Trazodone received U.S. Food and Drug Administration (FDA) approval in 1981 as a treatment for major depressive disorder (MDD). Its novel triazolopyridine chemical structure distinguished it from the tricyclic antidepressants (TCAs), and clinical trials suggested an improved safety and tolerability compared with TCAs. There were high expectations that it would replace the older drugs as a mainstay of treatment for depression. However, the extreme sedation associated with trazodone, even at subtherapeutic doses, limited the clinical effectiveness of the drug. However, its soporific properties made trazodone a favorite alternative to standard hypnotics as a sleep-inducing agent. Unlike conventional sleeping pills, trazodone is not a controlled substance.

In 2010, the U.S. FDA approved an extended-release, once-daily formulation (Oleptro) as a treatment for MDD in adults. In the trial leading to the approval of the extended-release formulation, the most common adverse events were somnolence or sedation, dizziness, constipation, and blurred vision. Surprisingly, only 4 percent of patients in the trazodone group discontinued treatment because of somnolence or sedation. If the low incidence of these side effects is confirmed in real-world practice, trazodone may get another chance to prove itself as an effective antidepressant, especially because its side effect profile is so different from that of the selective serotonin reuptake inhibitors.