Agomelatine versus other antidepressive agents for major depression: Cochrane systematic review
Assessed as up to date: 2013/07/01
Major depressive disorder (MDD), or depression, is a syndrome characterised by a number of behavioural, cognitive and emotional features. It is most commonly associated with a sad or depressed mood, a reduced capacity to feel pleasure, feelings of hopelessness, loss of energy, altered sleep patterns, weight fluctuations, difficulty in concentrating and suicidal ideation. There is a need for more effective and better tolerated antidepressants to combat this condition. Agomelatine was recently added to the list of available antidepressant drugs; it is a novel antidepressant that works on melatonergic (MT1 and MT2), 5-HT 2B and 5-HT2C receptors. Because the mechanism of action is claimed to be novel, it may provide a useful, alternative pharmacological strategy to existing antidepressant drugs.Objectives
The objective of this review was 1) to determine the efficacy of agomelatine in alleviating acute symptoms of major depressive disorder in comparison with other antidepressants, 2) to review the acceptability of agomelatine in comparison with other antidepressant drugs, and, 3) to investigate the adverse effects of agomelatine, including the general prevalence of side effects in adults.Search methods
We searched the Cochrane Collaboration's Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) to 31 July 2013. The CCDANCTR includes relevant randomised controlled trials from the following bibliographic databases: CENTRAL (the Cochrane Central Register of Controlled Trials) (all years), EMBASE (1974 onwards), MEDLINE (1950 onwards) and PsycINFO (1967 onwards). We checked reference lists of relevant studies together with reviews and regulatory agency reports. No restrictions on date, language or publication status were applied to the search. Servier Laboratories (developers of agomelatine) and other experts in the field were contacted for supplemental data.Selection criteria
Randomised controlled trials allocating adult participants with major depression to agomelatine versus any other antidepressive agent.Data collection and analysis
Two review authors independently extracted data and a double-entry procedure was employed. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability.Main results
A total of 13 studies (4495 participants) were included in this review. Agomelatine was compared to selective serotonin reuptake inhibitors (SSRIs), namely paroxetine, fluoxetine, sertraline, escitalopram, and to the serotonin–norepinephrine reuptake inhibitor (SNRI), venlafaxine. Participants were followed up for six to 12 weeks. Agomelatine did not show any advantage or disadvantage over the other antidepressants for our primary outcome, response to treatment (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.95 to 1.08, P value 0.75 compared to SSRIs, and RR 1.06; 95% CI 0.98 to 1.16, P value 0.16 compared to venlafaxine). Also, agomelatine showed no advantage or disadvantage over other antidepressants for remission (RR 0.83; 95% CI 0.68 to 1.01, P value 0.07 compared to SSRIs, and RR 1.08; 95% CI 0.94 to 1.24, P value 0.73 compared to venlafaxine). Overall, agomelatine appeared to be better tolerated than venlafaxine in terms of lower rates of drop outs (RR 0.40; 95% CI 0.24 to 0.67, P value 0.0005), and showed the same level of tolerability as SSRIs (RR 0.95; 95% CI 0.83 to 1.09, P value 0.44). Agomelatine induced a lower rate of dizziness than venlafaxine (RR 0.19, 95% CI 0.06 to 0.64, P value 0.007).
With regard to the quality of the body of evidence, there was a moderate risk of bias for all outcomes, due to the number of included unpublished studies. There was some heterogeneity, particularly between published and unpublished studies. The included studies were conducted in inpatient and outpatient settings, thus limiting the generalisability of the results to primary care settings. With regard to precision, the efficacy outcomes were precise, but the tolerability outcomes were mostly imprecise. Publication bias was variable and depended on the outcome of the trial. Our review included unpublished studies, and we think that this reduced the impact of publication bias. The overall methodological quality of the studies was not very good. Almost all of the studies were sponsored by the pharmaceutical company that manufactures agomelatine (Servier), and some of these were unpublished. Attempts to contact the pharmaceutical company Servier for additional information on all unpublished studies were unsuccessful.Authors' conclusions
Agomelatine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. Agomelatine was better tolerated than paroxetine and venlafaxine in terms of overall side effects, and fewer participants treated with agomelatine dropped out of the trials due to side effects compared to sertraline and venlafaxine, but data were limited because the number of included studies was small. We found evidence that compared agomelatine with only a small number of other active antidepressive agents, and there were only a few trials for each comparison, which limits the generalisability of the results. Moreover, the overall methodological quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning the efficacy and tolerability of agomelatine.
Guaiana Giuseppe, Gupta Sumeet, Chiodo Debbie, Davies Simon JC, Haederle Katja, Koesters Markus
Agomelatine versus other antidepressant medication for depression
Why is this review important?
Major depression is a serious illness that can cause significant distress both to sufferers and their families. Major depression affects people's work, relationships and self-esteem. It also affects people physically, changing their sleep patterns, concentration and appetite. The symptoms of major depression can lead people to feel hopeless and even suicidal. Antidepressant medications are an effective treatment option for major depression, but many have unpleasant side-effects.
This review is important because it compares a new antidepressant, called agomelatine, with some other antidepressants used to treat major depression. Agomelatine works in a different way to existing antidepressants, it affects the hormone melatonin in the brain, and stimulates release of the brain chemicals dopamine and norepinephrine.
Who may be interested in this review?
People affected by major depression.
General Practitioners (GPs), psychiatrists and pharmacists.
Professionals working in adult mental health services.
Families and friends of people who suffer from major depression.
What questions does this review aim to answer?
Does agomelatine work better than other antidepressant medications?
Do patients tolerate agomelatine better than other antidepressants?
How do the side-effects of agomelatine compare with other antidepressants?
Which studies were included in the review?
In July 2013, we used electronic medical databases to find all published and unpublished medical trials that compared agomelatine with any other antidepressant. We also contacted Servier Laboratories (the developers of agomelatine) for additional information. To be included in the review, medical trials had to have a randomised design (i.e. be randomised controlled trials), and have adult participants (aged over 18) with a diagnosis of major depression.
We identified 13 medical trials, involving a total of 4495 participants, that could be included in the review. The reviewers rated the overall quality of the trials as 'moderate'. Almost all of the trials included were sponsored by the pharmaceutical company that developed agomelatine (Servier), which could introduce bias (research shows that funding strongly affects the outcomes of research studies).
What does the evidence from the review tell us?
The review included trials comparing agomelatine with a group of antidepressants called selective serotonin reuptake inhibitors (SSRIs), and one antidepressant from the serotonin–norepinephrine reuptake inhibitor group, called venlafaxine. Participants in the studies were followed up for between six to 12 weeks.
- Agomelatine was no more or less effective in reducing symptoms of depression than any of the other antidepressants.
- Agomelatine was no more or less effective in preventing relapse of depression than any of the other antidepressants.
- Agomelatine was tolerated better than venlafaxine (fewer people discontinued treatment), but the same as the SSRIs.
- Agomelatine caused a lower rate of dizziness than venlafaxine.
- Agomelatine caused a lower rate of vomiting, nausea and sexual side-effects than SSRIs.
What should happen next?
The reviewers conclude that agomelatine is not more effective than other antidepressants currently on the market. It did seem to be more tolerable to patients in terms of lower rates of some side-effects, however, the quality of trials was low and there were only a few trials that compared agomelatine with each medication. No firm conclusion on agomelatine can be made because of problems with reporting of data in the trials included. The authors recommend that further trials of agomelatine versus placebo (dummy pill), particularly in primary care settings (where the majority of patient/practitioner contact take place, e.g. GP surgeries), should be carried out to improve the quality of evidence.
Implications for practice
The results of this review suggest that agomelatine does not offer any significant advantage over other new antidepressant agents in the acute-phase treatment of major depression (with the exception of venlafaxine in terms of tolerability and acceptability). In terms of tolerability, agomelatine did not show a statistically significant higher rate of liver function test abnormalities compared to paroxetine, fluoxetine, or sertraline for up to 12 weeks of initial treatment, but risk ratios for all comparisons were high. There is weak evidence that agomelatine may be tolerated better overall than venlafaxine and paroxetine. We only found evidence comparing agomelatine with a small number of other active antidepressive agents and found only a few trials for each comparison. This limits the generalisability of the results. It is important to point out that no firm conclusion regarding the efficacy and tolerability of agomelatine can be drawn, due the low quality of the studies included.
Implications for research
Given the limited number of studies comparing agomelatine with other antidepressants, it is essential that more high quality randomised controlled trials (RCTs) are designed to compare agomelatine with other antidepressants. These RCTs should be independently funded. The studies included in the present review were relatively short-term (no more than 12 weeks). No data from RCTs are available currently for agomelatine compared to other active treatments in the medium- to long-term. There is a need to explore the use of agomelatine beyond 12 weeks, so future trials should be designed with longer follow-up times. Also, the population included in trials in this review may not be representative of the population routinely seen in primary care clinics or mental health services. RCTs using less restrictive criteria would be useful for elucidating the role of agomelatine in a wider patient population.Get full text at The Cochrane Library
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