The authors respond =================== * Dan Siskind * William G. Honer * Scott Clark * Christoph U. Correll * Alkomiet Hasan * Oliver Howes * John M. Kane * Deanna L. Kelly * Robert Laitman * Jimmy Lee * James H. MacCabe * Nick Myles * Jimmi Nielsen * Peter F. Schulte * David Taylor * Helene Verdoux * Amanda Wheeler * Oliver Freudenreich We thank Dr. Remington and Ms. Powell for their thoughtful comments1 on our consensus statement regarding the adapted monitoring of patients receiving clozapine treatment during the coronavirus disease 2019 (COVID-19) pandemic. 2 We agree that all decisions regarding frequency of monitoring need to be made on a case-by-case basis in consultation among the treating team, patients and families/carers. In the absence of clear data on the absolute risk of severe neutropenia in the 6–12 months after clozapine commencement, we did not feel that blanket guidance could be provided at this time. Hence, we have encouraged prescribers, patients and families/carers to reflect on the risks and benefits for individual cases. We hope that the managers of clozapine monitoring programs will provide access to deidentified data on time to severe neutropenia events to allow the Treatment Response and Resistance in Psychosis (TRRIP) working group and other researchers to analyze these data to better inform clozapine monitoring protocols. The timing of clozapine monitoring varies from country to country.3 As Remington and Powell note,1 in Canada biweekly monitoring is recommended in the 6–12 months after starting clozapine, while in Australia and other jurisdictions monitoring is required only every 4 weeks after 18 weeks on clozapine. Clinicians in jurisdictions with biweekly monitoring may wish to consider monitoring every 4 weeks after 6 months on clozapine if access to biweekly monitoring is not practical. It is worth noting, however, that even weekly monitoring may not identify all relevant cases of true severe neutropenia because the time from normal absolute neutrophil count (ANC) to the nadir may be less than 1 week.4,5 The threshold for lowest historical ANC of 2000/μL (or < 1500/μL if history of benign ethnic neutropenia) since starting clozapine was set conservatively, given the absence of specific data to guide this value. The number of patients who may be potentially excluded by this higher threshold is unclear. Information from monitoring systems would be very helpful in establishing the percentage affected. Monitoring system data may also allow ascertainment of a relationship, if any, between episodes of ANC between 1000 and 2000/μL and risk of future episodes of ANC < 500/μL. A thorough discussion of the historical background of the hematological adverse effects of clozapine was beyond the scope of the consensus statement. We note that a recent meta-analysis found the risk of neutropenia associated with clozapine was not significantly higher than the risk associated with other antipsychotics.6 However, for patients with COVID-19, health care providers would be wise to be vigilant regarding possible effects of antipsychotic drugs beyond clozapine (as well as carbamazepine) on white blood cells. ## Footnotes * **Competing interests:** W. Honer has received consulting fees or sat on paid advisory boards for the Canadian Agency for Drugs and Technology in Health, AlphaSights, Guidepoint, In Silico, Translational Life Sciences, Otsuka, Lundbeck and Newron. S. Clark has received an investigator-initiated grant, participated in an advisory and an educational board and received speaker fees from Lundbeck-Otsuka Australia and received an investigator-initiated grant from Janssen-Cilag Australia. He has received speaker fees from Servier Australia. C. Correll has been a consultant and/or advisor to or has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda and Teva. He has provided expert testimony for Janssen and Otsuka. He served on a data safety monitoring board for Lundbeck, Rovi, Supernus and Teva. He has received grant support from the Berlin Institute of health, Janssen, the National Institute of Mental Health, Patient Centered Outcomes Research Institute, Takeda and the Thrasher Foundation. He has received received royalties from UpToDate and is a stock option holder of LB Pharma. A. Hasan has been on the advisory boards and has received speaker fees from Janssen, Lundbeck and Otsuka. O. Howes reports receiving speaker fees, participating on advisory boards, and/or receiving investigator-initiated funding from manufacturers of anti-psychotics, including clozapine. J. Kane declares consulting fees/honoraria from Acadia, Alkermes, Allergan, Eli Lilly, Forum, Genentech, Sumitomo Dainippon, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceutical, Jazz Pharma, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda and Teva, as well as grant support from Otsuka, Lundbeck and Janssen. He is also a shareholder in Vanguard Research Group and LB Pharmaceuticals, Inc. D. Kelly has served as a consultant for Lundbeck, HLS Therapeutics and Alkermes, and is a joint holder of a patent for analytical micro-devices for mental health treatment monitoring (US9581536B2). J. MacCabe has received research grants from and acted as an unpaid consultant to Lundbeck and Saladax Biomedical. D. Taylor has received research funding from Janssen and Sunovion and lecture payments form Janssen, Lundbeck, Otsuka and Recordati. O. Freudenreich has received a grant from Avanir for a clinical trial involving patients taking clozapine and royalties from UpToDate for the entry on clozapine. No other authors declared competing interests. ## References 1. Remington G, Powell V.Clozapine and COVID-19.J Psychiatry Neurosci 2020;45Ex-x 2. Siskind D, Honer WG, Clark S, et al.Consensus statement on the use of clozapine during the COVID-19 pandemic.J Psychiatry Neurosci 2020;45200061 3. Nielsen J, Young C, Ifteni P, et al.Worldwide differences in regulations of clozapine use.CNS Drugs 2016;30:149–61. 4. Almaghrebi AH.Safety of a Clozapine Trial Following Quetiapine-Induced Leukopenia: A Case Report.Curr Drug Saf 2019;14:80–3. 5. Patel NC, Dorson PG, Bettinger TL.Sudden late onset of clozapine-induced agranulocytosis.Ann Pharmacother 2002;36:1012–5. [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1345/aph.1A417&link_type=DOI) [PubMed](http://jpn.ca/lookup/external-ref?access_num=12022904&link_type=MED&atom=%2Fjpn%2F45%2F4%2FE1.2.atom) 6. 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;53:403–12.