In the management of treatment-resistant schizophrenia, clozapine remains unparalleled in efficacy, yet its administration is complicated by the risk of neutropenia—an abnormally low count of neutrophils, vital white blood cells integral to immune defense. Globally, clozapine prescribing guidelines mandate rigorous monitoring of neutrophil counts, imposing strict thresholds for initiation and continuation of the drug. These precautions, while medically prudent, inadvertently exclude a subset of patients who harbor a benign genetic condition known as ACKR1/DARC-associated neutropenia (ADAN). ADAN is characterized by persistently low neutrophil counts without an associated increase in infection risk, linked to a homozygous variant in the ACKR1 gene. Recent discourse in psychiatric pharmacogenetics underscores the necessity of incorporating ACKR1 genetic testing into clinical workflows to distinguish ADAN from pathological neutropenia, thereby preventing unnecessary cessation of clozapine and enhancing therapeutic accessibility.
This paradigm-shifting perspective emerges from the comprehensive analysis by Murtough et al., who advocate for a universal shift towards proactive genetic screening before the initiation of clozapine treatment. The crux of their argument lies in the recognition that conventional neutrophil count thresholds are insufficiently nuanced, lacking the granularity to account for the benign hematological variation conferred by the ACKR1 polymorphism. Consequently, many individuals with genetically mediated low neutrophil counts face unwarranted treatment delays or discontinuations due to misclassification. Confirming ADAN through targeted genetic testing allows clinicians to safely apply adjusted neutrophil thresholds, thus preserving clozapine therapy for patients who would otherwise be deprived of it.
At the molecular level, the ACKR1 gene encodes the Duffy antigen receptor for chemokines, prominently expressed on erythrocytes and various other cell types. The variant responsible for ADAN results in diminished expression of this receptor, which serendipitously lowers circulating neutrophil counts but does not impair innate immune functionality. This distinction is critical; it challenges traditional hematological paradigms where neutropenia is synonymous with elevated infection risk. Within populations of African descent, where the prevalence of the ACKR1 homozygous variant is markedly higher, ADAN’s incidence underscores a pharmacogenomic intersection with profound clinical relevance. Ignoring these genetic nuances inadvertently perpetuates health disparities, disproportionately affecting minority groups’ access to clozapine.
Current clinical practice relies heavily on serial complete blood counts (CBC) to guide clozapine dosing, with predefined cutoffs for the absolute neutrophil count (ANC). Standard protocols often demand an ANC above 1.5 × 10^9/L for initiation and maintenance, with cessation advised if counts drop below 1.0 × 10^9/L. However, individuals with ADAN consistently record neutrophil counts below these thresholds despite lacking clinical neutropenia’s hallmark susceptibility to infections. Murtough and colleagues propose leveraging ACKR1 genetic testing to redefine these thresholds, allowing adjusted ANC cutoffs that reflect benign neutrophil suppression rather than pathological reductions. Such recalibration could expedite treatment initiation and decrease unjustified therapy interruptions.
Adoption of ACKR1 genetic screening necessitates the development of robust eligibility criteria tailored for international applicability. The authors recommend a dual approach encompassing both pre-emptive and reactive strategies. Pre-emptive screening involves testing individuals prior to clozapine initiation, facilitating baseline determination of genetic neutrophil modulation. Reactive testing, conversely, targets individuals exhibiting unexpected neutropenia during treatment, assessing whether the observed hematological changes align with ADAN rather than drug-induced agranulocytosis. This multidimensional framework ensures maximal detection accuracy, minimizes clinical risk, and fosters tailored treatment regimens.
Beyond clinical implications, the economic impact of ACKR1 genetic testing emerges as compelling evidence for its integration into standard psychiatric practice. The health economic modeling presented by the researchers estimates cost savings for the UK National Health Service ranging from approximately £42,700 to nearly £728,000 within the first year of implementation. These savings are primarily attributed to reducing unnecessary clozapine discontinuations, minimizing hospital admissions due to psychiatric relapses, and decreasing the burden of additional hematological investigations. This fiscal prudence, coupled with enhanced patient outcomes, positions ACKR1 testing as a cost-effective adjunct to contemporary schizophrenia management protocols.
Notably, this paradigm complements expanding awareness of personalized medicine’s role in psychiatry, an area historically lagging behind other medical disciplines. Incorporating pharmacogenetic data into prescribing practices holds promise for mitigating adverse effects and optimizing efficacy, particularly in populations where traditional metrics yield ambiguous interpretations. The identification of benign genetic variants influencing drug tolerance exemplifies this progression, pointing toward a future where genotype-informed treatment decisions become the norm rather than the exception.
Implementation of genetic testing, however, carries logistical and ethical considerations. Service infrastructure must support rapid genetic diagnostics, ideally integrating results into electronic health records to facilitate clinician access and decision-making. Additionally, informed consent protocols must address the implications of genetic testing, including privacy concerns and potential stigma. Multidisciplinary collaboration—encompassing psychiatry, hematology, genetics, and ethics—is paramount to navigating these complexities and ensuring equitable access across diverse healthcare contexts.
A crucial facet underscored by Murtough et al. pertains to health equity. Given the elevated frequency of the ACKR1 variant among individuals of African and Middle Eastern descent, failure to identify ADAN effectively institutionalizes a form of genetic discrimination through systemic exclusion from clozapine therapy. Rectifying this gap aligns with broader commitments to social justice in medicine, promoting culturally competent care and addressing long-standing disparities in mental health outcomes. ACKR1 testing emerges not only as a scientific innovation but as a moral imperative.
Pragmatically, integrating ACKR1 testing into clinical pathways could be operationalized via screening algorithms embedded within psychiatric services. These would trigger genetic testing when initial ANC readings fall below standard thresholds but lack clinical infection risk markers, expediting diagnoses and preventing avoidable treatment cessation. Furthermore, educational initiatives targeting clinicians and patients can improve awareness of the genetic underpinnings of benign neutropenia and reduce diagnostic uncertainty.
From a research perspective, this advancement opens avenues for exploring other genetic variants that modulate hematological parameters and influence drug safety profiles. The investigative framework applied to ACKR1 offers a blueprint for delineating complex gene-treatment interactions, fostering a more refined understanding of individualized drug response. This approach may ultimately facilitate precision psychiatry interventions across a spectrum of psychotropic agents and adverse effect profiles.
Delving into the molecular interactions, the deletion of the ACKR1 receptor alters chemokine signaling dynamics, albeit without compromising neutrophil functional capacity. This intriguing dissociation raises fundamental questions regarding neutrophil trafficking and lifespan in individuals with ADAN and implicates potential protective mechanisms that preserve immune competence despite low peripheral neutrophil counts. Further mechanistic studies are warranted to elucidate these pathways, potentially revealing new targets for immunomodulation.
In summation, the case for routine ACKR1 genetic testing prior to clozapine therapy is robust, encompassing clinical efficacy, patient safety, economic benefit, and social equity. By distinguishing benign genetic neutropenia from clozapine-induced agranulocytosis, healthcare providers can make informed decisions that safeguard treatment continuity. As schizoaffective disorders remain a pressing challenge worldwide, innovations such as these not only enhance therapeutic outcomes but also exemplify the transformative potential of genomics-informed psychiatry.
As this new standard of care gains traction, it will be imperative to develop international guidelines reflecting these genetic insights, underpinned by consensus from multidisciplinary experts. Such guidelines would harmonize practices, minimize regional disparities, and ensure that patients receive the most appropriate and personalized treatment available. The promise of ACKR1 genetic testing heralds a new era in the management of treatment-resistant schizophrenia, where genetic literacy becomes as integral as clinical acumen.
Ultimately, the integration of genetic testing into the schizophrenia treatment algorithm exemplifies the evolving intersection of genomics and mental health care. This fusion promises not only improved disease management but also profound reductions in health inequities and system burdens. The implementation challenge now lies in translating genomic knowledge from research settings into routine clinical practice, a hurdle that, once overcome, will mark a paradigm shift benefitting millions worldwide.
Subject of Research: Genetic testing of the ACKR1 gene variant to identify benign neutropenia in patients undergoing clozapine treatment for treatment-resistant schizophrenia
Article Title: ACKR1 genetic testing should be offered before starting clozapine treatment
Article References:
Murtough, S., Mills, D., Khani, N.S. et al. ACKR1 genetic testing should be offered before starting clozapine treatment. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-025-00554-9
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