Longitudinal analysis of absolute neutrophil count (ANC) variability and neutropenia incidence in African American schizophrenia patients by ACKR1 genotype

Schizophr Res. 2025 Nov:285:124-131. doi: 10.1016/j.schres.2025.09.011. Epub 2025 Sep 18.

Abstract

Background: About 30-50 % of schizophrenia patients are unresponsive to treatment. Clozapine is the only FDA-approved antipsychotic for treatment-resistant schizophrenia (TRS) but is disproportionally underutilized in African American populations due to concern over clozapine-induced neutropenia (absolute neutrophil count [ANC] < 1500 cells/mm3). Healthy Black individuals have a lower normative ANC, associated with the "ACKR1-null" CC genotype (SNP rs2814778) and termed Benign Ethnic Neutropenia (BEN).

Methods: To elucidate clozapine risk in this population, we characterized the natural ANC progression in 72 African American schizophrenia patients over 7-weeks to establish a necessary baseline for comparison. Weekly blood tests and TaqMan PCR genotyping were performed. Mixed-effects models (MEM) assessed ANC variability and multinomial logistic regression analyzed neutropenia incidence. Factors included ACKR1 genotype, age, sex, and study site. Medication effects (lithium, antidepressants, anticholinergics, anticonvulsants) on ANC were assessed using generalized estimating equations (GEE).

Results: 51/72 participants (70.83 %) were ACKR1-null, exhibiting significantly lower ANC (2800.80 ± 1425.87) compared to the CT/TT group (4958.72 ± 1900.30) (p = 3.99 × 10-15). Neutropenia was more prevalent in the ACKR1-null group (31.4 % [16/51]) compared to the CT/TT group (0 % [0/21]) (p = 0.004), and participants with neutropenia averaged 2.1 ± 1.6 episodes over the 7-week period. Lithium was significantly correlated with higher ANC (p < 0.001). Antidepressant effects varied by genotype, increasing ANC in C-type (p = 0.007) and decreasing ANC in T-type (p < 0.001).

Conclusions: Findings suggest that nearly one-third of healthy African Americans experience neutropenia without clozapine-use. Baseline ANC resembles levels seen during clozapine, reinforcing its safety for broader utilization.

Keywords: ACKR1 gene; Absolute neutrophil count; Benign ethnic neutropenia; Clozapine; Genotype; Schizophrenia.

MeSH terms

  • Adult
  • Antipsychotic Agents* / adverse effects
  • Antipsychotic Agents* / therapeutic use
  • Black or African American* / genetics
  • Clozapine* / adverse effects
  • Clozapine* / therapeutic use
  • Female
  • Genotype
  • Humans
  • Incidence
  • Leukocyte Count
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Neutropenia* / blood
  • Neutropenia* / chemically induced
  • Neutropenia* / epidemiology
  • Neutropenia* / ethnology
  • Neutropenia* / genetics
  • Neutrophils*
  • Polymorphism, Single Nucleotide
  • Schizophrenia* / blood
  • Schizophrenia* / drug therapy
  • Schizophrenia* / genetics
  • Schizophrenia, Treatment-Resistant* / blood
  • Schizophrenia, Treatment-Resistant* / drug therapy
  • Schizophrenia, Treatment-Resistant* / genetics
  • White

Substances

  • Antipsychotic Agents
  • Clozapine