ACKR1 genetic testing should be offered before starting clozapine treatment

Clozapine is the most effective therapy for treatment-resistant schizophrenia, although it can cause 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 start and continue clozapine. 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 economic analysis, estimating total cost savings between £42,732 and £727,990 for the UK healthcare system during the first year of testing. Finally, we propose how to integrate these criteria into clinical practice to enable equitable access to clozapine. This Perspective considers the addition of ACKR1 genetic testing for identifying ACKR1/DARC-associated neutropenia in patients receiving clozapine, recommending eligibility criteria and testing strategies while estimating substantial cost savings for the UK healthcare system and enhancing equitable treatment access.

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Publication Details

Journal
Nature Mental Health
Published
2026-01-07
DOI
https://doi.org/10.1038/s44220-025-00554-9
Primary Topic
Blood disorders and treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

ACKR1 genetic testing should be offered before starting clozapine treatment

Jessica Woodley, Lauren Varney, Antonio F. Pardiñas, Suzanne Reeves et al.
Nature Mental Health
Blood disorders and treatments
article

ACKR1 genetic testing should be offered before starting clozapine treatment

Jessica Woodley, Lauren Varney, Antonio F. Pardiñas, Suzanne Reeves, Robert Howard, Jane Sarginson, Sophie E. Legge, Jana de Villiers, Yogita Dawda, James T.R Walters, Andrew McQuillin, Anna Skowrońska, Dyfrig Hughes, Sarah Curran, Noushin Saadullah Khani, Rosemary Abidoph, Huajie Jin, Daniele Panconesi, Maria Richards-Brown, Sara Stuart-Smith, Arthur M. Martin, D. R. Mills, Dharmisha Chauhan, Oriella Stellakis, Alvin Richards-Belle, Elvira Bramon, Stephen Murtough, Munir Pirmohamed, Nicholas Bass, Shreyans Gandhi, Frances Elmslie, Beverley Chipp, Marius Cotic, Olubanké Dzahini
article en

Abstract

Clozapine is the most effective therapy for treatment-resistant schizophrenia, although it can cause 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 start and continue clozapine. 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 economic analysis, estimating total cost savings between £42,732 and £727,990 for the UK healthcare system during the first year of testing. Finally, we propose how to integrate these criteria into clinical practice to enable equitable access to clozapine. This Perspective considers the addition of ACKR1 genetic testing for identifying ACKR1/DARC-associated neutropenia in patients receiving clozapine, recommending eligibility criteria and testing strategies while estimating substantial cost savings for the UK healthcare system and enhancing equitable treatment access.

Nature Mental HealthVol. 4(1)
Manchester Metropolitan University (GB), Royal Marsden NHS Foundation Trust (GB), University of Liverpool (GB), Bangor University (GB), King's College London (GB), South London and Maudsley NHS Foundation Trust (GB), Central and North West London NHS Foundation Trust (GB), North East London NHS Foundation Trust (GB), Great Ormond Street Hospital (GB), St George’s University Hospitals NHS Foundation Trust (GB), State Hospital (GB), King's College Hospital NHS Foundation Trust (GB), Side by Side (US), Birmingham Women’s and Children’s NHS Foundation Trust (GB), University College London (GB), Royal College of Psychiatrists (GB), Cardiff University (GB)
Mental Health Research UK, Wellcome Trust, National Institute for Health and Care Research, British Medical Association, King's College London, University College London, Cardiff University, University College London Hospitals NHS Foundation Trust, Innovative Medicines Initiative, Medical Research Council, Economic and Social Research Council
Openalex Percentile: Top 95%
Blood disorders and treatments
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