A simple and rapid LC-MS/MS method for the simultaneous determination of eight antipsychotics in human serum, and its application to therapeutic drug monitoring

A simple and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and used to determine eight antipsychotics (aripiprazole, clozapine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) in human serum for practical clinical usage. Stable isotope-labeled internal standards were used for all drugs to compensate for method variability, including matrix effects, ion extraction and ionization variations. Samples were prepared by simple protein precipitation with methanol. Chromatographic separation was accomplished in less than 3.3 min on a KINTEX C18 column (50 mm × 3.0 mm, 5 μm) using a gradient elution of 2 mM aqueous ammonium formate and methanol at a flow rate of 0.5 mL/min. Quantification was performed by multiple reaction monitoring (MRM) in the positive mode. The method was fully validated according to the latest recommendations of international guidelines. The correlation coefficients of calibration curves were all greater than 0.9945. Internal standard-normalized matrix effects ranged from 96.3% to 115%, and extraction recoveries were between 88.1% and 107%. Coefficients of variation ranged from 1.82 − 13.5% for intra-day precision, 5.69–14.7% for inter-day precision, and the relative error for accuracy did not exceed ± 13.5% for any analyte. The method was successfully applied to routine clinical therapeutic drug monitoring for 2,173 samples.