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.