The aim of the study was to develop a LC-MS-MS method able to detect and quantify a number of frequently prescribed antipsychotic and antidepressant drugs for toxicological purposes. Separation of compounds was performed on a C-18 RP column by Ultra High-Pressure Chromatography over a 11 min run. A modified single step QuEChERS protocol consisted essentially by the addition of acetonitrile, potassium carbonate and magnesium sulfate in 100 μL of sample, vortexing, centrifugation and evaporation has been selected. The method achieves satisfactory recoveries for 15 psychotropic drugs with a mean R% of 85% and provides efficient purification of the sample from endogenous interferences, simplicity and short sample handling times. The method was validated and provided satisfactory accuracy with recoveries ranging from 85 to 113% and precision with CV ranging from 1.2 to 13.2%. LODs were determined to be from 0.0003 to 0.017 μg/mL while LOQs were from 0.001 to 0.05 μg/mL for the 15 drugs. Matrix effect was below 20% and the analytes were stable in the matrix for 3 weeks. The method proved to be suitable for both analysis of clinical samples for Therapeutic Drug Monitoring and antemortem or postmortem whole blood samples of forensic cases. A number of samples with clinical and forensic interest were successfully analyzed demonstrating the effectiveness of QuEChERS in this field.