Sustained efficacy of agomelatine 10 mg, 25 mg, and 25-50 mg on depressive symptoms and functional outcomes in patients with major depressive disorder. A placebo-controlled study over 6 months.

This randomized placebo-controlled "dose relation study" was conducted in patients who met criteria for major depressive disorder, to evaluate the efficacy and safety of agomelatine during 24 weeks at 3 doses (i) low fixed dosage (10 mg/day, n=100 patients entered the extension period), (ii) fixed dosage (25 mg/day, n=111) and (iii) a flexible dosage with up-titration in case of insufficient improvement at week 2 (25-50 mg/day, n=115) versus placebo (n=85). Mood was evaluated using the Hamilton rating scale for depression (HAM-D17) and Clinical Global Impression (CGI) scale. The functional status was examined with the Sheehan Disability Scale (SDS). At last post-baseline assessment, there were significant placebo-agomelatine differences on mean HAM-D17 total scores in favour of each agomelatine dose regimen (4.51±1.06 points, p<0.0001 at 10 mg; 7.74±1.05 points, p<0.0001 at 25 mg and 7.72±1.05 points, p<0.0001 at 25-50 mg). The response rate according to HAM-D17 was significantly higher in patients taking agomelatine than those taking placebo (difference of 21.8% at 10mg p<0.001; 36.4% and 35.4% respectively at 25 mg and 25-50 mg, p<0.0001). The remitter rate was significantly higher in patients taking agomelatine than those taking placebo (difference of 16.7% at 10 mg p=0.003; 33.8% and 35.4% respectively at 25 mg and 25-50 mg, p<0.0001). The effects of agomelatine were corroborated by CGI scores. Agomelatine improved symptom-related functional impairment on all domains of the SDS scale for the fixed dose 25 mg, and the one step titration 25-50 mg dose regimen. Similar findings were obtained for all measures in the subgroup of severely depressed patients. All dose regimens of agomelatine were well tolerated and no unexpected adverse event was reported. Long term agomelatine treatment improves both mood symptoms and social and occupational functioning of moderately to severely depressed patients. There is a dose effect between 10 mg and higher dose regimens of agomelatine. The threshold dose of 25 mg for initiating treatment can be maintained over 6 months in depressed patients.

A placebo-controlled study of three agomelatine dose regimens (10 mg, 25 mg, 25-50 mg) in patients with major depressive disorder.

A randomised placebo-controlled "dose relation study" was conducted in 549 patients who met the criteria for major depressive disorder, to evaluate the efficacy and safety of three doses regimens of agomelatine during 6 weeks: low fixed dosage (10 mg/day, n=133), fixed dosage (25 mg/day, n=138) and a flexible dosage with up-titration in case of insufficient improvement at week 2 (25-50 mg/day, n=137). At last post-baseline assessment, there were significant and incremental placebo-agomelatine differences on mean HAM-D17 total scores in favour of each agomelatine dose regimen (2.46 ± 0.76 points, p=0.001 at 10 mg; 4.71+0.75 points, p<0.0001 at 25 mg and 4.92 ± 0.76 points, p<0.0001 at 25-50 mg) with statistically significant differences between 25 mg and 25-50 mg dose regimens compared to the 10 mg dose. The response rate according to HAM-D17 was significantly higher in patients taking agomelatine than those taking placebo (difference of 16.1% at 10 mg p=0.005; 25.9% and 27.4% respectively at 25 mg and 25-50 mg, p<0.0001). The benefit of agomelatine was demonstrated in the subgroup of severely depressed patients in the 25 mg and 25-50 mg/day regimens. Consistent clinical response according to CGI variables and better social functioning were found in patients receiving agomelatine. All dose regimens of agomelatine were well tolerated and no unexpected adverse event was reported. This study provides evidence of a dose effect for agomelatine between 10 mg and the therapeutic dose regimen of agomelatine 25-50 mg: the efficacy of the higher dose regimens being more efficacious than the lowest (10 mg) daily dose. The data support a definitive statement regarding the utility of 25 mg as the threshold dose for initiating agomelatine in depressed patients.

Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial.

In the present randomized, controlled, double-blind trial (12 wk treatment plus double-blind extension for 12 wk), 25-50 mg/d agomelatine (n = 164) and 10-20 mg/d escitalopram (n = 160) were compared for short- and long-term efficacy, subjective sleep and tolerability. The effects of these drugs on emotional experiences were also compared in patients having completed the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants (agomelatine: n = 25; escitalopram: n = 20). Agomelatine and escitalopram similarly improved depressive symptoms, with clinically relevant score changes over 12 and 24 wk and notable percentage of remitters (week 12: 60.9 and 54.4%; week 24: 69.6 and 63.1% respectively). Over the 12 and 24-wk treatment periods, the 'global satisfaction on sleep' scores increased in both treatment groups and did not differ between groups. Satisfaction with sleep-wake quality was high in both groups; the 'wellness feeling on waking' was more improved with agomelatine than with escitalopram (p = 0.02). In patients with pronounced sleep complaints, quality of sleep and feeling on waking were significantly more improved with agomelatine than with escitalopram (p = 0.016 and p = 0.009, respectively). Emotional blunting was less frequent on agomelatine than on escitalopram. Indeed, 28% of patients on agomelatine vs. 60% on escitalopram felt that their emotions lacked intensity and 16% of patients on agomelatine vs. 53% on escitalopram felt that things that they cared about before illness did not seem important any more (p = 0.024). The tolerability profile of agomelatine was found to be superior to that of escitalopram and the incidence of patients with at least one emergent adverse event leading to treatment discontinuation was lower in the agomelatine group than in the escitalopram group (5.5 vs. 10.6%). The findings suggest that agomelatine displays additional long-term clinical benefits on sleep-wake quality and emotional experiences over escitalopram in the management of depression.