Sex differences in clozapine prescription: results from an Italian 30-year health records registry

Background Clozapine is the only approved medication for treatment-resistant schizophrenia which is equally prevalent on male and female patients. However, studies showed that clozapine is less frequently prescribed to women compared to men. Aims This study aims to investigate the role of sex in clozapine prescription, taking into account potential sociodemographic and clinical confounding factors. Methods Patients aged 18-65, with a diagnosis of schizophrenia spectrum disorders were selected from the 46,222 individuals who had access to outpatient psychiatric services of Ferrara, Italy, from 1991 to 2021. Sociodemographic and clinical information including clozapine prescription timing and dosage were analyzed. Results Among 3,901 patients with a schizophrenia spectrum disorders, those who had been prescribed clozapine (189, 4.8%) were significantly more likely to be male (57%), younger at admission to care (30 vs 39.7 years old) and with a schizophrenia diagnosis (77% vs. 49%) compared to those without clozapine prescription. Within patients with a diagnosis of schizophrenia (n=145), women (n=60, 41%), compared to men, experienced twice the delay to be prescribed clozapine, both from the prescription of the first antipsychotic to clozapine (mean 1265.7 vs 746.6 days in men, p=0.03) and from the prescription of the third antipsychotic to clozapine (mean 1214.5 vs 725.8 days in men, p=0.03). Also, within those diagnosed with schizophrenia, women with a diagnosis of schizophrenia were less likely than men to be prescribed clozapine after the first and third antipsychotic considering both crude (HR=0.66, p=0.07; HR=0.53, p=0.025) and adjusted hazard ratios (HR=0.65, p=0.07; HR=0.51, p=0.021). Conclusions This study showed disparities based on sex in both the use and timing of clozapine, which disadvantages women diagnosed with schizophrenia. Further interventions are needed to increase awareness of possible sex-based barriers to clozapine use in clinical practice, measurement of sources of gender specific bias, and quality improvement initiatives to continuously address challenges in providing adequate treatment to this vulnerable population.