Agomelatine is a relatively new antidepressant with a mechanism of action that is different from the usual amine reuptake mechanisms that characterize the selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs), which have become widely accepted as effective and well-respected treatments of major depressive disorder (MDD). Agomelatine is an agonist at melatonergic M1 and M2 receptors, and an antagonist at the 5-HT2c receptors. The synergism of these two mechanisms produces an antidepressant with particular benefits on circadian rhythms (Kasper and Hamon, 2009). This is achieved without increasing the amine levels in the plasma, which lead to the well-known serotonergic or noradrenergic adverse events associated with SSRIs or SNRIs, such as nausea, agitation, palpitations and dry mouth (Racagni et al., 2011).
Agomelatine is an effective antidepressant, as found in studies compared with placebo in the short-term (Loo et al., 2002; Kennedy and Emsley, 2006; Olie and Kasper, 2007) and in long-term treatment (Goodwin et al., 2009). Agomelatine was approved for the treatment of major depressive episodes in adults by the Committee for Medicinal Products for Human Use of the European Medicines Agency in February 2009 and is currently licensed in 29 European countries and more than 50 other countries. The efficacy of agomelatine has been reviewed recently (Hickie and Rogers, 2011). Agomelatine is effective in severe depression (Montgomery and Kasper, 2007) and exerts rapid symptomatic effects. It has a decided advantage in the lack of discontinuation symptoms following the abrupt withdrawal of treatment (Montgomery et al., 2004) and is associated with fewer sexual side effects than venlafaxine XR (Kennedy et al., 2008). Although a new antidepressant may be clearly effective, it is difficult to determine its relative efficacy without double-blind comparisons against the major classes of existing antidepressants such as the SSRIs and the SNRIs.
The most convincing data showing the superior efficacy of an antidepressant compared with other antidepressants are from direct comparisons in randomized, double-blind head-to-head studies investigating superiority. A review of available studies by a group of experts has concluded that, applying the usual regulatory criteria that require the demonstration of superior efficacy in at least two individual double-blind randomized studies using the licensed dose, only three antidepressants had superior efficacy: escitalopram, venlafaxine and clomipramine (Montgomery et al., 2007). This review was published before the licensing of agomelatine as an antidepressant and before comparator studies on agomelatine were available. There are now three randomized double-blind studies in which agomelatine was found to have a significantly greater reduction of the primary depression efficacy scale (HAM-D) to sertraline (Kasper et al., 2010) and fluoxetine (Hale et al., 2010), and on the Clinical Global Impression-Improvement (CGI-I) scale to venlafaxine (Lemoine et al., 2007).
An alternative method for examining data for the comparison of efficacy is a meta-analysis of the direct double-blind randomized head-to-head comparisons within the licensed dose range of one antidepressant with another. For example, taking the raw data from individual studies, escitalopram was found to be superior in efficacy to other antidepressants (SSRIs and SNRIs) (Kennedy et al., 2006), and venlafaxine was shown to be associated with superior efficacy compared with SSRIs (Nemeroff et al., 2008). The present paper reports the results of a meta-analysis of the individual patient data from the direct head-to-head double-blind randomized studies comparing agomelatine with other antidepressants that used the HAM-D17 as the primary depression efficacy measure.
Meta-analyses have the advantage of dealing with greater patient numbers and this increases the power to identify possible differences between groups. The disadvantage of meta-analyses is, among other considerations (Huf et al., 2011), the assumption that all studies are of equal design and scientific merit, and that they all contribute equally towards the result. This may or may not be true. However, the present studies were very similar in design, with the same primary efficacy scale and analysis, and were deemed to be a valid base for comparison of relative efficacy. The main variation was the different durations of the acute treatment period (6–12 weeks).
Indirect meta-analysis does not avoid the assumption that all studies are equally informative irrespective of the population studied or the methodology used. The method substitutes an estimate of likely response compared with a particular comparator by an indirect comparison with other comparisons in completely different studies including different populations and using different methodologies. Inevitably, there is an increased risk of potential errors and misleading results. An additional weakness is that these indirect comparisons of a very large number of studies by necessity use summary responder data, despite the use of different efficacy scales and even different versions of the same scale, which reduces the sensitivity of the analysis.
Indirect comparison network analysis is an alternative method of meta-analysis that has been proposed (Cipriani et al., 2009). The advantage of this method is that very large numbers of comparator studies may be included and thus provide the power to investigate potential differences in both responder rates and dropout rates. The most attractive feature of this type of indirect analysis is that it allows some estimate of differential efficacy and tolerability between different individual antidepressants, even when no such comparator studies have been carried out. Although less valid than direct comparisons, this can be useful.
To further investigate the place of agomelatine in treatment relative to SSRIs and SNRIs, a meta-analysis of six short-term studies was carried out. The present meta-analysis included the full individual results of all patients entering these studies and can therefore be expected to provide more valid conclusions than meta-analyses relying on statistical summary data published from the individual studies.
The criteria used for identifying the studies to be included in the meta-analysis were (a) head-to-head, double-blind, randomized studies comparing the efficacy of agomelatine and another antidepressant, (b) the doses used were within the licensed range, (c) the primary efficacy scale was the 17-item HAM-D17 and (d) they were not placebo-controlled studies in which a comparator antidepressant was used as a check on assay sensitivity, as the presence of placebo in a study is known to alter the population studied (Khan et al., 2003), the discontinuation rate and therefore the relative efficacy. Six studies were identified that fulfilled these conditions and they were all included in the meta-analysis. The trials were all international, multicentre (secondary care), randomized, double-blind, parallel-group studies in depressed outpatients in which the primary efficacy analysis was against venlafaxine, sertraline, fluoxetine and escitalopram (Table 1) (Lemoine et al., 2007; Hale et al., 2010; Kasper et al., 2010; Quera Salva et al., 2011), and included two studies not yet fully published: one comparing agomelatine with paroxetine and the other with escitalopram (Corruble, 2011).
The study comparing agomelatine with paroxetine was a 12-week randomized double-blind study assessing the effect on the quality of sleep in MDD patients aged 60 years or older. The study comparing agomelatine with escitalopram (Corruble, 2011) was a 12-week randomized double-blind study assessing the subjective sleep in MDD outpatients. In both studies, the primary depression efficacy scale was the HAM-D17.
Two studies were excluded because the primary depression efficacy scale was not the HAM-D17 (Montgomery et al., 2004; Kennedy and Rizvi, 2010). Placebo-controlled studies with a comparator arm for assay sensitivity (including CL3-022, CL3-23 and CL3-024) (Loo et al., 2002; European Medicines Agency, 2009; Kennedy and Rizvi, 2010) were excluded because the comparison of the active treatments was not protocolled and the response rates in placebo-controlled studies were compromised. Studies with a safety purpose such as sexual acceptability (Kennedy et al., 2008) or discontinuation syndrome (Montgomery et al., 2004) and that did not use the HAM-D17 were also excluded. Briefly, the studies included male and female patients aged older than 18 years, who had a diagnosis of MDD according to the DSM-IV or DSM-IV-TR criteria (American Psychiatric Association, 1994, 2000) with an entry HAM-D17 score of at least 20/22 (moderate to severe), except for one study, in which the HAM-D17 score was at least 25 (severe) (Hale et al., 2010). All the studies used flexible dosing schedules with an agomelatine dosage of 25–50 mg/day administered in the evening. Comparator antidepressant dosages and administration were within licensed dose ranges and in line with clinical practice. All the studies were carried out in accordance with the ethical principles laid out in the Declaration of Helsinki (1964), and its text revisions applicable at the time, and were approved by relevant local ethics committees. All patients had provided written informed consent.
The primary short-term depression efficacy analysis in the individual studies varied from 6 weeks versus escitalopram (Quera Salva et al., 2011), sertraline (Kasper et al., 2010) and venlafaxine (Lemoine et al., 2007) to 8 weeks versus fluoxetine (Hale et al., 2010) and 12 weeks in the unpublished studies versus escitalopram and paroxetine. The primary depression efficacy measure was the HAM-D17 even where the primary objective of the study was pharmacodynamic or sleep parameters; the secondary scales were the CGI-I and the responder analysis, 50% or greater change from the baseline on the HAM-D17 or the CGI-I score of 1 or 2, much or very much improved. The CGI Severity (CGI-S) scale was used in all studies, with the exception of venlafaxine (Lemoine et al., 2007), and this study was excluded from the CGI-S analysis.
The population of the six studies that compared agomelatine directly with SSRI/SNRI comparators was pooled. The relative efficacy was examined using the HAM-D17 total score, the CGI scales and the rates of response using the last postbaseline observation carried forward (LOCF) analysis at 6, 8 or 12 weeks depending on the study. A subgroup of more severely depressed patients (defined as a baseline HAM-D17 total score of ≥25) was also analysed separately.
The safety data were derived from spontaneous reporting of adverse events and were analysed as the number and percentage of emergent adverse events, the cumulative incidence of withdrawals attributed to adverse events and emergent gastrointestinal disorders over 6 weeks. The number of patients with abnormal liver function tests (three times above the upper limit of normal) in each group was analysed.
The randomized set included all patients who were included and randomized in the six studies. The full analysis set (FAS) used in the efficacy analysis was defined as patients in the randomized set who took at least one dose of the study treatment with at least one postbaseline evaluation for the primary criterion. The subgroup with severe depression included all patients in the FAS with HAM-D17 total score at least 25 at baseline. Baseline characteristics are presented using descriptive statistics.
The difference between treatments was analysed in the FAS and the subgroup with severe depression on parameters expressed as the last postbaseline value (6/8/12 weeks). The estimates of the overall treatment effect of agomelatine as compared with SSRI/SNRI and their accuracy were assessed on the basis of the results of the six studies using meta-analytical methods. For each study, between-group differences were calculated adjusted for baseline and centre (two-way analysis of covariance). The level of significance was fixed at 5%. The homogeneity of the efficacy results across the studies was assessed using descriptive statistics and a test of homogeneity.
Safety data were evaluated using the randomized population in an integrated analysis of safety of the six studies and using a pooled analysis, including all patients who received at least one dose of agomelatine or SSRI/SNRI in the safety set.
The randomized set of the pooled analysis included a total of 2034 outpatients (n=1019 agomelatine and n=1015 SSRI/SNRI). The baseline characteristics of this population are presented in Table 2. The mean age in the pooled population was 48 years and the majority were women (73%). The population was typical of a depressed population (mean HAM-D17 total score 26.9±3.0) and a mean of 2.9 previous depressive episodes, including the current one, which had a duration of ∼4.3 months. There were no relevant differences between the group of patients receiving agomelatine and the group receiving SSRI/SNRI. The subgroup of more severely depressed patients included 1590 patients (793 agomelatine, 797 SSRI/SNRI) with a mean HAM-D17 score of 27.9±2.4 at baseline.
The FAS comprised 1997 patients (1001 agomelatine, 996 SSRI/SNRI). Within the FAS, 1556 patients had severe depression (777 agomelatine, 779 SSRI/SNRI). The overall safety set included 2027 patients (1014 agomelatine, 1013 SSRI/SNRI). The percentage of patients with a dose increase in each group is presented in Table 1.
The HAM-D17 total score at last observation was 10.6±7.3 in the agomelatine group and 11.4±8.0 in the SSRI/SNRI group (Table 3). There was a significant difference between the HAM-D17 total scores, with a greater reduction in score with agomelatine than with SSRI/SNRI [E(SE), 0.86 (0.35), 95% confidence interval 0.18–1.53, P=0.013]. There were significant between-group differences in the rates of response on the HAM-D17 scale (P=0.012) and the CGI-I scale (P=0.032) (Table 3). Similar results were found in the patients with severe depression, including significant differences in the rates of response on the HAM-D17 scale (P=0.019) and the CGI-I scale (P=0.041) (Table 3).
There were numerically fewer emergent adverse events with agomelatine (62.9%) than with SSRI/SNRI (65.1%). Significantly fewer patients withdrew because of adverse events with agomelatine (6.9%) than with SSRI/SNRI (10.7%) (P<0.001). The cumulative incidence of withdrawals for adverse events is shown in Fig. 1a. A significantly lower proportion of agomelatine patients discontinued treatment because of emergent adverse events than with SSRI/SNRI from the first week of treatment (P<0.001). The cumulative incidence of gastrointestinal emergent adverse events was significantly lower in patients who received agomelatine compared with those who received SSRI/SNRI from the first week of treatment (P<0.001) (Fig. 1b).
An increase of more than three times the upper limit of normal for alanine aminotransferase and/or aspartate aminotransferase was observed in 16 agomelatine-treated patients (two increases occurred after the end of the treatment period) and in five SSRI/SNRI-treated patients (two on venlafaxine, one on fluoxetine, one on paroxetine and one on escitalopram). In all six studies, these increases in transaminases were isolated, occurred mainly within the first month of treatment, were not associated with clinical signs and were, in all cases where follow-up data were available, reversible.
MDD is a dangerous and disabling disorder and is one of the leading causes of disability worldwide (Murray and Lopez, 1997; Lopez et al., 2006; Wittchen et al., 2011). Effective treatment is required to reduce the suffering, reverse the disability and lower the risks of the disorder. The particular choice of antidepressant will depend on the assessment of benefit and risk of the antidepressant, and its efficacy relative to others. Meta-analysis of the comparator studies is a useful way to determine the relative efficacy of an antidepressant and the results of the present analysis show that agomelatine has significantly better efficacy compared with a range of accepted and widely used antidepressants. The comparator antidepressants in the analysis include some that have themselves been shown to have superior efficacy, for example, escitalopram and venlafaxine (Montgomery et al., 2007), and escitalopram and sertraline (Cipriani et al., 2009).
In this meta-analysis of the comparator studies with agomelatine, a significant clinical advantage in favour of agomelatine was observed against a pool of SSRI antidepressants fluoxetine, sertraline, paroxetine and escitalopram and the SNRI venlafaxine. The significant advantage of agomelatine is found in the primary depression efficacy measure used, the LOCF final score on the HAM-D17 as well as on the two responder measures examined.
The doses of the comparators in these studies are in line with prescriber information provided by the manufacturers. Increasing the dose of fluoxetine or sertraline in nonresponders has been shown to have no extra benefit compared with remaining on the lower dose (Wernicke et al., 1989; Schweizer et al., 2001; Licht and Qvitzau, 2002). Similar results were found with paroxetine. The design of the studies in our analysis is such that the doses do not change with time, in contrast to the classical dose-flexible studies; the dose remains stable once it is increased.
The significant advantage for agomelatine compared with other antidepressants fulfils the generally used criteria for establishing clinical relevance. The difference observed is significant on the primary HAM-D17 scale in the LOCF analysis, but is also significant in the two responder analyses. The 50% change from baseline on the HAM-D is the conventional widely used definition of responders and reflects a standard criterion of the substantial improvement in the symptoms of depression. The CGI-I scale reflects the opinion of the investigator, derived under double-blind conditions, that the individual patient is much improved (CGI-I score 2) or very much improved (CGI-I score 1). A significant difference on the CGI-I responder criterion registers the overall view of the treating physician on whether response has been achieved rather than symptomatic improvement alone, and is therefore clinically relevant by definition.
The magnitude of the advantage on the HAM-D scale also reflects the clinical relevance of the extra response in favour of agomelatine. In the EPAR 2009 on agomelatine, taking all studies together, the mean difference from placebo was 1.5 points on the HAM-D including the subtherapeutic doses, which were not licensed. This is in agreement with an analysis of all antidepressants in the wider FDA database where the difference from placebo was 1.8 points on the HAM-D (Khin et al., 2011). In the present meta-analysis, a difference of ∼1 point (0.86) is observed on the LOCF final score compared with all comparators, which indicates an increase in efficacy of 50%.
It is difficult to compare the results of different meta-analyses of various antidepressants because of the obvious differences in the populations studied and the measures reported. The significant advantage of agomelatine versus comparators of 5% in responder rates is consistent with the advantage in responders of 4.2% on the basis of the Montgomery–Asberg Depression Rating Scale (MADRS) reported for escitalopram, which is claimed to be a superior antidepressant (Kennedy et al., 2006). The responder rates for venlafaxine are not published in meta-analyses, but the results are consistent with the advantage on remission of 5.9% for venlafaxine versus comparators (Nemeroff et al., 2008). The advantage of agomelatine versus comparator antidepressants is more striking because three of the comparators in four out of the six studies included in the present meta-analysis (escitalopram, venlafaxine and sertraline) were themselves reported to be superior antidepressants.
The efficacy of agomelatine in severe depression is well established, both in the individual placebo-controlled studies and in the meta-analysis of the three placebo-controlled studies (Montgomery and Kasper, 2007). The present analysis also shows that agomelatine is significantly more effective in severe depression than the pool of comparator antidepressants, despite lower numbers and reduced power, on both responder analyses, but not on the final HAM-D analysis. The results showing the greater efficacy of agomelatine in severe depression are of considerable interest, as two of the comparator antidepressants had themselves shown superior efficacy in severe depression compared with a pool of antidepressants, for example, escitalopram (Kennedy et al., 2006).
An assessment of relative tolerability has also reported a high level of dropouts with some antidepressants that had been shown to be more effective (Cipriani et al., 2009). Venlafaxine, for example, has a high level of dropouts and this is more marked with the higher doses and believed by some to be associated with better efficacy. With SNRIs and SSRIs, the major adverse events are related to the serotonin reuptake inhibition, which leads to nausea and vomiting as well as nervousness and agitation. Agomelatine is recognized as having a benign adverse event profile, with only dizziness showing a significant increase over placebo out of the large range of adverse events recorded in the placebo-controlled studies. Agomelatine has also been shown to have low levels of sexual dysfunction compared with venlafaxine XR (Kennedy et al., 2008) and to have no withdrawal symptoms when stopped abruptly (Montgomery et al., 2004).
Agomelatine is associated with a better tolerability overall than the pool of comparators, with a lower level of adverse events than SSRI/SNRIs. The better tolerability is also reflected in the significantly lower number of patients who withdrew from the studies because of adverse events with agomelatine than with SSRI/SNRI (P<0.001) overall and in the first week of treatment. There were significantly fewer discontinuations from agomelatine because of the group of gastrointestinal disorders, which was observed as early as the first week and at each assessment until the sixth week. The better tolerability of agomelatine, which has been reported in individual studies, is confirmed in this pooled safety analysis. The increased incidence of abnormal transaminases on agomelatine compared with SSRI/SNRI reported in the EPAR was also observed in the present analysis, but in all the six studies, these increases were isolated, not associated with clinical signs and were, in all cases where follow-up data were available, reversible.
A limitation of this analysis is common to all meta-analyses, in that studies are grouped together, which may have investigated different populations or used differing methodologies. The duration of the studies of acute efficacy varied: three studies were for 6 weeks, one for 8 weeks and two for 12 weeks. However, this might allow the result of the present analysis to be generalized to a wider population. All the studies used the same diagnostic scale, the HAM-D17, as the primary depression efficacy scale and the CGI-I as the secondary scale. The protocolled analysis of efficacy was the same in the different studies and all of these constants allow some confidence in the homogeneity of the methodology used in this meta-analysis.
A possible limitation is that the primary goal in some of the studies was either an assessment of chronobiological properties or investigation of sleep parameters, but all studies included the primary depression efficacy measure of HAM-D17. One study, which found an advantage for agomelatine, was excluded because the MADRS was the primary depression efficacy measure and not the HAM-D17 (Kennedy et al., 2008). The present analysis also excluded studies where the primary aim was a comparison with placebo and where a comparator was included in a placebo-controlled study as a check on assay sensitivity. The rationale for excluding these studies is that the populations studied and the discontinuation (dropout) rates are known to be different in placebo-controlled studies and this could bias the analysis. The present meta-analysis includes all the studies where the protocol required a direct comparison of the relative efficacy of agomelatine and comparator antidepressant on the HAM-D17.
Agomelatine was shown to have significantly greater efficacy, reflected by the HAM-D17 difference, than the pool of comparators in studies in which the HAM-D17 was the primary depression efficacy scale.
Agomelatine was also shown to have a significant advantage in efficacy over the comparator antidepressants on the responder analyses assessed on both the HAM-D17 and the CGI-I responder criteria, which confirms that the difference observed is clinically relevant. The range of comparators comprised the SSRIs paroxetine, fluoxetine, sertraline and escitalopram along with the SNRI venlafaxine, and was wide enough for the results to be generalized to a wider population. As three of these comparator antidepressants have themselves been shown to have superior antidepressant efficacy compared with other antidepressants, the finding of a favourable efficacy for agomelatine may be accepted with greater confidence.
Agomelatine has been shown to be well tolerated, with fewer adverse events in this pooled comparison. Agomelatine had significantly fewer discontinuations for adverse events than the comparators antidepressants at the first week of treatment and at each assessment point over the 6-week analysis (Fig. 1). The same advantage was observed examining discontinuations for gastrointestinal disorders from the first week through until the fourth week. This is consistent with literature reports that nausea and gastrointestinal disorders are commonly a cause for discontinuation for SSRIs and SNRIs in other studies, particularly in the first weeks of treatment. The results confirm the benign tolerability profile of agomelatine. This benign tolerability profile has also been confirmed in a naturalistic study of more than 3300 patients (Laux, 2012).
The combination of favourable efficacy and better tolerability of agomelatine compared with this range of SSRIs and SNRIs including some antidepressants that are themselves considered to have superior efficacy is striking. According to these data, agomelatine deserves, on the basis of a benefit–risk analysis, to be a first-line treatment of MDD.
This study was supported by Servier. The authors have received honoraria, research grants or both from Servier.
Conflicts of interest
Dr Kasper has received grant/research support from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Merck Sharp and Dome (MSD), Novartis, Organon, Pfizer, Schwabe, Sepracor, and Servier; and has served on speakers’ bureaus for Angelini, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Pfizer, Pierre Fabre, Schwabe, Sepracor and Servier. Dr Corruble has served as a consultant or on advisory boards for Servier, Lundbeck, Sanofi, Pfizer, Bristol-Myers Squibb, AstraZeneca, Janssen, Eisai. Dr Hale has received support or given advisory board input for Eli Lilly, Lundbeck, AstraZeneca, Janssen, Shire and Bristol-Myers Squibb. Dr Lemoine has no conflict of interest to declare. Professor Montgomery has received honoraria or been a consultant for AstraZeneca, Bionevia, Bristol-Myers Squibb, GlaxoSmithKline, Intellect Pharma, Johnson & Johnson, Lilly, Lundbeck, Merck, Merz, M’s Science, Neurim, Otsuka, Pierre Fabre, Pfizer, Pharmaneuroboost, Richter, Roche, Sanofi, Sepracor, Servier, Shire, Synosis, Takeda, Theracos, Targacept, Transcept, UBC, Xytis and Wyeth. Dr Quera Salva has received grant/research support from Servier; French Association Against Myopathies (AFM) and the Vinci Foundation consultant or on advisory board for Servier and Ferrer.
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