Targeted Comprehensive Screening of Neuropsychiatric Drugs in Serum by LC-MS/MS: Method Development and Three-Year Clinical Utility

Background: The increasing prevalence of neuropsychiatric medication misuse highlights the critical need for efficient drug screening in clinical laboratories. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) application for broad serum drug screening remains limited in many clinical settings. Serum analysis is particularly valuable for identifying current drug exposure, confirming the cause of intoxication, and monitoring patient medication adherence. Purpose: This study aimed to develop and validate an LC-MS/MS method using multiple reaction monitoring followed by information-dependent acquisition-triggered enhanced product ion scans for the simultaneous qualitative identification of 77 neuropsychiatric drugs, and to present its large-scale clinical application over three years. Methods: Validation included precision, accuracy, recovery, matrix effects, selectivity, and interference. A minimal serum volume (20 μL) underwent simple protein precipitation, with preparation time under 15 minutes per batch. This method was applied to 1,021 clinical serum specimens. Results: Chromatographic separation was completed in 15 minutes. The precisions (CV) for calculated concentrations and retention times were < 30% and < 1.5%, respectively. Accuracy was assessed for 60 of the 77 analytes (100% agreement). Mean recovery and matrix effects were 93.1% and 99.9%, respectively. Most test orders originated from psychiatry and neurology outpatients. Although fewer orders came from the Department of Emergency Medicine (EM), the EM patients exhibited a higher positivity rate. The most frequently detected drug classes were benzodiazepines (37.9%), antidepressants (30.7%), and antipsychotics (19.7%). Common specific analytes included clonazepam/7-aminoclonazepam (10.2%) and lorazepam (10.0%). Conclusion: We developed and validated a LC-MS/MS method for the simultaneous detection of a wide range of neuropsychiatric drugs. The method proved essential for verifying medication history, identifying non-adherence, and diagnosing acute intoxication. Our findings highlight the critical role of broad-spectrum serum screening in managing medication-related emergencies and optimizing long-term therapeutic care.