19 was reported in patients on clozapine. Patients using clozapine may have a higher risk of infection than patients with schizophrenia spectrum disorders (SSD) using other antipsychotics. SARS-CoV-2 infection can result in a dangerous increase of clozapine plasma levels, and granulocytopenia and lymphocytopenia (generally mild and short-term) may also occur, usually not as a result of clozapine treatment. Clozapine intoxication, pneumonia and delirium are the main complications of COVID-19 in patients on clozapine. In order to prevent clozapine intoxication, reduction of the original dose by half is generally recommended in clozapine users who contract COVID-19. When a cytokine storm is suspected in an advanced stage of COVID-19, reduction by three quarters seems more appropriate. If COVID-19 patients on clozapine develop granulocytopenia, SARS-CoV-2, rather than clozapine, should be considered as the cause. Schizophrenia patients in general and clozapine users in particular belong to a high-risk group that warrants early vaccination on a medical indication.

Key words

antipsychotic drugs - schizophrenia - immune system - clozapine - COVID-19

Publication History

Received: 23 May 2021
Received: 21 July 2021

Accepted: 24 July 2021

Article published online:
01 September 2021

• References

• 1 Govind R, Fonseca de Freitas D, Pritchard M. et al. Clozapine treatment and risk of COVID-19 infection: Retrospective cohort study. Br J Psychiatry 2020; doi:10.1192/bjp.2020.151, online ahead of print
• 2 Ponsford MJ, Pecoraro A, Jolles S. Clozapine-associated secondary antibody deficiency. Curr Opin Allergy Clin Immunol 2019; 19: 553-562
• 3 Wang Q, Xu R, Volkow ND. Increased risk of COVID-19 infection and mortality in people with mental disorders: Analysis from electronic health records in the United States. World Psychiatry 2021; 20: 124-130
• 4 Jeon HL, Kwon JS, Park SH. Association of mental disorders with SARS-CoV-2 infection and severe health outcomes: Nationwide cohort study. Br J Psychiatry 2021; doi:10.1192/bjp.2020.251, online ahead of print
• 5 Fond G, Pauly V, Leone M. et al. Disparities in intensive care unit admission and mortality among patients with schizophrenia and COVID-19: A national cohort study. Schizophr Bull 2020; 47: 624-634
• 6 Tzur Bitan D, Krieger I, Kristin K. et al. COVID-19 prevalence and mortality among schizophrenia patients: A large-scale retrospective cohort study. Schizophr Bull 2021; sbab012 doi:10.1093/schbul/sbab012, online ahead of print
• 7 Nemani K, Li C, Olfson M. et al. Association of psychiatric disorders with mortality among patients with COVID-19. JAMA Psychiatry 2021; 78: 380-386 doi: 10.1001/jamapsychiatry.2020.4442
• 8 Cranshaw T, Harikumar T. COVID-19 Infection may cause clozapine intoxication: case report and discussion. Schizophr Bull 2020; 46: 751
• 9 Dotson S, Hartvigsen N, Wesner T. et al. Clozapine toxicity in the setting of COVID-19. Psychosomatics 2020; 61: 577-578
• 10 Tio N, Schulte PFJ, Martens HJM. Clozapine intoxication in COVID-19. Am J Psychiatry 2021; 178: 123-127
• 11 Clark SR, Warren NS, Kim G. et al. Elevated clozapine levels associated with infection: a systematic review. Schizophr Res 2018; 192: 50-56
• 12 De Leon J, Ruan C-J, Verdoux H. et al. Clozapine is strongly associated with the risk of pneumonia and inflammation. Gen Psychiatry 2020; 33: e100183
• 13 Siskind D, Honer WG, Clark S. et al. Consensus statement on the use of clozapine during the COVID-19 pandemic. J Psychiatry Neurosci 2020; 45: 200061
• 14 Smits F, Bogers JPAM, De Leeuw M. Leukocytopenie: clozapine of COVID-19. Tijdschr Psychiatr 2021; Accepted for publication
• 15 Cron RQ. COVID-19 cytokine storm: targeting the appropriate cytokine. Lancet Rheumatol 2021; 3: e236-e237
• 16 Gee S, Taylor D. The effect of COVID-19 on absolute neutrophil counts in patients taking clozapine. Ther Adv Psychopharmacol 2020; 10: 2045125320940935
• 17 Gee S, Taylor D. COVID-10 infection causes a reduction in neutrophil counts in patients taking clozapine. J Psychiatry Neurosci 2021; 46: E232-E237
• 18 Bonaccorso S, Ricciardi A, Ouabbou S. et al. Clozapine, neutropenia and Covid-19: should clinicians be concerned? 3 months report. Brain Behav Immun Health 2021; 13: 100212
• 19 Baranski B, Young N. Hematologic consequences of viral infections. Hematol Oncol Clin North Am 1987; 1: 167-183
• 20 Butler M, Bano F, Calcia M. et al. Clozapine prescribing in COVID-19 positive medical inpatients: A case series. Ther Adv Psychopharmacol 2020; 10: 2045125320959560
• 21 Llesuy JR, Sidelnik SA. Death from COVID-19 in a patient receiving clozapine: factors involved and prevention strategies to consider. Prim Care Companion CNS Disord 2020; 22: 20l02699
• 22 Thompson D, Delorme CM, White RF. et al. Elevated clozapine levels and toxic effects after SARS-CoV-2 vaccination. J Psychiatry Neurosci 2021; 46: E210-E211
• 23 Schulte PFJ. The risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring. Ann Pharmacother 2006; 40: 683-688
• 24 Boland X, Dratcu L. Clozapine in the time of COVID-19. Clin Psychopharmacol Neurosci 2020; 18: 450-453
• 25 Silva E, Gee S, Smith S. et al. Clozapine and COVID-19. B J Psych Bull 2020; 44: 179-180
• 26 Raaska K, Raitasuo V, Neuvonen PJ. Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia. Eur J Clin Pharmacol 2001; 57: 705-708
• 27 Morgan ET. Regulation of cytochrome p450 by inflammatory mediators: why and how?. Drug Metab Dispos 2001; 29: 207-212
• 28 Zamani B, Moeini Taba SM. et al. Systemic lupus erythematosus manifestation following COVID-19: A case report. J Med Case Rep 2021; 15: 29
• 29 Pathak S, Cherry S, Samad S. et al. Successful clozapine rechallenge in a patient with suspected drug induced lupus. BMJ Case Rep 2019; 12: e228574
• 30 Bektas A, Schurman SH, Sen R. et al. Human T cell immunosenescence and inflammation in aging. J Leukoc Biol 2017; 102: 977-988