Abstract: A total of 13 studies (4495 participants) were included in this review. Agomelatine was compared to selective serotonin reuptake inhibitors (SSRIs), namely paroxetine, fluoxetine, sertraline, escitalopram, and to the serotonin–norepinephrine reuptake inhibitor (SNRI), venlafaxine. Participants were followed up for six to 12 weeks. Agomelatine did not show any advantage or disadvantage over the other antidepressants for our primary outcome, response to treatment (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.95 to 1.08, P value 0.75 compared to SSRIs, and RR 1.06; 95% CI 0.98 to 1.16, P value 0.16 compared to venlafaxine). Also, agomelatine showed no advantage or disadvantage over other antidepressants for remission (RR 0.83; 95% CI 0.68 to 1.01, P value 0.07 compared to SSRIs, and RR 1.08; 95% CI 0.94 to 1.24, P value 0.73 compared to venlafaxine). Overall, agomelatine appeared to be better tolerated than venlafaxine in terms of lower rates of drop outs (RR 0.40; 95% CI 0.24 to 0.67, P value 0.0005), and showed the same level of tolerability as SSRIs (RR 0.95; 95% CI 0.83 to 1.09, P value 0.44). Agomelatine induced a lower rate of dizziness than venlafaxine (RR 0.19, 95% CI 0.06 to 0.64, P value 0.007). With regard to the quality of the body of evidence, there was a moderate risk of bias for all outcomes, due to the number of included unpublished studies. There was some heterogeneity, particularly between published and unpublished studies. The included studies were conducted in inpatient and outpatient settings, thus limiting the generalisability of the results to primary care settings. With regard to precision, the efficacy outcomes were precise, but the tolerability outcomes were mostly imprecise. Publication bias was variable and depended on the outcome of the trial. Our review included unpublished studies, and we think that this reduced the impact of publication bias. The overall methodological quality of the studies was not very good. Almost all of the studies were sponsored by the pharmaceutical company that manufactures agomelatine (Servier), and some of these were unpublished. Attempts to contact the pharmaceutical company Servier for additional information on all unpublished studies were unsuccessful. Agomelatine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. Agomelatine was better tolerated than paroxetine and venlafaxine in terms of overall side effects, and fewer participants treated with agomelatine dropped out of the trials due to side effects compared to sertraline and venlafaxine, but data were limited because the number of included studies was small. We found evidence that compared agomelatine with only a small number of other active antidepressive agents, and there were only a few trials for each comparison, which limits the generalisability of the results. Moreover, the overall methodological quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning the efficacy and tolerability of agomelatine.

Plain-language summary: The review included trials comparing agomelatine with a group of antidepressants called selective serotonin reuptake inhibitors (SSRIs), and one antidepressant from the serotonin–norepinephrine reuptake inhibitor group, called venlafaxine. Participants in the studies were followed up for between six to 12 weeks. - Agomelatine was no more or less effective in reducing symptoms of depression than any of the other antidepressants. - Agomelatine was no more or less effective in preventing relapse of depression than any of the other antidepressants. - Agomelatine was tolerated better than venlafaxine (fewer people discontinued treatment), but the same as the SSRIs. - Agomelatine caused a lower rate of dizziness than venlafaxine. - Agomelatine caused a lower rate of vomiting, nausea and sexual side-effects than SSRIs. The reviewers conclude that agomelatine is not more effective than other antidepressants currently on the market. It did seem to be more tolerable to patients in terms of lower rates of some side-effects, however, the quality of trials was low and there were only a few trials that compared agomelatine with each medication. No firm conclusion on agomelatine can be made because of problems with reporting of data in the trials included. The authors recommend that further trials of agomelatine versus placebo (dummy pill), particularly in primary care settings (where the majority of patient/practitioner contact take place, e.g. GP surgeries), should be carried out to improve the quality of evidence.