Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Valdoxan (Servier)
25 mg tablets
Approved indication: major depression
Australian Medicines Handbook section 18.1

Agomelatine is a synthetic analogue of melatonin. The manufacturers claim that as well as agonising melatonin, it also antagonises the serotonin 5HT2C receptors.

Numerous placebo-controlled trials have assessed the efficacy of agomelatine for major depression.1–5 The primary endpoint in these studies was based on the 17-item Hamilton rating scale for depression. At baseline, average scores were around 27 out of a possible 52. After 6–8 weeks, both agomelatine (25 or 50 mg) and placebo had reduced the scores (to between 12.8 and 19.6). Although agomelatine reduced the score significantly more than placebo in most comparisons, the mean difference between agomelatine and the placebo was never more than a few points. For example in a trial of 503 randomised patients, mean scores were reduced to 17.1 with placebo and to 15.0 and 15.9 with agomelatine 25 mg and 50 mg.5

Agomelatine has also been compared with other antidepressants. A comparative trial with sertraline favoured agomelatine after six weeks, however, the difference in mean scores (Hamilton rating scale) between treatments was only 1.68.6 Agomelatine has also been compared to fluoxetine and paroxetine. However, superiority of the active treatments over placebo was not consistently shown and most of these studies have not been published.

The ability of agomelatine to prevent relapse of major depression has also been investigated in a 24-week trial of patients who had already responded to 8–10 weeks of agomelatine treatment. Relapse rates were significantly lower for patients who continued agomelatine (after 8–10 weeks) compared to those who switched to placebo (20.6% vs 41.4%).7 However in a similar but unpublished study, relapse rates for agomelatine and placebo were not significantly different (25.9% vs 23.5%).

After oral administration, agomelatine is rapidly absorbed with peak plasma concentrations reached within 1–2 hours. Bioavailability is low and varies considerably between individuals. It is increased by oral contraceptives and female gender and decreased by smoking. Agomelatine is rapidly metabolised by the cytochrome P450 isoenzyme CYP1A2, and to a lesser extent by CYP2C9 and CYP2C19. The inactive metabolites are mainly eliminated in the urine. Potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin, are contraindicated with agomelatine and caution is urged if patients are taking a moderate inhibitor such as propranolol.

Over 3900 patients took agomelatine in the depression trials. The most common adverse effects were headache (14.1%), nausea (7.7%), dizziness (5.5%), dry mouth (3.5%), diarrhoea (3.1%), somnolence (2.9%), fatigue (2.6%), abdominal pain (2.4%) and insomnia (2.4%). These were mostly mild to moderate. There were four deaths out of 3956 patients who took agomelatine and one out of 826 patients who took placebo – these were all due to suicide. There were more suicide attempts with agomelatine than with placebo (0.6% vs 0.4%).

Increases in liver enzymes (more than three times the upper limit of normal range) occurred in around 1% of people taking agomelatine. This effect seemed to be dose-related. Serious hepatic reactions included hepatitis and a transaminase elevation more than 10 times the upper limit of the normal range. Agomelatine should not be given to people with cirrhosis or active liver disease. Liver function tests should be performed before a patient starts treatment and at regular intervals during treatment. Consuming alcohol with agomelatine is not advisable.

Caution is urged in patients with impaired renal function and those aged 65 or over. Agomelatine should not be used in elderly patients with Alzheimer's disease.

Although agomelatine reduces symptoms of depression on the Hamilton rating scale, its effect seems to be only marginally better than placebo, if at all. This questionable efficacy coupled with the potential risk of adverse hepatic reactions suggests that doctors are probably better continuing with the more established antidepressants.

Read about The Transparency Score manufacturer provided additional useful information

The Transparency Score () is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.



  1. Loo H, Hale A, D'haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002;17:239-47.
  2. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 2006;16:93-100.
  3. Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2c antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol and to a lesser extent by CYP2C9 and CYP2C19. The inactive 2007;10:661-73.
  4. Zajecka J, Schatzberg A, Stahl S, Shah A, Caputo A, Post A. Efficacy and safety of agomelatine in the treatment of major depressive disorder. J Clin Psychopharmacol 2010;30:135-44.
  5. Stahl SM, Fava M, Trivedi MH, Caputo A, Shah A, Post A. Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial. J Clin Psychiatry 2010;71:616-26.
  6. Kasper S, Hajak G, Wulff K, Hoogendijk WJG, Montejo AL, Smeraldi E, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry 2010;71:109-20.
  7. Goodwin GM, Emsley R, Rembry S, Rouillon F; Agomelatine Study Group. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2009;70:1128-37.