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ACKR1 genetic testing should be offered before starting clozapine treatment

Nature Mental Health volume 4, pages 30–41 (2026)Cite this article

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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.

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Fig. 1: Flow diagram showing how ACKR1 genetic testing could be integrated into clinical practice.

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Data availability

Underlying data for the health economic analysis (Table 3) were calculated from publicly available data or provided as personal communications. No other data were generated for this manuscript. All data and calculations are shown in Supplementary Appendix 2.

Code availability

Full calculations and formulas for the health economic analysis are shown in Supplementary Appendix 2.

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Acknowledgements

Funding received by the authors has not influenced the content of this review. The below lists relevant funding for the authors. This study was funded by the following: the Medical Research Council (G1100583, MR/W020238/1, MR/Z504816/1), the National Institute for Health and Care Research (NIHR200756), Mental Health Research UK John Grace QC Scholarship 2018, an Economic Social Research Council’s co-funded doctoral award (ES/P000592/1), a British Medical Association Margaret Temple Fellowship, a Medical Research Council New Investigator and Centenary Award (G0901310) and the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (BRC1114/MH). A.R.-B. is funded by the Wellcome Trust through a PhD Fellowship in Mental Health Science (218497/Z/19/Z). This research was funded in whole or in part by the Wellcome Trust. For the purposes of open access, the authors have applied a CC BY public copyright licence to any author accepted manuscript (AAM) version arising from this submission. M.P. is supported by funding from the Economic and Social Research Council, the Medical Research Council, the NHS Genomics Unit, the NHS Race and Health Observatory, Health Data Research UK, the National Institute for Health and Care Research, the EU Innovative Medicines Initiative, Innovate UK and MC Diagnostics. N.B. is funded for one programmed activity per week by North Thames Genomic Medicine Service Alliance (Great Ormond Street Hospital) for a Mental Health Lead role. S.R. and R.J.H. are supported by the National Institute for Health and Care Research (NIHR) University College London Hospitals Biomedical Research Centre. Work in Cardiff University by J.T.R.W., A.F.P. and S.E.L. was supported by a Medical Research Council Program grant (MR/Y004094/1), and the Brain and Genomics Hub of the Mental Health Platform (MR/Z503745/1). We thank F. Smith and D. Rees from King’s College Hospital (London, UK) for kindly providing us with a cost estimate for a locally offered ACKR1 genetic test.

Author information

Author notes

  1. These authors contributed equally: Stephen Murtough, Daisy Mills.

Authors and Affiliations

  1. Division of Psychiatry, University College London, London, UK

    Stephen Murtough, Daisy Mills, Noushin Saadullah Khani, Marius Cotic, Lauren Varney, Alvin Richards-Belle, Rosemary Abidoph, Nicholas Bass, Robert J. Howard, Alexander Martin, Andrew McQuillin, Daniele Panconesi, Suzanne Reeves, Maria Richards-Brown, Oriella Stellakis & Elvira Bramon

  2. Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK

    Marius Cotic

  3. The Royal Marsden NHS Foundation Trust, London, UK

    Dharmisha Chauhan

  4. South London and Maudsley NHS Foundation Trust, London, UK

    Sarah Curran

  5. Central and North West London NHS Foundation Trust, London, UK

    Yogita Dawda

  6. Royal College of Psychiatrists, London, UK

    Jana de Villiers

  7. The State Hospital, Carstairs, UK

    Jana de Villiers

  8. St George’s University Hospitals NHS Foundation Trust, London, UK

    Frances Elmslie

  9. Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK

    Sophie E. Legge, Antonio F. Pardiñas & James TR Walters

  10. North London NHS Foundation Trust, London, UK

    Daniele Panconesi & Elvira Bramon

  11. Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK

    Jane Sarginson

  12. Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK

    Anna Skowronska & Jessica Woodley

  13. Side-By-Side Network, London, UK

    Beverley Chipp

  14. Department of Haematology, King’s College Hospital NHS Foundation Trust, London, UK

    Shreyans Gandhi & Sara Stuart-Smith

  15. Centre for Health Economics and Medicines Evaluation, North Wales Medical School, Bangor University, Bangor, UK

    Dyfrig A. Hughes

  16. Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

    Munir Pirmohamed

  17. King’s Health Economics, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Huajie Jin

  18. Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK

    Olubanké Dzahini

  19. Institute of Pharmaceutical Science, King’s College London, London, UK

    Olubanké Dzahini

Authors
  1. Stephen Murtough
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  2. Daisy Mills
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  3. Noushin Saadullah Khani
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  30. Dyfrig A. Hughes
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  31. Munir Pirmohamed
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  32. Huajie Jin
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  34. Elvira Bramon
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Contributions

S.M. contributed to conceptualization, formal analysis, methodology, project administration, visualization and writing (original draft). D.M. contributed to conceptualization, methodology, project administration, visualization and writing (original draft). N.S.K. contributed to conceptualization, methodology and writing (review and editing). M.C., L.V., A.R.-B., R.A., N.B., D.C., S.C., Y.D., J.d.V., F.E., S.E.L., A. Martin, A. McQuillin, D.P., A.F.P., M.R.-B., J.S., A.S., O.S., A.F.P., J.T.R.W., J.W., B.C. and S.G. contributed to conceptualization and writing (review and editing). R.J.H. and S.R. contributed to writing (review and editing). S.S.-S., M.P., H.J. and O.D. contributed to conceptualization, methodology and writing (review and editing). D.A.H. contributed to conceptualization, formal analysis, methodology and writing (review and editing). E.B. contributed to conceptualization, methodology, project administration, resources, supervision and writing (review and editing).

Corresponding authors

Correspondence to Stephen Murtough or Elvira Bramon.

Ethics declarations

Competing interests

D.A.H. is Chair of the National Pharmacogenomics Group for NHS Wales and co-chair of the Pharmacogenomics Test Evaluation Group for NHS England. J.T.R.W. has received funding for research and consultancy work unrelated to this manuscript from Akrivia Health and funding for work unrelated to this manuscript from Takeda Pharmaceuticals. M.P. is Advisory Board Chair for Bosch Health Foundation (Stuttgart, Germany), Vice Chair for Qatar Precision Health Initiative, Chair for the Commission on Human Medicines, Medical Trustee for the British Heart Foundation, Council Member for the Medical Research Council and Chair for the Prix Galien Foundation UK. E.B. is a member of the Pharmacogenomics Test Evaluation Group for NHS England and a member of the NHS England National Genomics Education Programme GeNotes Mental Health Working Group. S.M. is a member of the NHS England National Genomics Education Programme GeNotes Mental Health Working Group. The remaining authors declare no competing interests.

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Nature Mental Health thanks Jose Rubio, Hiroyoshi Takeuchi and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary information

Source data

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Murtough, S., Mills, D., Khani, N.S. et al. ACKR1 genetic testing should be offered before starting clozapine treatment. Nat. Mental Health 4, 30–41 (2026). https://doi.org/10.1038/s44220-025-00554-9

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