Depression, the most common mental health problem of the elderly, is often under-diagnosed and under-treated. As patients age, antidepressant pharmacologic treatment becomes more complicated due to an increased risk of adverse drug events. These risks are associated with age-related physiological changes and individual variability in drug metabolism related to several factors, the most frequent of which is polymedication as a result of coexisting chronic illnesses. Comedications induce drug interactions that depend on the patient's metabolic capacity linked to the genetically determined cytochrome P450 enzyme (CYP450) function. The effect of some isoenzyme polymorphism on the pharmacokinetics of many antidepressants and other psychotropic drugs is well characterized. The author approaches successively the notions of the cytochrome P450 (2D6), its role in the drug biotransformation, and the importance of knowing its substrates, inhibitors and inducers in order to predict drug interactions. The clinical significance of this notion, and the help that could be given by genotyping and phenotyping, are also explained. The author's experience on the relation between drug side effects and patient metabolic status, and on the antidepressant interactions with fluoxetine, fluvoxamine and citalopram, is given in order to rationalize and individualize antidepressant choice in elderly.