Development and application of an LC-MS/MS method for the determination of 15 antipsychotic and 15 psychotic drugs and metabolites in plasma

Antipsychotic drugs play a critical role in the treatment of schizophrenia and related psychiatric disorders. However, their therapeutic effects and adverse reactions vary significantly due to individual metabolic differences and drug-drug interactions (DDIs) as well as genetic polymorphisms in drug-metabolizing enzymes. Although, therapeutic drug monitoring (TDM) is essential for optimizing treatment outcomes, TDM for most antipsychotics remains underutilized in Japan. This study builds upon our previous research, which developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the simultaneous analysis of 15 antipsychotics, 15 psychiatric drugs and 4 active metabolites. The method was optimized for sensitivity, reproducibility, and accuracy by selected reaction monitoring transitions and optimizing gradient elution parameters. Validation followed FDA bioanalytical guideline, demonstrating excellent linearity (R² > 0.98), intra- and inter-day precision (<15% RSD for 87% compounds), and acceptable matrix effects. Stability tests revealed variable degradation patterns among certain analytes, necessitating further refinements. Application of this method to plasma samples from patients with schizophrenia revealed significant inter-individual variability in drug concentrations. Some patients exhibited plasma levels outside the therapeutic range, highlighting the clinical necessity of TDM. By integrating a broader range of psychotropic drugs, this study extends our previous findings and enhances clinical decision-making in psychiatric pharmacotherapy. The developed LC-MS/MS method enables rapid, same-mode quantification suitable for real-time clinical use and provides a valuable tool for assessing the impact of DDIs and optimizing therapeutic strategies in schizophrenia. • A simultaneous LC–MS/MS method for 30 psychotropic drugs was developed. • The developed method showed acceptable sensitivity, precision, and accuracy. • The stability characteristics of multiple analytes were systematically evaluated. • The method was successfully applied to plasma samples from schizophrenia patients.