CYP2D6 PMs have higher plasma concentrations of the parent drug than EMs and are, therefore, more likely to experience dose-dependent adverse drug reactions. In 50 psychiatric patients receiving amitriptyline 150 mg/d, carriers of two functional CYP2D6 alleles (EMs) had a significantly lower risk of side effects than IM (12.1% vs. 76.5%). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele. The combination of normal (fast) CYP2C19 and slightly diminished CYP2D6 function leads to high concentrations of toxic intermediate metabolites and an increase of adverse events. On the other hand, CYP2D6 UMs may be at risk for sub-therapeutic concentrations resulting in poor therapeutic response. Thus, genetically determined differences in blood concentrations of antidepressants make dose adjustments advisable. However, these findings and dose recommendations have only been evaluated for psychiatric patients and no investigation on antidepressants as low-dosed co-analgesics are available up to now.