Methodological Optimization and Clinical Application Value Analysis of LC-MS/MS for Monitoring Antipsychotic Blood Concentrations

Objective: To address the problems of cumbersome pretreatment, low detection efficiency and insufficient coverage of some drugs in clinical monitoring of antipsychotic blood concentrations, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was systematically optimized. Its analytical performance was validated, and its application value in personalized treatment of psychiatric disorders was explored, aiming to provide a standardized technical solution for therapeutic drug monitoring (TDM) in primary healthcare institutions. Methods: Five commonly used clinical antipsychotics—haloperidol, amisulpride, olanzapine, clozapine, and perphenazine—were selected as target analytes. The sample pretreatment process (precipitant ratio, centrifugation conditions, and injection volume) was optimized, along with the chromatographic gradient elution program and mass spectrometry ion source parameters, to establish an optimized LC-MS/MS method. Comprehensive validation was performed according to the guiding principles of Section 9012, Part IV of the 2020 Chinese Pharmacopoeia, assessing selectivity, linearity, precision, accuracy, matrix effect, and stability. For samples exceeding the validated linear range (10 - 250 ng·mL^？1), serial dilution (2- to 5-fold) with blank serum was performed before reanalysis, and the final concentration was calculated by multiplying the detected value by the corresponding dilution factor A total of 100 patients with schizophrenia prospectively enrolled in The Second People’s Hospital of Baise from January to December 2025 were included, who received monotherapy with haloperidol, amisulpride, olanzapine, clozapine, or perphenazine (20 patients per group). All patients were excluded from smoking history, hepatic or renal impairment, and concomitant use of CYP450 enzyme modulators. Medication adherence was verified by outpatient follow-up, medication records and the trend of blood drug concentrations. The optimized method was used to determine the steady-state trough serum concentrations in the morning before medication after 4 weeks of treatment. According to the AGNP 2011 guidelines and the serum matrix-adapted quantitative therapeutic windows (haloperidol 50 - 150 ng·mL^？1, amisulpride 80 - 200 ng·mL^？1, olanzapine 20 - 80 ng·mL^？1, clozapine 350 - 600 ng·mL^？1, perphenazine 4 - 12 ng·mL^？1), patients were stratified into three groups: within the therapeutic