Review
Agomelatine: A narrative review

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Abstract

Long-term antidepressant treatment success should be viewed as the result of the cumulative effects of treatment at each stage of major depressive disorder (MDD), and as a balance between efficacy and tolerability/safety. Depression is a heterogeneous disorder and different mechanisms of action of different antidepressants probably capitalize on this response heterogeneity. Results from clinical trials with agomelatine, a melatonergic receptor agonist (MT1/MT2) and 5HT2C receptor antagonist, have shown that it is efficacious in both the acute phase and the continuation phase of treatment of depression. Agomelatine's efficacy is observed in different depressive symptom clusters (core depression symptoms, sleep symptoms, anxiety, retardation, somatic symptoms, and work and activities). Active comparator trials show at least comparable efficacy with other antidepressants (paroxetine, venlafaxine, sertraline, fluoxetine) and efficacy has also been demonstrated in severe depression and in treating anxiety symptoms associated with major depression. The tolerability profile shows some clinically significant advantages especially in the lower incidence of treatment emergent sexual dysfunction and of weight gain, two adverse events experienced by patients as most bothersome. Transient aminotransferase elevations without clinical signs of liver damage have been observed more frequently than with placebo (1.1% versus 0.7%), and a hepatic monitoring schedule is therefore recommended.

Introduction

Suboptimal efficacy of antidepressants and suboptimal adherence to antidepressant treatment are still major obstacles to an optimal outcome in major depression.

A recent meta-analysis of 182 studies showed that response rates in short-term randomized clinical trials are 53.8% for antidepressants and 37.3% for placebo (Papakostas and Fava, 2009). In observational studies (more ‘real-world’ but more severely ill STAR*D patients –Sequenced Treatment Alternatives to Relieve Depression–) response rates of 47% after 12 weeks of treatment with citalopram were observed, and the 77.8% of patients who could not have been enrolled in RCTs even had a 10% lower response rate than the 22.2% of patients who could have been enrolled in RCTs (Trivedi et al., 2006). Depression is a heterogeneous disorder and antidepressants with different mechanisms of action could well target depressive symptoms in a different way and each mechanism of action could possibly capitalize on this response heterogeneity (Katz et al., 2010). This is in line with the finding that in the case of partial response, switching across classes tends to be a more favorable strategy than changing within class (Papakostas et al., 2008). Indeed, the presence of a specific depressive symptom profile seems to be the most important predictor of which antidepressant a psychiatrist prescribes (Zimmerman et al., 2004), although from an evidence-based point of view it is still debatable whether antidepressants with a different mechanism of action have a qualitatively different antidepressant activity (Nelson et al., 2005).

A drug's efficacy is only fully realized when it is taken regularly and for a long enough period. A large Spanish observational study showed that more than 40% of patients starting an antidepressant treatment discontinue it within a month and that 56% of patients discontinue within 4 months. When taking into account adherence (at least 80% intake of medication over a time period), only one patient in five was fully compliant after 4 months (Serna et al., 2010). Tolerability but also psychological issues clearly impair the capacity of antidepressants to ensure stable recovery and to prevent relapse (Demyttenaere et al., 2001). A large US study including 266,665 real-world patients found that 6-month compliance with antidepressants ranged from only 12.4% with first-generation antidepressants to 33.6% with the newer antidepressants, again suggesting that differential tolerability is reflected in a differential duration of treatment (Sheehan et al., 2008).

Agomelatine is an antidepressant with a melatonergic receptor agonist (MT1/MT2) and 5HT2C receptor antagonist activity and has recently been approved in Europe (European Marketing Authorization, 2009). In this paper, the antidepressant efficacy and tolerability of agomelatine at the different treatment phases will be discussed, both in terms of how it compares with placebo and with other well-established antidepressants.

Section snippets

Acute phase trials with agomelatine versus placebo

One consequence of the finding that response rates in short-term trials are 53.8% for antidepressants and 37.3% for placebo is, of course, a poor signal detection for antidepressant efficacy (although this 16.5% difference results in a clinically significant number needed to treat [NNT] of about 6) (Papakostas and Fava, 2009). It also means that 70% of the effect is due to the placebo and slightly less than 1/3 to the antidepressant. So, for each individual antidepressant a considerable

Antidepressant efficacy in active comparator trials

Multiple attempts have been made to establish whether some antidepressants are better than others or whether all antidepressants are equal, as discussed in comments on the interesting but debatable ‘multiple treatments meta-analysis’ of new-generation antidepressants published by Cipriani et al. (Cipriani et al., 2009, Gartlehner and Gaynes, 2009, Gartlehner and Hansen, 2009). Comparative efficacy has indeed been investigated in various ways: in head-to-head trials (placebo-controlled or not),

Agomelatine and efficacy in reducing anxiety symptoms

Anxiety symptoms are common in patients with MDD, and in daily practice comorbidity with anxiety disorders, which is frequent, impairs outcome.In the Loo study, the reduction in HAM-A score was similar for agomelatine 25 mg and paroxetine 20 mg, both of which performed significantly better than placebo (Loo et al., 2002). In the agomelatine versus fluoxetine trial in patients with severe MDD, both drugs were effective in reducing the HAM-A total score as well as the HAM-A psychic anxiety and the

Agomelatine: Tolerability and safety

The assessment of a new antidepressant should always be a harm/benefit analysis. With the exception of dizziness, the side effect profile of agomelatine has been shown to be good in individual trials as well as in pooled analyses (Kennedy and Rizvi, 2010). Furthermore, there were no increases in specific side effects such as sexual dysfunction and increases in body weight, which are common with some classes of antidepressants (Kennedy and Rizvi, 2010, Kennedy et al., 2008, Montejo et al., 2010

Conclusions

Results from clinical trials have shown that agomelatine, with its melatonergic receptor agonist (MT1/MT2) and 5-5HT2C receptor antagonist activity, is as efficacious as other well-established antidepressants. From initiation of treatment to remission, improvements in mood, anxiety, daytime alertness, and quality of sleep have been observed in placebo-controlled as well as in comparator trials. Agomelatine seems to have a favorable balance between efficacy and tolerability profile (no weight

Role of the funding source

Koen Demyttenaere received honoraria for preparing this supplement.

Contributor

Koen Demyttenaere.

Conflict of interest

Koen Demyttenaere: speaker bureau/ad board/research funding: Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, GSK, Lundbeck, Servier, Takeda.

Acknowledgments

None.

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