This study focused on the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, rs6311 polymorphisms to investigate possible correlations between resistance to antipsychotic agents and genotypes in a real-world sample of patients affected by various difficult-to-treat mental disorders. This evidence concerns the gene DRD2 and mental disorder.