Clozapine and neutrophil response in patients of African descent: A six-month, multinational, prospective, open-label clinical trial.

INTRODUCTION: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent. METHODS: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology. RESULTS: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm3) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm3) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %). CONCLUSION: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN.

Anti-aggressive effects of clozapine in involuntarily committed black patients with severe mental illness.

INTRODUCTION: Patients with severe mental illness are falsely characterized as aggressive by the media, perpetuating stigma. While exaggerated, some patients with severe mental illness are more aggressive without treatment. Clozapine may have a unique anti-aggressive effect in patients with schizophrenia-related disorders, independent of antipsychotic or sedative effects. Limited data in forensic and involuntary committed patients is currently available. PURPOSE: This study evaluates clozapine's effects on hostility and aggression in court-ordered Black patients. METHODS: This study analyzes a subgroup of Black patients from a larger prospective 24-week open-label clozapine study. All patients were involuntarily committed and enrolled from two participating state psychiatric hospitals. The primary outcome measured was total use of 'as needed' (PRN) or 'immediate need' (STAT) medications for aggression/hostility. Secondary outcomes included number and duration of seclusion and restraint (S/R) episodes, and changes in Brief Psychiatric Rating Scale (BPRS) hostility factor score. RESULTS: Sixty-nine patients were included in our analysis. Significant reductions were noted in PRN/STAT medication use over time (χ2 = 6.90; p = 0.008) and the BPRS hostility factor score was reduced by 30% over the 24 weeks (F = 4.34, df = 62, p = 0.002). CONCLUSIONS: Treatment with clozapine effectively reduced hostility and aggression within this cohort of involuntarily committed Black patients with mental illness compared to baseline. Specifically, it helped lower the total number of PRN/STAT medication administrations and improved clinician-rated hostility factor scores on the BPRS. Our findings are pertinent as data in forensic settings is lacking and Black patients have been infrequently included in large prospective clinical trials with clozapine. GOV IDENTIFIER: NCT02404155.

Feasibility and patient-reported satisfaction using a novel point-of-care fingerstick method for monitoring absolute neutrophil count for clozapine.

BACKGROUND: Clozapine is an effective antipsychotic for treatment-resistant schizophrenia. One limitation of clozapine use is required monitoring of absolute neutrophil count (ANC) because of the risk of clozapine-induced neutropenia. Standard monitoring requires venous blood draws, which is a significant barrier to clozapine use. METHODS: This study assesses the feasibility of use and physician and patient satisfaction of a novel point-of-care (POC) measure of ANC using Athelas One, a device that calculates white blood cell count and ANC using a fingerstick blood sample. This is a subanalysis of a prospective, open-label clinical trial of clozapine treatment, during which patients received a venous blood draw and a capillary fingerstick at baseline and Week 2 of the study, and completed a 5-point Likert scale, comparing the 2 methods. RESULTS: Patients reported benefits from the fingerstick technology, including POC testing being important for their doctors and their health, improved treatment, avoiding sending blood away, and convenience. There was a trend for less concern about the effects of blood draws on health with a fingerstick, and greater physician satisfaction with POC sampling. CONCLUSIONS: This study suggests the feasibility, satisfaction, and ease by both clinicians and patients of using POC testing for ANC monitoring during clozapine treatment.