Combinations of antidepressants with both serotonergic and noradrenergic activity may be especiallyeffective and thus useful in treating refractory patients and severely depressed patients. In the current report,studies of combinations of serotonin selective reuptake inhibitors (SSRIs) and noradrenergic tricyclicsor of SSRIs and bupropion are reviewed, and practical issues pertaining to their use are discussed.