Pharmacological treatment of depression in old age is associated with an increased risk of adverse pharmacokinetic and pharmacodynamic drug interactions. Elderly patients may have multiple disease states and, therefore, may require a variety of other drugs. In addition to polypharmacy, other factors such as age-related physiological changes, diseases, genetic constitution and diet may alter drug response and, therefore, predispose elderly patients to adverse effects and drug interactions. Antidepressant drugs currently available differ in their potential for drug interactions. In general, older compounds, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), have a higher potential for interactions than newer compounds, such as selective serotonin reuptake inhibitors (SSRIs) and other relatively novel agents with a more specific mechanism of action. In particular, TCAs and MAOIs are associated with clinically significant pharmacodynamic interactions with many medications frequently prescribed to elderly patients. Moreover, TCAs may be susceptible to pharmacokinetic interactions when given in combination with inhibitors or inducers of the cytochrome P450 (CYP) isoenzymes involved in their metabolism. Because of a more selective mechanism of action, newer antidepressants have a low potential for pharmacodynamic drug interactions. However, the possibility of the serotonin syndrome should be taken into account when drugs affecting serotonergic transmission, such as SSRIs, venlafaxine or nefazodone, are coadministered with other serotonergic agents. Newer agents have a differential potential for pharmacokinetic interactions because of their selective effects on CYP isoenzymes. Within the group of SSRIs, fluoxetine and paroxetine are potent inhibitors of CYP2D6, while fluvoxamine predominantly affects CYP1A2 and CYP2C19 activity. Therefore, these agents should be closely monitored or avoided in elderly patients treated with substrates of these isoforms, especially those with a narrow therapeutic index. On the other hand, citalopram and sertraline have a low inhibitory activity on different drug metabolising enzymes and appear particularly suitable in an elderly population. Among other newer antidepressants, nefazodone is a potent inhibitor of CYP3A4 and its combination with substrates of this isoform should be avoided.