Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel

Dan Siskind¹, Korinne Northwood², Toby Pillinger³, Sherry Chan⁴, Christoph Correll⁵, Robert O Cotes⁶, Susanna Every-Palmer⁷, Maggie Hahn⁸, Oliver D Howes⁹, John M Kane¹⁰, Deanna Kelly¹¹, Nicole Korman², Julia Lappin¹², Cristián Mena¹³, Nick Myles¹⁴, Robert A McCutcheon¹⁵; Clozapine Delphi Expert Panel

Collaborators, Affiliations

Collaborators

Clozapine Delphi Expert Panel:
Dan Siskind, Robert A McCutcheon, Korinne Northwood, Toby Pillinger, Sherry Chan, Christoph U Correll, Robert Cotes, Susanna Every-Palmer, Margaret Hahn, Oliver Howes, John M Kane, Deanna L Kelly, Nicole Korman, Julia Lappin, Cristián Mena, Nicholas Myles, Ofer Agid, Celso Arango, Laila Asmal, Olatunde O Ayinde, Trino Baptiste, Laurent Béchard, Istvan Bitter, Robert A Bittner, Dagmar Breznoscakova, Eric Chen, Eka Chkonia, Leslie Citrome, Scott R Clark, Olivier Corbeil, Rodrigo Cordoba, Nicolas Crossley, Andrea de Bartolomeis, Bjørn H Ebdrup, Emilio Fernandez-Egea, Helio Elkis, Yassin Eltorki, Ivona Šimunović Filipčić, Renato de Filippis, Wolfgang Fleischhacker, Oliver Freudenreich, Ary Gadelha, Clarissa S Gama, Fiona Gaughran, Siobhan Gee, Daniel Guinart, Jaime Eduardo Cecilio Hallak, Anthony Harris, Alkomiet Hasan, William Honer, Mahesh Jayaram, Tetsufumi Kanazawa, Hirotsugu Kawashima, Dolores Keating, Se Hyun Kim, Jun Soo Kwon, Hsien-Yuan Lane, Jimmy Lee, Belinda Lennox, Jose de Leon, Jonathan G Leung, Jurjen J Luykx, James MacCabe, Graham Murray, Jimmi Nielsen, Brian O'Donoghue, Ebenezer Oloyede, Mishal Qubad, Gary Remington, Marc-André Roy, Jose Rubio, Marina Sagud, Peter F J Schulte, Jean-Paul Selten, Tianmei Si, Lesley Smith, Iris Sommer, Suresh Sundram, Heidi Taipale, Hiroyoshi Takeuchi, Rajiv Tandon, Timothy Tanzer, David Taylor, Jagadisha Thirthalli, Jari Tiihonen, Hiroyuki Uchida, Ganesan Venkatasubramanian, Hélène Verdoux, Elias Wagner, Yu Xin, A Elif Anıl Yağcıoğlu, Alison Yung

Affiliations

¹ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Addiction and Mental Health Service, Metro South Health, Brisbane, QLD, Australia; Queensland Centre for Mental Health Research, Brisbane, QLD, Australia. Electronic address: d.siskind@uq.edu.au.
² Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Addiction and Mental Health Service, Metro South Health, Brisbane, QLD, Australia; Queensland Centre for Mental Health Research, Brisbane, QLD, Australia.
³ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
⁴ Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.
⁵ Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra and Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Northwell Health, New Hyde Park, NY, USA; Charité, Department of Child and Adolescent Psychiatry, Universitätsmedizin Berlin, Berlin, Germany; German Center for Mental Health, Berlin, Germany.
⁶ Emory University School of Medicine, Atlanta, GA, USA.
⁷ University of Otago Wellington, Wellington, New Zealand.
⁸ Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, Institute of Medical Sciences, Department of Psychiatry, and Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁰ Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra and Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
¹¹ Maryland Psychiatric Research Center, Baltimore, MD, USA.
¹² Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, NSW, Australia; South Eastern Sydney Local Health District, Sydney, NSW, Australia.
¹³ Early Intervention Program, Instituto Psiquiátrico Dr J Horwitz Barak, Santiago, Chile; School of Medicine, Universidad Finis Terrae, Santiago, Chile.
¹⁴ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹⁵ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.

PMID: 40617246
DOI: 10.1016/S2215-0366(25)00098-7

Review

Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel

Dan Siskind et al. Lancet Psychiatry. 2025.

. 2025 Jul 1:S2215-0366(25)00098-7.

doi: 10.1016/S2215-0366(25)00098-7. Online ahead of print.

Authors

Collaborators

Clozapine Delphi Expert Panel:
Dan Siskind, Robert A McCutcheon, Korinne Northwood, Toby Pillinger, Sherry Chan, Christoph U Correll, Robert Cotes, Susanna Every-Palmer, Margaret Hahn, Oliver Howes, John M Kane, Deanna L Kelly, Nicole Korman, Julia Lappin, Cristián Mena, Nicholas Myles, Ofer Agid, Celso Arango, Laila Asmal, Olatunde O Ayinde, Trino Baptiste, Laurent Béchard, Istvan Bitter, Robert A Bittner, Dagmar Breznoscakova, Eric Chen, Eka Chkonia, Leslie Citrome, Scott R Clark, Olivier Corbeil, Rodrigo Cordoba, Nicolas Crossley, Andrea de Bartolomeis, Bjørn H Ebdrup, Emilio Fernandez-Egea, Helio Elkis, Yassin Eltorki, Ivona Šimunović Filipčić, Renato de Filippis, Wolfgang Fleischhacker, Oliver Freudenreich, Ary Gadelha, Clarissa S Gama, Fiona Gaughran, Siobhan Gee, Daniel Guinart, Jaime Eduardo Cecilio Hallak, Anthony Harris, Alkomiet Hasan, William Honer, Mahesh Jayaram, Tetsufumi Kanazawa, Hirotsugu Kawashima, Dolores Keating, Se Hyun Kim, Jun Soo Kwon, Hsien-Yuan Lane, Jimmy Lee, Belinda Lennox, Jose de Leon, Jonathan G Leung, Jurjen J Luykx, James MacCabe, Graham Murray, Jimmi Nielsen, Brian O'Donoghue, Ebenezer Oloyede, Mishal Qubad, Gary Remington, Marc-André Roy, Jose Rubio, Marina Sagud, Peter F J Schulte, Jean-Paul Selten, Tianmei Si, Lesley Smith, Iris Sommer, Suresh Sundram, Heidi Taipale, Hiroyoshi Takeuchi, Rajiv Tandon, Timothy Tanzer, David Taylor, Jagadisha Thirthalli, Jari Tiihonen, Hiroyuki Uchida, Ganesan Venkatasubramanian, Hélène Verdoux, Elias Wagner, Yu Xin, A Elif Anıl Yağcıoğlu, Alison Yung

Affiliations

¹ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Addiction and Mental Health Service, Metro South Health, Brisbane, QLD, Australia; Queensland Centre for Mental Health Research, Brisbane, QLD, Australia. Electronic address: d.siskind@uq.edu.au.
² Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Addiction and Mental Health Service, Metro South Health, Brisbane, QLD, Australia; Queensland Centre for Mental Health Research, Brisbane, QLD, Australia.
³ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
⁴ Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.
⁵ Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra and Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Northwell Health, New Hyde Park, NY, USA; Charité, Department of Child and Adolescent Psychiatry, Universitätsmedizin Berlin, Berlin, Germany; German Center for Mental Health, Berlin, Germany.
⁶ Emory University School of Medicine, Atlanta, GA, USA.
⁷ University of Otago Wellington, Wellington, New Zealand.
⁸ Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, Institute of Medical Sciences, Department of Psychiatry, and Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁰ Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra and Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
¹¹ Maryland Psychiatric Research Center, Baltimore, MD, USA.
¹² Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, NSW, Australia; South Eastern Sydney Local Health District, Sydney, NSW, Australia.
¹³ Early Intervention Program, Instituto Psiquiátrico Dr J Horwitz Barak, Santiago, Chile; School of Medicine, Universidad Finis Terrae, Santiago, Chile.
¹⁴ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹⁵ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.

PMID: 40617246
DOI: 10.1016/S2215-0366(25)00098-7

Erratum in

Correction to Lancet Psychiatry 2025; published online July 2. https://doi.org/10.1016/S2215-0366(25)00098-7.
[No authors listed] [No authors listed] Lancet Psychiatry. 2025 Sep;12(9):e17. doi: 10.1016/S2215-0366(25)00239-1. Epub 2025 Jul 16. Lancet Psychiatry. 2025. PMID: 40683280 No abstract available.
Correction to Lancet Psychiatry 2025; published online July 2. https://doi.org/10.1016/S2215-0366(25)00098-7.
[No authors listed] [No authors listed] Lancet Psychiatry. 2025 Sep;12(9):e17. doi: 10.1016/S2215-0366(25)00241-X. Epub 2025 Jul 22. Lancet Psychiatry. 2025. PMID: 40712623 No abstract available.

Abstract

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 10⁹ cells per L (0·5 × 10⁹ cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.

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Conflict of interest statement

Declarations of interest DS has received grant support from NHMRC (GNT1194635). RAM has received funding from Wellcome Trust; has been a consultant to Boehringer Ingelheim, has received payment or honoraria for Janseen and Otsuka; has received financial support from Karuna and Boehringer Ingelheim; has participated as an advisor on a board for Karuna, Newron and Viatris; and has co-directed a company called Pharmatik. TP has been a consultant to Boehringer Ingelheim; has received payment and honoraria from Recordati, Lundbeck, Otsuka, Janssen, CNX Therapeutics, Sunovion, ROVI Biotech, Schwabe Pharma, and Lecturing Minds Stockholm AB; and has co-directed a company called Pharmatik. SC has received grants from the Health and Medical Research Fund and the General Research Fund. CC has received grants from Boehringer-Ingelheim, Janssen and Teva; has been a consultant to AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen, Karuna, LB Pharma, Lundbeck, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora Therapeutics, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Saladax, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, Viatris and Xenon Pharmaceuticals; has received payment or honoraria for AbbVie, Allergan, Angelini, Boehringer Ingelheim, Bristol-Meyers Squibb, Cerevel, Compass, Gedeon Richter, Hikma, Janssen, Karuna, LB Pharma, Lundbeck, MedInCell, Merck, Neurelis, Neurocrine, Newron, Novo Nordisk, Otsuka, Recordati, Rovi, Sage, Seqirus, Life Science, Sunovion, Supernus, Tabuk, Takeda, Teva, Vertex, and Viatris; has received payment for expert testimony from Janssen, Lundbeck and Otsuka; has participated as an advisor on a board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; and has stock or stock options for Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Medlink, Mindpax, Quantic and Terran. ROC has received research funding from Alkermes, Karuna, Roche, and Otsuka; has received contracts from US Substance Abuse and Mental Health Services Administration and Springer; has been a consultant to IQVIA, Boehringer Ingelheim, Saladax Biomedical, and Clozapine Product Manufacturers Group; has received payment or honoraria for Saladax Biomedical; and has participated as an advisor on a board for Hope Atlanta, Georgia Psychiatric Physicians Association and American Association for Community Psychiatry. MH has been a consultant for Merck and Alkermes; and has participated as an advisor on a board for Alkermes. ODH has received research funding from Angelini, Autifony, Biogen, BMS (Karuna), Boehringer-Ingelheim, Delix, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Janssen, Karuna, Lundbeck, Merck, Neumora, Neurocrine, Ontrack/Pangea, Otsuka, Sunovion, Teva, Recordati, Roche, Rovi, and Viatris/Mylan; has participated in advisory meetings for AbbVie, Alkermes, Boehringer-Ingelheim and Merck; and has previously been a part-time employee of Lundbeck A/V. JMK has received contracts from Lundbeck, Janssen, Otsuka and Sunovion; has been a consultant for AbbVie, Alkermes, Allergan, Boehringer-Ingelheim, Bristol Meyer-Squibb, Cerevel, Dainippon Sumitomo, H. Lundbeck, HealthRhythms, HLS Therapeutics, Indivior, Intracellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Mapi, Maplight, Merck, Minerva, Neurocrine, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion and Teva; has received payment or honoraria for AbbVie, Alkermes, Allergan, Boehringer-Ingelheim, Bristol Meyer-Squibb, Cerevel, Dainippon Sumitomo, H. Lundbeck, HealthRhythms, HLS Therapeutics, Indivior, Intracellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Mapi, Maplight, Merck, Minerva, Neurocrine, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion and Teva; has participated as an advisor on a board for AbbVie, Alkermes, Boehringer-Ingelheim, Cerevel, Click Therapeutics, BMS, Lundbeck, Merck, Newron, Novartis, Otsuka, Sumitomo, Teva and Terran; and has stock or stock options for HealthRhythms, LB Pharmaceuticals, Inc., North Shore Therapeutics, Vanguard Research Group, NW Pharmatech, Saladax, Reviva, Terran and Intracellular Therapies. DK has been a consultant for Alkermes, Teva, and Karuna; and participated as an advisor on a board for Zucker Hillside Hospital DSMB. NK has received research funding from the University of Queensland Community and Consumer Funding Grant (CCI); has received grant funding from the Queensland Mental Health Branch; and has received payment or honoraria for Otsuka. All other authors declare no competing interests.

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Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel

Collaborators

Affiliations

Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

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