[11][2] Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder.

[9][14] In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed agomelatine to be one of the most effective and one of only two medications found to be more tolerable than placebo.

[16] Controlled studies in humans have shown that agomelatine is at least as effective as the SSRI antidepressants paroxetine, sertraline, escitalopram, and fluoxetine in the treatment of major depression.

[10] However, the body of research on agomelatine has been substantially affected by publication bias, prompting analyses which take into account both published and unpublished studies.

[9][18][19] These have confirmed that agomelatine is approximately as effective as more commonly used antidepressants (e.g. SSRIs), but some qualified this as "marginally clinically relevant",[19] being only slightly above placebo.

[2] It has been found more effective than placebo in the treatment of in a number of short-term double-blind placebo-controlled studies and in long term relapse prevention.

[12] It is not recommended in Europe or Australia for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

[11] According to information disclosed by Servier in 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the European Medicines Agency.

Inhibitors of these enzymes, e.g. the SSRI antidepressant fluvoxamine, reduce its clearance and can lead to an increase in agomelatine exposure, and possibly serotonin syndrome .

[35] By antagonizing the serotonin 5-HT2C receptor, agomelatine has been found to disinhibit and increase norepinephrine and dopamine release in the frontal cortex in animals, although notably not in the striatum or nucleus accumbens.

[35][38][36] In contrast to agomelatine, other serotonin 5-HT2C receptor antagonists and inverse agonists, such as SB-242084 and SB-206553, have been found to increase dopamine and norepinephrine levels in the nucleus accumbens.

[35] Although agomelatine is widely claimed to act as a serotonin 5-HT2C receptor antagonist, the clinical significance of this action has been disputed by some researchers.

[42] Unlike with other serotonin 5-HT2C receptor antagonists, therapeutic doses of agomelatine fail to acutely increase slow-wave sleep in humans.

Agomelatine has been found to resynchronize circadian rhythms in animal models of delayed sleep phase syndrome (DSPS).

[45] In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin onset.

In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax.

[55] It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012.