Which study was this?
A conference presentation of Goodwin G, Rouillon F and Emsley R. Long term efficacy of agomelatine, a novel antidepressant, in the prevention of relapse in outpatients with major depressive disorder (MDD). Presentation at European College of Neuropsychopharmacology Annual Congress, Vienna. October 2007. The Journal of the European College of Neuropsychopharmacology 2007; 17 (Suppl 4); S361.
Why is this of interest?
Agomelatine is a novel antidepressant that acts on melatonin receptors. It was refused a marketing authorisation in 2006 by the European Medicines Agency (EMEA) due to concerns regarding effectiveness, particularly with regard to long-term efficacy and prevention of relapse. Servier recently re-submitted a license application to the EMEA which may may include data from the above study.
What happened in this study?
This study, which is still only available as a conference presentation, was a multisite (psychiatrists and general practitioners) trial involving 492 outpatients with recurrent major depressive disorder (MDD). After an unspecified run-in period, patients received open-label agomelatine 25mg daily which, at week 2, could be increased to 50mg daily for patients with insufficient improvement. At 8-10 weeks responders to treatment (n=339), defined as achieving a total score on the accepted standard Hamilton Rating Scale for Depression (HAM-D) of ≤ 10, were randomised into a double-blind study comparing agomelatine (n=165) vs. placebo (n=174) for 24 weeks. Amongst the agomelatine-treated patients, 141 (85.5%) received the 25mg dose and 24 (14.5%) were on the 50mg dose. The primary endpoint of the study was relapse defined as HAM-D score ≥ 16 or withdrawal due to lack of efficacy, or suicide/suicide attempt.
What were the results?
The incidence of relapse was lower in the agomelatine group compared to placebo, 21.7% vs. 46.1%; P=0.0001. The number needed to treat (NNT) was 4 – i.e. four patients would need to be treated for a period of at least six months to prevent one relapse. The authors of the poster state that the low number of early relapses (up to 8 weeks after randomisation) occurring in the placebo group may be linked to the absence of withdrawal symptoms after abrupt cessation of agomelatine. However, should the drug obtain a licence it remains to be seen what will happen in clinical practice.
This trial shows that patients maintained on agomelatine are less likely to relapse than those transferred to placebo. However, we don’t know how this drug would compare with another established antidepressant used as a comparator instead of placebo. The period when all patients received agomelatine was relatively short to achieve stabilisation of depression (8-10 weeks) – this may have disadvantaged those patients switched to placebo.
NICE guidance recommends SSRIs as first-line treatment in moderate to severe depression. Should the first-choice agent prove ineffective or poorly-tolerated, and the decision is made to offer a further course of antidepressants, then another single antidepressant should be offered. This is discussed in further detail on the depression section of NPC.
If licensed and marketed, agomelatine may have a role in the treatment of depression not responding to initial or subsequent drug therapy. However, there are currently several alternative options with evidence of efficacy and safety, as illustrated in the NICE guidance. On the basis of currently available evidence, initial use of agomelatine by prudent clinicians will be limited.
The National Prescribing Centre produces the “On the Horizon-Future Medicines” resource to provide key senior decision-makers in the NHS with advance information. This sensitises the NHS to significant new medicines, and assists in facilitating local planning, commissioning and a more effective managed introduction. Due to the nature of the information before launch this is available on NHSnet only.