Cumulative anticholinergic burden is associated with lower clozapine metabolic ratios: a cross-sectional study

Clozapine is the most effective treatment for treatment-resistant schizophrenia, yet substantial interindividual variability in serum concentrations complicates dose optimization and therapeutic drug monitoring. While factors such as smoking and inflammation are known to influence clozapine metabolism, a substantial portion of the variability remains unexplained. Anticholinergic burden, reflecting cumulative exposure to anticholinergic medications, may be a clinically relevant yet underexplored factor associated with pharmacokinetic variability. This retrospective cross-sectional study included 93 patients diagnosed with schizophrenia spectrum and other psychotic disorders according to DSM-5 and receiving clozapine treatment at a tertiary psychiatric center. Serum clozapine and norclozapine concentrations were obtained under routine clinical conditions and used to calculate clozapine metabolic ratios, including the concentration-to-dose (C/D) ratio (serum concentration divided by daily dose) and the clozapine/norclozapine (C/N) ratio (serum clozapine concentration divided by serum norclozapine concentration). Anticholinergic burden was quantified using the Anticholinergic Cognitive Burden calculator. Clinical variables, including age, sex, smoking status, C-reactive protein, and neutrophil-to-lymphocyte ratio, were extracted from medical records. Associations between clinical variables and clozapine metabolic ratios were assessed using Spearman correlation analyses, and factors independently associated with metabolic ratios were identified using multivariate linear regression models. The mean anticholinergic burden score was 2.67 ± 2.02, and 52.7% of patients had clinically significant anticholinergic burden (≥ 3). Higher anticholinergic burden was significantly associated with lower concentration-to-dose ( r = − 0.349, p = 0.001) and clozapine/norclozapine ratios ( r = − 0.429, p < 0.001). In multivariate regression analyses, anticholinergic burden remained independently associated with lower clozapine/norclozapine (β = −0.400, p < 0.001) and concentration-to-dose ratios (β = −0.334, p = 0.001). Smoking was independently associated with lower concentration-to-dose ratio (β = −0.230, p = 0.038), but not with clozapine/norclozapine ratio. Other variables, including age, sex, C-reactive protein abnormality, and neutrophil-to-lymphocyte ratio, were not significant predictors. Cumulative anticholinergic burden was independently associated with lower clozapine metabolic ratios in routine clinical practice. These findings suggest that anticholinergic burden may serve as a clinically accessible and practical indicator associated with variability in clozapine exposure and may aid in the interpretation of therapeutic drug monitoring. Further prospective studies are needed to clarify underlying mechanisms.