The safety of agomelatine in standard medical practice in depressed patients: A 26-week international multicentre cohort study.

OBJECTIVE: The present observational cohort study documented the safety of agomelatine in current medical practice in out-patients suffering from major depressive disorder. METHOD: The 6-month evolution of agomelatine-treated patients was assessed with a focus on safety (emergent adverse events, liver acceptability), severity of depression using the Clinical Global Impression Severity (CGI-S) score, and functioning measured by the Sheehan Disability Scale (SDS). RESULTS: A total of 8453 depressed patients from 761 centres in 6 countries were analysed (female: 67.7%; mean age: 49.1 ± 14.8 years). Adverse events reported were in accordance with the known safety profile of agomelatine. Cutaneous events were reported in 1.7% of the patients and increased hepatic transaminases values were reported in 0.9 % of the patients. The incidence of events related to suicide/self-injury was 1.0%. Two completed suicides, not related to the study drug, were reported. CGI-S total scores and SDS sub-scores improved and numbers of days lost or underproductive decreased over the treatment period. CONCLUSIONS: In standard medical practice, agomelatine treatment was associated with a low incidence of side effects. No unexpected events were reported. A decrease in the severity of the depressive episode and improved functioning were observed. TRIAL REGISTRATION NAME: Observational cohort study to evaluate the safety of agomelatine in standard medical practice in depressed patients. A prospective, observational (non-interventional), international, multicentre cohort study. TRIAL REGISTRATION NUMBER: ISRCTN53570733.

Agomelatine in Standard Medical Practice in Depressed Patients: Results of a 1-Year Multicentre Observational Study In France.

BACKGROUND AND OBJECTIVES: Non-interventional studies are a valuable source of evidence that is complementary to traditional randomised, blinded and controlled clinical trials, for evaluating antidepressants in a real-world setting. The aim of the present study was to document the use of agomelatine in current medical practice and evaluate its effectiveness and safety in outpatients prescribed agomelatine to treat their current depressive episode. METHODS: This 12-month observational French study included patients initiating agomelatine treatment. The intensity and severity of depression were assessed using the 17-item Hamilton Depression Rating Scale (HAM-D17) total score and the Clinical Global Impression-Severity of Illness (CGI-S) scale. Patients' quality of life and functioning were measured using the Quality of Life in Depression Scale and the Sheehan Disability Scale, respectively. The safety measures included emergent adverse events and biological samplings, with a focus on liver acceptability. RESULTS: A total of 1484 patients (70% of women; 49.6 ± 15.4 years of age) were enrolled in the study. Most patients (62.3%) were treated with agomelatine for at least 6 months and 28.8% were treated for at least 1 year. Mean HAM-D17 total score and mean CGI-S scores decreased by 13.6 ± 8.1 and 2.1 ± 1.5 points, respectively, from baseline to last visit on agomelatine. Rates of responders (i.e. with a decrease in HAM-D17 total score by at least 50%) and remitters (HAM-D total score < 7) at the last visit were 90.7% and 56.0%, respectively. The mean HAM-D total score decreased after agomelatine withdrawal (- 4.1 ± 6.7) until the last visit. The quality of life and daily functioning of patients improved, while the numbers of days lost and underproductive days decreased over the follow-up period. Safety findings were in accordance with the known information regarding agomelatine. CONCLUSION: In the current medical practice, this study confirms the effectiveness and good tolerability of agomelatine administered for a treatment period in agreement with guideline recommendations. TRIAL REGISTRATION NUMBER: ISRCTN53570733 on 27 August 2010.

12-week double-blind randomized multicenter study of efficacy and safety of agomelatine (25-50 mg/day) versus escitalopram (10-20 mg/day) in out-patients with severe generalized anxiety disorder.

Treatment of severely symptomatic patients with generalized anxiety disorder (GAD) raises particular concerns for clinicians. This 12-week double-blind study evaluated the efficacy of agomelatine (25-50 mg/day) in the treatment of patients with severe GAD, using escitalopram (10-20 mg) as active comparator. The primary outcome measure was the change from baseline of the total score on the Hamilton Anxiety scale (HAM-A) at week 12. Secondary outcome measures included rate of response to treatment (at least 50% score reduction from baseline) in the HAM-A psychic and somatic anxiety sub-scores, Clinical Global Impression severity and change scores, the Toronto Hospital Alertness Test, the Snaith-Hamilton Pleasure Scale, and the Leeds Sleep Evaluation Questionnaire Scores. Sixty one clinical centers (Australia, Canada, Czech Republic, Finland, Germany, Hungary, Poland, Russia, Slovakia) participated from April 2013 to February 2015. Patient characteristics and demographic data were comparable between treatment groups. Both treatments were associated with a clinically significant decrease in HAM-A total score at week 12; the non-inferiority of agomelatine versus escitalopram was not demonstrated (E(SE) = -0.91(0.69), 95%CI = [-2.26, 0.44], p = 0.195). At week 12, the response rate was 60.9% in the agomelatine group, and 64.8% in the escitalopram group. In both treatment arms, HAM-A psychic and somatic anxiety scores decreased, alertness and sleep parameters improved, and ability to experience pleasure increased. In these secondary outcome measures, there were no significant differences between the treatment groups. Agomelatine was well-tolerated, with a lower incidence of adverse events than escitalopram. Agomelatine and escitalopram are efficacious in treating GAD patients with severe symptoms.

Effect of agomelatine 25-50 mg on functional outcomes in patients with major depressive disorder.

PURPOSE: The purpose of this work is to investigate the effect of agomelatine on functioning compared with placebo in patients suffering from Major Depressive Disorder (MDD). METHODS: Data from two randomized, parallel, double-blind, placebo-controlled short-term agomelatine trials conducted by the manufacturer, one in adult and one in older patients, that evaluated the effect on social functioning, were pooled. The short term effect of agomelatine on social functioning was assessed using the Sheehan Disability Scale (SDS), according to SDS total and sub-item scores, as well as on functional response and remission rates. The Hamilton Depression rating scale was used to quantify severity of depression symptoms. A meta-analytic method using a random effect model was used to assess differences in treatment. RESULTS: In total, 633 patients (422 on agomelatine; 211 on placebo) were included in the analyses. At endpoint, there was a significant difference in favor of agomelatine vs placebo of 3.47 (0.62) (95% confidence interval: [2.26; 4.67]; P < 0.001) on the SDS total score. Rates of symptomatic response and remission according to HAM-D17 total score were significantly higher in patients taking agomelatine (54.3% and 18.3% respectively) than in those taking placebo (29.4% and 9.5% respectively) with respective differences of 24.9%, p < 0.001 and 9.3%, p < 0.001. The functional response rates were 52.9% on agomelatine and 34.5% on placebo, with a significant placebo-agomelatine difference in favor of agomelatine of 18.30 ±â€¯4.39% (95% CI: [9.69; 26.91], p < 0.001). The functional remission rates were 22.3% with agomelatine and 10.2% with placebo, with a significant difference in favor of agomelatine of 11.7 ±â€¯3.11% (95% CI: [5.61; 17.79], p < 0.001). Combined symptomatic and functional response rates were 42.1% on agomelatine and 23.2% on placebo (p < 0.001), and the combined symptomatic and functional remission rates were 13.9% on agomelatine and 6.8% on placebo (p < 0.005). CONCLUSION: This study confirms the efficacy of agomelatine in improving social functioning in MDD patients.

Antidepressant effect in older depressed patients: the lessons of two agomelatine trials.

The present paper reports in parallel the findings of the two phase III trials that evaluated the efficacy of agomelatine in older depressed patients. It describes how the particular methodological innovations (particularly in relation to patient selection, design and accuracy of diagnosis of depression) introduced in study 2 have improved the quality of recruitment of patients and the assay sensitivity. Study 1 lacked assay sensitivity, and among the many differences with study 2, the inclusion of unexpected mildly ill patients could have inflated the placebo response. The increased demands on investigators in study 2 appear to have reduced the placebo effect and showed a robust benefit of agomelatine. The two agomelatine studies offer the opportunity to discuss hypotheses that have been raised to explain the low level of response of older patients to available antidepressants.

Efficacy and safety of agomelatine (10 or 25 mg/day) in non-depressed out-patients with generalized anxiety disorder: A 12-week, double-blind, placebo-controlled study.

Agomelatine is efficacious in reducing symptoms and preventing relapse in placebo-controlled trials in generalised anxiety disorder (GAD). Nevertheless, fixed dose studies of agomelatine in GAD have not been undertaken. To determine the minimally effective optimal dose of agomelatine in GAD, the efficacy of two doses of agomelatine (10 and 25mg/day) was investigated in a 12-week, placebo-controlled, double-blind, international study in patients with a primary diagnosis of GAD. The primary outcome measure was the Hamilton Anxiety scale (HAM-A). The study was undertaken in 35 clinical centers in Finland, Russia, Poland, Slovakia and Ukraine from August 2013 to January 2015. 131 out-patients were included in the agomelatine 10mg group, 139 in the agomelatine 25mg group, and 142 in the placebo group. Both doses of agomelatine were associated with significant decreases in the HAM-A at week 12 (difference versus placebo of 7.16±1.00 at 10mg and 11.08±0.98 at 25mg, p<0.0001). Significant effects on all secondary measures were found for both doses at week 12; including psychic and somatic HAM-A subscales, response rate, remission on the HAM-A, and functional impairment. Findings were confirmed in subsets of more severely ill patients on all endpoints. The low placebo response rate observed in this study was consistent with an increase in the quality of data collected. Agomelatine was well-tolerated by patients, with minimal distinctions from placebo. There was a dose effect of agomelatine, with a greater placebo-agomelatine difference in the agomelatine 25mg group, compared to the agomelatine 10mg group.The present data support early work indicating the efficacy and tolerability of agomelatine in the treatment of GAD.

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.

Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial.

BACKGROUND: Adjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy. AIMS: To examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression. METHOD: Patients who were currently depressed despite taking lithium or valproate for at least 6 weeks were randomised to treatment with agomelatine (n = 172) or placebo (n = 172) for 8 weeks of acute therapy and 44 weeks of continuation therapy (trial registration: ISRCTN28588282). RESULTS: No significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery-Åsberg Depression Rating Scale scores from baseline to end-point. Adverse events including switches into mania/hypomania were low and similar in both groups. CONCLUSIONS: Agomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression.

How to switch to agomelatine after an unsuccessful try with paroxetine or venlafaxine.

OBJECTIVE/INTRODUCTION: The present trial informs clinicians about switching conditions with the antidepressant agomelatine after the failure of a treatment with either paroxetine or venlafaxine. METHODS: The total number of discontinuation-emergent symptoms, according to the Discontinuation-Emergent Signs and Symptoms checklist, was compared in double-blind conditions after 3 switching options: immediate substitution or initiation of agomelatine (25 mg/day p.o.) with either a short- or long-tapering of the previous drug. Secondary objectives included tolerability and safety assessments and the early clinical benefit after the switch. RESULTS: For all switching options, a withdrawal syndrome was observed 1 week after cessation of the selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) treatment. Psychic symptoms were the most frequently reported, and somatic symptoms were comparatively few. Early discontinuation symptoms after cessation of SSRI/SNRI treatment did not prejudice the antidepressant benefits of agomelatine over 8 weeks. CONCLUSIONS: Both abrupt and start-taper switching with agomelatine are options in everyday practice for those patients who have not responded to either paroxetine or venlafaxine. However, regardless of the switching strategy, the present double-blind study shows that early discontinuation symptoms that arise upon cessation of SSRI/SNRI can alter the patients' perception of the clinical benefit of the new antidepressant. Both practitioners and patients must be warned about these early discontinuation symptoms to prevent the symptoms from being confounded with a lack of therapeutic benefit of the new treatment.

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.

Is it time to shift to better characterization of patients in trials assessing novel antidepressants? An example of two relapse prevention studies with agomelatine.

The present paper reports in parallel the findings of the two studies that evaluated the efficacy of agomelatine in preventing relapse of depression. It describes the methodological adjustments made between the first and the second trial, particularly in relation to patient selection and accuracy of diagnosis of depression. Patients with major depressive disorder who responded to an 8/10-week course of agomelatine 25-50 mg treatment were randomly assigned to receive continuation treatment with agomelatine or placebo during a 24-week, randomized, double-blind treatment period with an optional 18- or 20-week double-blind extension period. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. Study 1 lacked assay sensitivity because of an unexpectedly low relapse rate in the placebo arm, but was instructive in showing that the agomelatine effect was better than placebo only in those patients with higher symptom levels at baseline. Study 2 showed a robust benefit of agomelatine - a two-fold reduction in the relapse rate - observed at least up to 10 months in both the overall population and the more severely depressed patients. The methodological adjustments introduced in study 2 (e.g. a minimum subscore calculated from eight specific Hamilton Depression Rating Scale items, the use of the self-rating questionnaire Hospital Anxiety Depression Scale and the Sheehan questionnaire) have assured an adequate severity of depression not only on the basis of ratings of symptom severity but also on measures of functional impairment. We did not find increased severity of symptoms in study 2, but we hypothesize that the increased demands on investigators improved the quality of recruitment to represent more real-world patients. Adopting these innovations could contribute towards lower failure rates for future placebo-controlled clinical trials in the field.

Agomelatine facilitates positive versus negative affective processing in healthy volunteer models.

Agomelatine is a new antidepressant with a novel profile of pharmacological action. The clinical efficacy of agomelatine has been established in major depression, but its actions on emotional bias are unknown. Consequently, the current experimental study assessed the effect of agomelatine on emotional processing in healthy volunteers using an Emotional Test Battery shown to be sensitive to serotonin and noradrenaline reuptake inhibitors. Volunteers were randomized to receive placebo, 25 mg or 50 mg of agomelatine over a 7-day period in a double-blind parallel groups design. Emotional processing (n = 48) was assessed on the morning of day 8 using the Emotional Test Battery which included facial expression recognition, emotional memory, attentional visual probe and emotion-potentiated startle. Mood and subjective state were monitored before and during treatment. Agomelatine (25 mg) decreased subjective ratings of sadness, reduced recognition of sad facial expressions, improved positive affective memory and reduced the emotion-potentiated startle response. The results show that agomelatine has more selective effects on the processing of social facial cues than conventional antidepressants, which could contribute to less blunting of emotional experience. The study highlights the potential value of volunteer models in drug development for screening and profiling of novel antidepressants.

Agomelatine, the first melatonergic antidepressant: discovery, characterization and development.

Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.

The DSM-IV-based Generalized Anxiety Disorder Severity Scale: preliminary validation using data from a trial of agomelatine versus placebo.

Currently available symptom severity measures for Generalized Anxiety Disorder (GAD) are not optimal. This study investigates the reliability and validity of a new measure for GAD. The Generalized Anxiety Disorder Severity Scale (DGSS), comprising 8 DSM-IV GAD symptoms assessed in terms of frequency and intensity, was used in a trial of agomelatine versus placebo for the treatment of GAD. Internal reliability, concurrent validity, responsiveness to change, most robust items, and factor structure were computed. The DGSS demonstrated good internal reliability, correlated significantly with the Hamilton Anxiety Scale and Clinical Global Impression severity scale, and demonstrated a clear change in response to agomelatine. The most robust DGSS items were derived, and an exploratory factor analysis yielded a 2-factor structure of the DGSS. The DGSS is potentially a useful scale for the assessment of GAD in clinical trials of this disorder.

Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Agomelatine is a novel agent that acts on melatonergic (MT(1), MT(2)) receptors and serotonergic (5-HT(2C)) receptors. Preclinical data and data from clinical trials in major depression suggest that agomelatine may have anxiolytic properties. A randomized, double-blind, placebo-controlled trial was designed to assess the efficacy of agomelatine in generalized anxiety disorder (GAD). METHODS: One hundred twenty-one patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition GAD and no comorbid disorders were randomized to agomelatine (25-50 mg/d) or placebo for 12 weeks. The primary outcome measure was the Hamilton Anxiety Rating Scale, whereas secondary outcome measures included the Clinical Global Impression scales, the Leeds Sleep Evaluation Questionnaire, and the Sheehan Disability Scale. Safety measures included assessment of spontaneously reported adverse events, laboratory monitoring, and the Discontinuation Emergent Signs and Symptoms Scale to evaluate discontinuation symptoms. RESULTS: Analysis of covariance of change in the last Hamilton Anxiety Rating Scale total score from baseline demonstrated significant superiority of agomelatine 25 to 50 mg as compared with placebo (E [SE] = -3.28 [1.58]; 95% confidence interval = -6.41 to -0.15; P = 0.040). Data on secondary outcome measures, including clinical response, symptoms of insomnia, and improvement in associated disability, were consistent with the efficacy of agomelatine. Safety analysis indicated that agomelatine was tolerated as well as placebo and was devoid of discontinuation emergent symptoms. CONCLUSIONS: This study suggests that agomelatine is effective in the treatment of GAD and is well tolerated. Additional trials, using an active comparator and extending over a longer period, are needed to delineate the place of agomelatine in the contemporary pharmacotherapy for anxiety disorders.

[Development of a new antidepressant : agomelatine]. / Comment développer un antidépresseur au mécanisme d'action innovant: l'exemple de l'agomélatine.

There are now many potentials for the development of more effective, better tolerated, and more rapidly acting antidepressants acting in association and/or beyond the monoamine hypothesis. One of these possibilities is the development of antidepressant drugs with melatonin agonist property. This holds much promise since various affective disorders, including depression, are characterized by abnormal patterns of circadian rhythms. In line with this, the melatoninergic agonist properties of agomelatine, an antidepressant with proven clinical efficacy, may represent a new concept for the treatment of depression. By way of behavioral studies in rodents, it has been shown that administration of agomelatine can mimic the action of melatonin in the synchronization of circadian rhythm patterns. Interest in agomelatine has increased in recent times due to its prospective use as a novel antidepressant agent, as demonstrated in a number of animal studies using well-validated animal models of depression (including the forced swimming test, the learned helplessness, the chronic mild stress). Interestingly, the melatoninergic agonist property of agomelatine may not, alone, be sufficient to sustain its clear antidepressant-like activity. Recent results from receptor binding and in vivo studies gave support to the notion that agomelatine's effects are also mediated via its function as a competitive antagonist at the 5-HT2C receptor. Finally, thanks to its absence of binding with a broad range of receptors and enzymes, agomelatine is particularly safe and devoid of all the deleterious effects reported with tricyclics and SSRIs.