Longitudinal trends in blood concentrations of clozapine and norclozapine, inflammatory markers, and clinical outcomes in Japanese patients: a 12-week prospective study

Introduction: Clozapine (CLZ) is the gold standard for treatment-resistant schizophrenia (TRS), but its use in Japan is limited by strict monitoring and titration-phase adverse events. This prospective 12-week study evaluated longitudinal trends in CLZ/norclozapine (NCLZ) levels, inflammatory markers, metabolic indices, and psychiatric symptoms. Methods: Twenty-one inpatients with TRS were analyzed. To focus on standard titration, patients with inflammatory symptoms (e.g., fever) requiring discontinuation were excluded. Serum CLZ and NCLZ were measured weekly via LC-MS/MS. Clinicians were blinded to these levels; dosing was guided solely by clinical observation. IL-6, HOMA-IR, TG/HDL-C ratios, and PANSS scores were assessed at baseline and designated intervals. Results: CLZ and NCLZ concentrations increased throughout the 12-week period. Significant sex differences emerged in CLZ concentration-to-dose (C/D) ratios, with females exhibiting significantly higher levels than males starting at week 2 (p < 0.05). While positive symptoms significantly improved (p < 0.05), no specific longitudinal correlations were found between CLZ/NCLZ levels and changes in IL-6, metabolic indices, or total PANSS scores. Discussion: A "start low, go slow" titration approach can effectively achieve therapeutic concentrations even without real-time therapeutic drug monitoring. However, the significantly higher concentrations observed in female subjects suggest that more cautious dose titration is necessary for female patients, likely due to hormonal influences on metabolic enzymes. Further research is needed on the relationship between clozapine dosage, plasma concentrations and inflammatory side effects.