Wastewater screening analysis for the determination of pharmaceutical drugs belonging to different classes, with particular focus on psychotropic drugs and their metabolites. Wastewater based epidemiology (WBE) recently emerged as an essential and complementary methodology for the evaluation of pharmaceutical and illicit drugs prevalence, by means of quantification of either the parent drugs or their human-specific metabolites in wastewater. Furthermore, water pollution by pharmaceutical drugs is becoming an unavoidable environmental issue of emerging concern, making the water quality monitoring crucial to safeguard its healthy supply to citizens. The most commonly used pharmaceuticals include non-steroidal anti-inflammatory drugs, cardiovascular drugs, anti-depressant and antipsychotic drugs; their Active Pharmaceutical Ingredients (APIs) and some of their metabolites are known to partially survive the conventional process of wastewater treatment. Our study involves a wide screening analysis on wastewater samples entering and leaving various purification plants in the Piedmont region (Italy) to identify the prevalent pharmaceutical drugs and metabolites present in it and so to provide important information about the diffusion of compounds of toxicological interest. A total of 140 target compounds (pharmaceuticals of various therapeutic classes, benzodiazepines and some of their metabolites) were investigated in wastewater samples using only 30 mL aliquots instead of the typical 500 mL reported in the literature. The filtered samples (0.22 μm filters) were extracted and purified by SPE and subsequently 5 μL of the concentrated samples was analyzed with UHPLC-QTOF-HRMS and UHPLC-MS/MS protocols. Thanks to the combined use of the two instruments, a full scan on the exact mass and MS/MS fragmentation data were collected for parent drugs and their main metabolites. 61 out of 119 targeted pharmaceutical drugs and 6 out of 21 targeted metabolites of psychotropic pharmaceutical drugs were detected over a wide concentration interval, ranging from ng/L to μg/L. The highest concentration was 62 μg/L detected for paracetamol. The classes of antidepressants, benzodiazepines, antiepileptics, and antipsychotic required particular attention as they are known to be harmful to aquatic flora and fauna. Among these, citalopram (mean concentration 25.8 ng/mL), lorazepam (mean concentration 32.2 ng/mL), trazodone (mean concentration 17.0 ng/mL) and carbamazepine (mean concentration 134 ng/mL) were detected in both the purifier's affluent and effluent waters. Since some environmental studies have shown that carbamazepine is one of the most frequently detected drugs in wastewater treatment plants, the presence of its main metabolites was explored. In particular, the presence of 10,11-dihydro-10-hydroxycarbamazepine, 10,11-dihydro-10,11-dihydroxycarbamazepine, oxarbamazepine and 10,11-dihydro-10,11-epoxycarbamazepine was revealed. The latter compound (approximately three times more concentrated than carbamazepine) proved to possess antiepileptic properties similar to carbamazepine, possibly producing neurotoxic effects. A reliable wastewater method of analysis involving a low sample volume, its SPE purification, and UHPLC-QTOF-HRMS and UHPLC-MS/MS targeted detection was developed for the simultaneous determination of 119 pharmaceutical drugs and 21 metabolites. The collected data are consistent with those available in the literature and confirm that many pharmaceutical drugs are present in wastewater at a level that pose some risk to flora and fauna, taking into account also the health issues associated with long-term simultaneous exposure to a large number of pharmaceutical products. In conclusion, wastewater surveillance is essential not only to identify the pharmaceutical drugs used in the area but also to monitor the purity of waters. In the future, analyses will be carried out to study the variation in the substances (including NPS) found over time and in the different territories at both intra- and inter-regional levels.