In spite of widely available different antidepressants, major depression does not respond adequately in up to one third of patients. Overall, the need for both reliable and well-tolerated treatment has remained unmet for a sizeable proportion of people with depression.

In the past couple of years, there has been controversy about the suitability of Agomelatine (Valdoxan) as a treatment for depression. Because its biological targets are different from common antidepressant drugs, some people have suggested it might be useful in patients showing inadequate response to standard medication. However, few controlled studies have been conducted and even systematic reviews often produce conflicting findings. Just to add even more confusion, three authoritative reviews have been published in the last seven months. This blog aims to synthesise findings from those most recent meta-analyses and give clinicians the knowledge they need about Agomelatine.

Meta-analyses on Agomelatine have produced inconsistent findings

The three recent reviews all assessed both published as well as unpublished studies and received their data from major medical databases. Here’s a summary of what they all found:

1. The most recent meta-analysis (Taylor et al, 2014) included 20 studies with 7,460 patients and found similar efficacy, but higher tolerability for Agomelatine compared with standard antidepressants (e.g. Fluoxetine)
2. These findings are similar to a current Cochrane review (Guaiana et al, 2013), which assessed 13 studies with 4,495 patients and likewise concluded that while more tolerable than standard antidepressants, Agomelatine had comparable efficacy in the acute-phase treatment of depression
3. In direct contrast, a systematic review and meta-analysis published earlier (Koesters et al, 2013) with 13 studies and 4,300 patients found that clinically relevant advantages of Agomelatine over placebo were unlikely

There was considerable overlap between the three meta-analyses, in terms of the studies they aggregated, and it remains speculative that part of why Taylor et al. (2014) and Guaiana et al. (2013) found antidepressant effects of Agomelatine was related to power issues.

All three meta-analyses do agree on some points, however:

• First, significant publication bias becomes apparent when comparing published with unpublished studies. Not very surprisingly, published studies were more likely than unpublished studies to have favourable outcomes for agomelatine. This suggests that analyses relying solely on studies that have reached scientific journal are highly likely to overestimate Agomelatine’s efficacy as an antidepressant
• Irrespective of publication, studies vary a lot in terms of sample characteristics (e.g. inpatients vs. outpatients), assessment of symptom relief and side effects, as well as study design. Overall methodological quality is not particularly convincing, making comparisons among primary studies cumbersome and difficult
• Likewise, influence of factors like sex, age or depression severity has not been systematically studied

What can take clinicians take away from this?

With Taylor et al. (2014) arguably providing the most comprehensive review of studies to date, it seems reasonable to suggest that Agomelatine tentatively possesses comparable efficacy to other drugs at higher overall tolerability.

In any case, it is clear that more research is needed before a final verdict can be passed. There is unlikely to be a single explanation as to why there have been so many conflicting findings, so clinicians should keep a few things in mind about Agomelatine:

• First of all, it is still patent-protected. This means that prescription costs are considerably higher than for compounds whose patents have expired already
• Second, while generally Agomelatine seems to have few “typical” side effects (e.g. dizziness or nausea), it has been associated with a low but important incidence (1.3%) of raised liver enzyme activity (Taylor et al., 2014). This makes monitoring of liver function at several time points during treatment mandatory, which is both cost-intensive and inconvenient
• Third, it has (at best) comparable efficacy with current drugs of choice, and it remains a bone of contention as to whether or not this effect size is clinically relevant

Altogether, grounds for prescribing Agomelatine are shaky. The lack of superiority over established and more affordable drugs, together with exponentially higher costs, rule out widespread usage in first-line treatment of depression. While it might be more effective in patients resistant to standard antidepressants, future trials are needed to prove this speculation.

Links

Guaiana G, Gupta S, Chiodo D, Davies SJC, Haederle K, Koesters M. Agomelatine versus other antidepressive agents for major depression. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008851. DOI: 10.1002/14651858.CD008851.pub2.

Koesters M, Guaiana G, Cipriani A, Becker T, Barbui C. Agomelatine efficacy and acceptability revisited: systematic review and meta-analysis of published and unpublished randomised trials. Br J Psychiatry. 2013 Sep;203(3):179-87. doi: 10.1192/bjp.bp.112.120196. [Abstract]

Taylor D ,Sparshatt A ,Varma S ,Olofinjana O. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ 2014;348:g1888.