ACKR1 genetic testing should be offered before starting clozapine treatment

Murtough, Stephen, Mills, Daisy, Khani, Noushin Saadullah, Cotic, Marius, Varney, Lauren, Richards-Belle, Alvin, Abidoph, Rosemary, Bass, Nicholas, Chauhan, Dharmisha, Curran, Sarah, Dawda, Yogita, de Villiers, Jana, Elmslie, Frances, Howard, Robert J., Legge, Sophie E., Martin, Alexander, McQuillin, Andrew, Panconesi, Daniele, Pardiñas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Reeves, Suzanne, Richards-Brown, Maria, Sarginson, Jane, Skowronska, Anna, Stellakis, Oriella, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Woodley, Jessica, Chipp, Beverley, Gandhi, Shreyans, Stuart-Smith, Sara, Hughes, Dyfrig A., Pirmohamed, Munir, Jin, Huajie, Dzahini, Olubanké and Bramon, Elvira 2025. ACKR1 genetic testing should be offered before starting clozapine treatment. nature mental health Item availability restricted.

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Abstract

Clozapine is the most effective therapy for treatment-resistant schizophrenia, although it can cause severe neutropenia. In many countries, neutrophil count monitoring is mandatory for people taking clozapine, who must remain above a minimum threshold to start and continue treatment. Some people have low neutrophil counts without increased infection risk, caused by a homozygous variant in ACKR1 and termed ACKR1/DARC-associated neutropenia (ADAN). When ADAN is confirmed, reduced neutrophil count thresholds are applied to allow people to continue treatment. However, ADAN diagnoses are often missed, resulting in reduced access to clozapine and unnecessary discontinuation. We review the evidence for ACKR1 genetic testing to rapidly identify ADAN in people taking clozapine. With multidisciplinary input, we recommend internationally relevant test eligibility criteria, comprising pre-emptive and reactive testing strategies, and we conduct a health economics analysis, estimating anti-conservative annual savings to the UK healthcare system of £727,990. Finally, we propose how to integrate these criteria into clinical practice to enable equitable access to clozapine.

Item Type:	Article
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Nature Research
Date of First Compliant Deposit:	28 November 2025
Date of Acceptance:	28 October 2025
Last Modified:	28 Nov 2025 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/182737

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