Robert H Howland

This article describes the pharmacology of the novel atypical antidepressant drug agomelatine, critically reviews and evaluates its clinical use for the treatment of major depression, and suggests areas for further research. Agomelatine is a synthetic analog of the hormone melatonin. It stimulates the activity of melatonin MT1 and MT2 receptors and inhibits the activity of serotonin 5HT-2C receptor subtypes. Three acute trials demonstrated clinically modest, but statistically significant benefits over placebo. Three acute trials did not find agomelatine more effective than placebo. A meta-analysis of these six trials demonstrated a small, statistically significant, marginally clinically relevant difference between agomelatine and placebo. The only placebo-controlled study in elderly patients did not demonstrate a significant benefit for agomelatine. It was more effective than placebo in only one of two relapse prevention studies. Agomelatine was generally well tolerated compared to placebo. Its side-effect profile is different than and compares favorably to other antidepressant drugs. The overall tolerability of agomelatine in head-to-head comparisons was not substantially better than active drug comparators. Agomelatine is contraindicated in patients with impaired liver function and in patients taking drugs that potently inhibit CYP-1A2 metabolic enzymes. Because elevated liver enzymes are common, and there is a rare risk of more serious liver reactions, routine laboratory monitoring of liver function is recommended periodically throughout treatment. Agomelatine does not have clinically significant advantages compared to other antidepressant drugs, and it has certain limitations and disadvantages. Because of its unique pharmacology and relatively benign tolerability profile, however, it may be a useful alternative for patients who do not respond to or cannot tolerate other antidepressant drugs.