Agomelatine: What do we know about this new antidepressant?

What is Agomelatine?

Agomelatine is an antidepressant drug, approved for general use regarding the treatment of major depressive disorders and anxiety in 2009 (1). Unlike other licensed drugs in the antidepressant market, it has no capability for interfering with the reuptake of the neurotransmitters of the brain (serotonin, noradrenaline and dopamine) that are fundamental to normal brain function and strongly influence patterns of mental behaviour (2). Its unique mode of action – acting through a combination of antagonistic activity at 5HT2C receptors and agonist activity at melatonergic MT1/MT2 receptors (3) – has distinguished it from similar antidepressants, with a suggestion that the action of its active ingredients may be more beneficial when compared with similar Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin-norepinephrine reuptake inhibitors (SNRIs) that are currently available on the market.

How does it compare

Comparisons in terms of benefits and side-effects to more commonly used SSRIs, SNRIs. MAOIs and TCAs.

In 2013, a comprehensive systematic review was undertaken by the Cochrane Collaboration in which all available published and unpublished studies concerning Agomelatine and its efficacy versus other antidepressant medication were scrutinised. The review aimed to answer some of the fundamental questions regarding its role in treating depression: whether it worked better than other medication, was tolerated better than other medication, or had less/more adverse side effects than other medication. A full review of the available literature identified 13 medical trials with a total of 4495 participants that were eligible for review (4). In terms of benefits and identified side effects, a number of facts concerning Agomelatine have been established:

• Agomelatine is tolerated better than velafaxine (an SNRI) with fewer people discontinuing treatment (although it has the same levels of tolerance commonly found in existing SSRIs in the market place)
• Agomelatine is associated with a lower rate of sexual dysfunction, vomiting and feelings of nausea when compared to other SSRIs
• Velafaxine causes more dizziness than Agomelatine

The role of agomelatine in future treatment

Is this the next big thing in managing depression and anxiety?

Of all the studies that have been undertaken and systematically reviewed, there is no evidence to suggest that Agomelatine is more or less effective in both reducing symptoms of depression and preventing the relapse of depression than any other antidepressants that are currently available. This is following the comparison of clinical outcomes according to the Hamilton Rating Scale for Depression (HAMD) in a range of active comparator studies. Whilst it does not have any significant clinical advantage of other medicines, it has been evidenced to have been more effective than a placebo in both short and longer-term trials. Although the clinical outcomes associated with agomelatine may not be drastically different to its pharmaceutical counterparts, it does stand out, in the trials that have taken place, as an antidepressant drug that is ‘better tolerated’ when compared with other drugs (5).

Many of the studies that have been reviewed report less negative side effects when compared with drugs that inhibit neurotransmitters, and its safety and side-effect profile is generally considered to be similar to other commonly used antidepressants. It is associated with a relatively low incidence of weight gain, but trials also indicate that patients taking Agomelatine display less sleep disturbance and sexual dysfunction when compared to other similar medications for depressive disorders.

The role of Agomelatine in the future treatment of major depressive disorders and anxiety remains to be seen. As the drug is still in its relatively early stages of implementation, and protected by patent, it remains considerably more expensive than the majority of generic alternatives that are currently available for patients. Similarly, many prescribing bodies and regulatory bodies around the world remain hesitant to recommend the drug on account of its relatively new status: a lack of long time comparative controlled studies makes long term outcome monitoring impossible, and prevents an accurate comparison with well established, evidence based treatment alternatives in the SSRI, SNRI, MAOIs and TCA categories.

Use in older patients

There is little evidence for use in older patients (age ≥ 65 years) and a number of other population groups, raising questions regarding both its effectiveness and safety in particular sections of the population.

This is recognised in the prescribing guidelines for Agomelatine, which advises physician caution in prescribing to older patients.

Its use in the general population is additionally restricted due to statutory requirements to undertake liver function tests (LFTs) at numerous points throughout the course of treatment (6) to a mandated responsibility given a small but significant incidence of raised liver enzyme activity and non-fatal ‘toxic hepatitis’ in a study conducted in Germany (7).

It should also be noted that none of the active comparator studies that have been conducted have used maximum doses of the compared drug, which may have introduced bias in favour of Agomelatine. Many of the active comparator studies were also funded directly by pharmaceutical companies with a specific interest in the development and bringing to market of Agomelatine itself. As a result of the lack of long-term study regarding potentially negative health impacts and its current high cost, evidence-based guidelines and cost-effectiveness studies in respect of Agomelatine tend to exercise caution in it being made widely available to the market at present (8).

In some parts of the world, it is not recommended as a first or second line treatment option due to its cost being 10 times that of commonly used antidepressants. Given the relatively limited number of trails that have taken place, and outstanding questions regarding the quality of how they have been administered, a large number of stakeholders (GPs, regulatory bodies, patient advisory groups and pharmaceutical companies) have recommended that further trials are conducted to increase the evidence base on which decisions regarding its prescribing can be made. As such, Agomelatine, at least at this early stage in its development, cannot be considered the next big thing in treating depression or anxiety. However, early indications show that it may be a welcome addition to the market in regards to reducing the known side effects that are currently associated with other SSRIs and SNRIs whilst also playing a part in treating major depressive disorders ineffectively treated by first or second line agents.

References

1. European Medicines Agency. Valdoxan (agomelatine). 2012. www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000915/human_med_001123.jsp&mid=WC0b01ac058001d124.
2. Blows, WT. (2000) Neurotransmitters of the brain: serotonin, noradrenaline (norepinephrine), and dopamine. J Neurosci Nurs. 2000 Aug;32(4):234-8.
3. Racagni G, Riva MA, Molteni R, Musazzi L, Calabrese F, Popoli M, et al. Mode of action of agomelatine: synergy between melatonergic and 5-HT2C receptors. World J Biol Psychiatry2011;12:574-87.
4. Cochrane Database of Systematic Reviews: Plain Language Summaries. Available online at http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0061425/ (last accessed 7th December 2014)
5. Taylor D, Sparshatt A, Varma S, Olofinjana O. (2014). Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ 2014;348:g1888 Available online at http://www.bmj.com/content/348/bmj.g1888 (last accessed 7th December 2014)
6. Sevier Laboratories. Summary of Product Characteristics. Valdoxan. Sevier, 2013.www.medicines.org.uk/emc/medicine/21830/SPC/Valdoxan/
7. Gahr M, Freudenmann RW, Connemann BJ, Hiemke C, Schönfeldt-Lecuona C. Agomelatine and hepatotoxicity: implications of cumulated data derived from spontaneous reports of adverse drug reactions. Pharmacopsychiatry2013;46:214-
8. Agomelatine in the management of depression: Agomelatine (June 2009). NHS. Available online at http://www.netag.nhs.uk/files/appraisal-reports/NETAG%20appraisal%20report%20-%20Agomelatine.pdf (last accessed 7th December 2014)