Abstract
Background/Objectives: Therapeutic drug monitoring (TDM) of antipsychotic medications plays an important role in optimizing treatment efficacy, reducing adverse effects, and supporting adherence. While Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) has long been the gold standard for antipsychotic quantification, recent advances in automated platforms and microsampling raise questions about its current clinical practicality. This systematic review evaluated the clinical applicability and analytical performance of UHPLC-based methods for monitoring antipsychotic drugs, focusing on precision, recovery, matrix effects, and suitability across various biological matrices. Methods: A systematic search of PubMed, Scopus, and Web of Science was conducted for studies published between 2013 and 2024 involving UHPLC-based quantification of antipsychotics in clinical samples from adult patients. Data on analytical parameters, sample matrices, and study characteristics were extracted. A custom quality checklist was used to assess methodological rigor. In addition to qualitative synthesis, non-traditional quantitative approaches were applied, including descriptive aggregation of recovery, matrix effects, and precision across studies, as well as correlation analyses to explore relationships among performance parameters. Results: Twelve studies were included, spanning a range of typical and atypical antipsychotics and metabolites. Plasma and serum demonstrated the highest analytical reliability (recovery >90%, minimal matrix effects), while dried blood spots (DBSs), whole blood, and oral fluid showed greater variability. Clinically, UHPLC-MS/MS enabled more accurate dose adjustments and identification of non-adherence, outperforming immunoassays in sensitivity, specificity, and metabolite detection. Microsampling methods showed promise for outpatient and decentralized care but require further clinical validation. Conclusions: UHPLC-MS/MS remains the most robust and reliable method for TDM of antipsychotics, especially when quantification of active metabolites is required. While logistical barriers remain, technological advances may enhance feasibility and support broader integration into routine psychiatric care.