Rapid On-Site Analysis of Psychotropic Drugs in Dried Blood Spots by Capillary-in-Capillary Electrospray Ionization (DBS-CC-ESI) Miniature Mass Spectrometry

Therapeutic drug monitoring (TDM) of psychotropic agents is essential for optimizing therapeutic efficacy and minimizing adverse effects. However, conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) workflows are poorly suited for point-of-care applications due to labor-intensive sample preparation, prolonged turnaround times, and dependence on centralized analytical laboratories. Here, we present a rapid, on-site analytical platform that integrates dried blood spot (DBS) sampling with a modified capillary-in-capillary electrospray ionization (CC-ESI) source coupled to a miniature mass spectrometer (mini-MS). The sampling capillary was re-engineered as a disposable polypropylene microtube capable of accommodating a DBS punch and extraction solvent, thereby enabling fully integrated online extraction, ionization, and mass analysis within minutes. Critical parameters, including infrared drying duration and extraction solvent composition, were systematically optimized. The method demonstrated excellent linearity (R² > 0.95) and precision for six widely prescribed psychotropic drugs: diazepam, flurazepam, clozapine, zolpidem, risperidone, and methaqualone. Analytical performance was comparable to that achieved using conventional solid-phase extraction, yet sample preparation time was reduced from several hours to mere minutes. Clinical utility was preliminarily demonstrated by the successful detection and confirmation of clozapine and aripiprazole in blood samples from patients receiving long-term pharmacotherapy. This DBS-CC-ESI-mini-MS platform represents a promising advance toward decentralized TDM of psychotropic drugs, offering minimal invasiveness, operational simplicity, and rapid, reliable quantitative capability.