Agomelatine Versus Other Antidepressive Agents For Major Depression

Agomelatine versus other antidepressive agents for major
depression (Review)
Guaiana G, Gupta S, Chiodo D, Davies SJC, Haederle K, Koesters M
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 12
http://www.thecochranelibrary.com
Agomelatine versus other antidepressive agents for major depression (Review)

Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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Figure 4.
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Figure 5.
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Figure 6.
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Figure 7.
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Figure 8.
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Figure 9.
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ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Agomelatine vs SSRI, Outcome 1 Response rates. . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Agomelatine vs SSRI, Outcome 2 Remission rates. . . . . . . . . . . . . .
Analysis 1.3. Comparison 1 Agomelatine vs SSRI, Outcome 3 Total drop outs. . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Agomelatine vs SSRI, Outcome 4 Drop out due to inefficacy. . . . . . . . . . .
Analysis 1.5. Comparison 1 Agomelatine vs SSRI, Outcome 5 Drop outs due to side effects. . . . . . . . . .
Analysis 1.6. Comparison 1 Agomelatine vs SSRI, Outcome 6 Total number of patients with side effects. . . . .
Analysis 1.7. Comparison 1 Agomelatine vs SSRI, Outcome 7 Sleepiness or drowsiness. . . . . . . . . . .
Analysis 1.8. Comparison 1 Agomelatine vs SSRI, Outcome 8 Insomnia. . . . . . . . . . . . . . . .
Analysis 1.9. Comparison 1 Agomelatine vs SSRI, Outcome 9 Dry mouth. . . . . . . . . . . . . . . .
Analysis 1.10. Comparison 1 Agomelatine vs SSRI, Outcome 10 Constipation. . . . . . . . . . . . . .
Analysis 1.11. Comparison 1 Agomelatine vs SSRI, Outcome 11 Dizziness. . . . . . . . . . . . . . . .
Analysis 1.12. Comparison 1 Agomelatine vs SSRI, Outcome 12 Agitation or anxiety. . . . . . . . . . . .
Analysis 1.13. Comparison 1 Agomelatine vs SSRI, Outcome 13 Suicide wishes, gestures or attempts. . . . . .
Analysis 1.14. Comparison 1 Agomelatine vs SSRI, Outcome 14 Completed suicide. . . . . . . . . . . .
Analysis 1.15. Comparison 1 Agomelatine vs SSRI, Outcome 15 Vomiting or nausea. . . . . . . . . . . .
Analysis 1.16. Comparison 1 Agomelatine vs SSRI, Outcome 16 Diarrhoea. . . . . . . . . . . . . . .
Analysis 1.17. Comparison 1 Agomelatine vs SSRI, Outcome 17 Sexual dysfunction. . . . . . . . . . . .
Analysis 1.18. Comparison 1 Agomelatine vs SSRI, Outcome 18 Abnormal liver function tests. . . . . . . . .
Analysis 1.19. Comparison 1 Agomelatine vs SSRI, Outcome 19 Depression scales endpoint score. . . . . . .
Analysis 1.20. Comparison 1 Agomelatine vs SSRI, Outcome 20 Subgroup analysis: dosing - response rates. . . .
Analysis 1.21. Comparison 1 Agomelatine vs SSRI, Outcome 21 Sensitivity analysis: excluding trials with > 20% drop outs
- response rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.22. Comparison 1 Agomelatine vs SSRI, Outcome 22 Sensitivity analysis: excluding imputed response rates.
Analysis 1.23. Comparison 1 Agomelatine vs SSRI, Outcome 23 Sensitivity analysis: excluding imputed remission rates.
Analysis 1.24. Comparison 1 Agomelatine vs SSRI, Outcome 24 Sensitivity analysis: excluding trials with imputed SDs.
Analysis 1.25. Comparison 1 Agomelatine vs SSRI, Outcome 25 Sensitivity analysis: response rates - best case. . .
Analysis 1.26. Comparison 1 Agomelatine vs SSRI, Outcome 26 Sensitivity analysis: response rates - worst case. . .
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Analysis 1.27. Comparison 1 Agomelatine vs SSRI, Outcome 27 Sensitivity analysis: remission rates - best case. . .
Analysis 1.28. Comparison 1 Agomelatine vs SSRI, Outcome 28 Sensitivity analysis:remission rates - worst case. . .
Analysis 1.29. Comparison 1 Agomelatine vs SSRI, Outcome 29 Sensitivity anal: excluding studies with bipolar participants
- response rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.30. Comparison 1 Agomelatine vs SSRI, Outcome 30 Additional subgroup analysis: unpublished vs published
trials - response rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Agomelatine vs SNRI, Outcome 1 Response rates. . . . . . . . . . . . . .
Analysis 2.2. Comparison 2 Agomelatine vs SNRI, Outcome 2 Remission rates. . . . . . . . . . . . . .
Analysis 2.3. Comparison 2 Agomelatine vs SNRI, Outcome 3 Total drop outs. . . . . . . . . . . . . .
Analysis 2.4. Comparison 2 Agomelatine vs SNRI, Outcome 4 Drop out due to inefficacy. . . . . . . . . .
Analysis 2.5. Comparison 2 Agomelatine vs SNRI, Outcome 5 Drop outs due to side effects. . . . . . . . .
Analysis 2.6. Comparison 2 Agomelatine vs SNRI, Outcome 6 Total number of patients with side effects. . . . .
Analysis 2.7. Comparison 2 Agomelatine vs SNRI, Outcome 7 Sleepiness or drowsiness. . . . . . . . . . .
Analysis 2.8. Comparison 2 Agomelatine vs SNRI, Outcome 8 Insomnia. . . . . . . . . . . . . . . .
Analysis 2.9. Comparison 2 Agomelatine vs SNRI, Outcome 9 Dry mouth. . . . . . . . . . . . . . .
Analysis 2.10. Comparison 2 Agomelatine vs SNRI, Outcome 10 Constipation. . . . . . . . . . . . . .
Analysis 2.11. Comparison 2 Agomelatine vs SNRI, Outcome 11 Dizziness. . . . . . . . . . . . . . .
Analysis 2.12. Comparison 2 Agomelatine vs SNRI, Outcome 12 Vomiting or nausea. . . . . . . . . . . .
Analysis 2.13. Comparison 2 Agomelatine vs SNRI, Outcome 13 Diarrhoea. . . . . . . . . . . . . . .
Analysis 2.14. Comparison 2 Agomelatine vs SNRI, Outcome 14 Depression scales endpoint score. . . . . . .
Analysis 2.15. Comparison 2 Agomelatine vs SNRI, Outcome 15 Subgroup analysis: dosing - response rates. . . .
Analysis 2.16. Comparison 2 Agomelatine vs SNRI, Outcome 16 Subgroup analysis: severity - response rates. . . .
Analysis 2.17. Comparison 2 Agomelatine vs SNRI, Outcome 17 Sensitivity analysis: excluding trials with > 20% drop
outs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.18. Comparison 2 Agomelatine vs SNRI, Outcome 18 Sensitivity analysis: excluding imputed remission
rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.19. Comparison 2 Agomelatine vs SNRI, Outcome 19 Sensitivity analysis: response rates - best case. . .
Analysis 2.20. Comparison 2 Agomelatine vs SNRI, Outcome 20 Sensitivity analysis: response rates - worst case. . .
Analysis 2.21. Comparison 2 Agomelatine vs SNRI, Outcome 21 Sensitivity analysis: remission rates - best case. . .
Analysis 2.22. Comparison 2 Agomelatine vs SNRI, Outcome 22 Sensitivity analysis: remission rates - worst case. .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

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[Intervention Review]
Agomelatine versus other antidepressive agents for major

depression
Giuseppe Guaiana1 , Sumeet Gupta2 , Debbie Chiodo3 , Simon JC Davies4 , Katja Haederle5 , Markus Koesters5
1 Department of Psychiatry, Western University, St Thomas, Canada. 2 General Adult Psychiatry, Tees, Esk & Wear Valleys NHS
Foundation Trust, Darlington, UK. 3 Social and Epidemiological Research Department, Centre for Addiction and Mental Health,
London, Canada. 4 School of Social and Community Medicine, University of Bristol, Bristol, UK. 5 Department of Psychiatry II, Ulm
University, Guenzburg, Germany
Contact address: Giuseppe Guaiana, Department of Psychiatry, Western University, Saint Thomas Elgin General Hospital, 189 Elm
Street, St Thomas, Ontario, N5R 5C4, Canada. Giuseppe.Guaiana@sjhc.london.on.ca. gguaiana@stegh.on.ca.
Editorial group: Cochrane Depression, Anxiety and Neurosis Group.
Publication status and date: New, published in Issue 12, 2013.
Review content assessed as up-to-date: 1 July 2013.
Citation: 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.
ABSTRACT
Background
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 Collaborations Depression, Anxiety and Neurosis Review Groups 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.
PLAIN LANGUAGE SUMMARY

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
peoples 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.


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Agomelatine compared to SSRI for major depression

Patient or population: patients with major depression
Settings: inpatients and outpatients
Intervention: agomelatine
Comparison: SSRI
Outcomes
Response rates
Number of participants
showing a reduction of at
least 50% on the Hamilton
Depression Rating Scale
for Depression, the Montgomery-Asberg Depression Rating Scale or any
other depression scale
Follow-up: 6 to 12 weeks
Illustrative comparative risks* (95% CI)
Assumed risk
Corresponding risk
SSRI
Agomelatine
Study population
610 per 1000
Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence

(GRADE)
RR 1.01
(0.95 to 1.08)
3826
(10 studies)

very low1,2
RR 0.83
(0.68 to 1.01)
3826
(10 studies)

very low1,2,3
Comments
616 per 1000

(579 to 658)
Moderate
557 per 1000
Remission rates
Study population
The number of participants who achieved remission as defined by:
a score of 7 or less
on the 17-item Hamilton
Depression Rating Scale;
10 or less on the Montgomery-Asberg Depression Rating Scale; not ill
or borderline mentally ill
563 per 1000

(529 to 602)
Most of the difference in
heterogeneity existed between published and unpublished studies

on the Clinical Global Impression - Severity; or any

other equivalent value on
363 per 1000
a depression scale defined by the authors
Moderate
264 per 1000
Total drop outs

Total number of participants who dropped out
during the trial as a proportion of the total number of randomised participants
Study population
Drop out due to inefficacy

who dropped out due to
inefficacy during the trial,
as a proportion of the total number of randomised
participants
Study population
189 per 1000
302 per 1000

(247 to 367)
219 per 1000

(180 to 267)
RR 0.95
(0.83 to 1.09)
3826
(10 studies)

very low1,2
RR 0.99
(0.71 to 1.37)
3377
(9 studies)

very low1,2,3
RR 0.68
(0.51 to 0.91)
3377
(9 studies)

very low1,2
180 per 1000

(157 to 206)
Moderate
188 per 1000
44 per 1000
179 per 1000

(156 to 205)
43 per 1000
(31 to 60)
Moderate
49 per 1000
Drop outs due to side ef- Study population

fects
side effects during the
trial, as a proportion of
49 per 1000
(35 to 67)

the total number of randomised participants

70 per 1000
47 per 1000
(35 to 63)
Moderate
65 per 1000
Total number of partici- Study population

pants with side effects
Total number of par- 594 per 1000
ticipants experiencing at
least one side effect
Follow-up: 6 to 12 weeks Moderate
611 per 1000
44 per 1000
(33 to 59)
RR 0.91
(0.84 to 0.98)
2490
(6 studies)

very low1,2
540 per 1000

(499 to 582)
556 per 1000

(513 to 599)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: we are very uncertain about the estimate
1
Most studies were funded by the pharmaceutical company that manufactures agomelatine (Servier). Four out of ten studies were
unpublished
2 The studies included in our review were conducted in inpatient and outpatient settings. Results may not be generalisable for a primary
care setting
3 Heterogeneity is very high
6
BACKGROUND
Description of the condition

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, hopelessness, loss of energy, altered sleep patterns, weight fluctuations, difficulty in concentrating and suicidal ideation (APA 2000). MDD is among the
most common medical illnesses. The National Co-morbidity Survey Replication estimated the lifetime prevalence of MDD to be
16.2% and the 12-month prevalence to be 6.6%, with a mean
depressive episode duration of 16 weeks (Kessler 2003). Women
were 1.7 times more likely than men to have MDD (Kessler 2003).
MDD is associated with marked personal, social and economic
morbidity; loss of functioning and productivity; and creates significant demands on service providers in terms of workload (NICE
2004). It is the third leading cause of burden from disease and
accounts for 4.5% of all human disability (WHO 2008). Additionally, MDD is expected to show a rising trend in the next 20
years (WHO 2008).
Description of the intervention

The treatment of depression includes both psychological (most
commonly cognitive behavioural and interpersonal therapies) and
pharmacological therapies. With the arrival of selective serotonin
reuptake inhibitors (SSRIs) in the 1980s, and subsequent new
antidepressant drugs, the use of antidepressants to treat depression has increased greatly (Middleton 2001). SSRIs have been recommended for first-line drug use in depression by most of the
treatment guidelines (APA 2000a; Lam 2009; NICE 2004; Taylor
2009), largely because of having a better safety profile, rather than
superior efficacy. SSRIs are not without problems. Their effect size
has been found to be small in comparison to placebo, in mild to
moderate depression (Fournier 2010). Moreover, in clinical trials,
SSRIs are associated with sexual dysfunction in 30% to 70% of
participants (Clayton 2006). SSRIs also cause difficulties in sleep
and agitation (Dording 2002). Therefore, the search is on for better
antidepressant drugs. The ideal medication for depression would
be a drug with a high level of effectiveness and a favourable side-effect profile. Until now there has been little evidence to support one
antidepressant over another. A number of previous meta-analyses
have concluded that there are no significant differences in either
efficacy or acceptability between the various second-generation
antidepressants currently on the market (AHRQ 2007; Hansen
2005), although a recent multiple treatment meta-analysis of 12
new-generation antidepressant drugs, which used both direct and
indirect data, reported the possible superiority of sertraline and escitalopram in terms of efficacy and acceptability (Cipriani 2009).
Agomelatine was recently added to the list of available antidepressant drugs; it works on melatonergic (MT1 and MT2 ), 5-HT2B
and 5-HT2C receptors. Since its mechanism of action is claimed to
be novel, it may provide a useful alternative pharmacological strategy to existing antidepressant drugs. Its positive effect on the sleepwake cycle and lack of serious side effects, including sexual side effects, may provide added advantages (Dolder 2008). Agomelatine
has been licensed in the EU for the treatment of depression since
2009 (EMEA 2009). Novartis discontinued the development of
agomelatine for the US market in 2011 (Novartis 2012).
How the intervention might work

Agomelatine is a new antidepressant drug with a unique mechanism of action. It acts as an agonist on melatonin MT1 and MT2
receptors, and an antagonist on 5-HT2B and 5-HT2C receptors.
The MT1 receptor directly inhibits firing of the neurons in the
suprachiasmatic areas in the hypothalamus, regulating the amplitude of circadian rhythmicity, whilst the MT2 receptor is responsible for the entrainment of circadian rhythms (San 2008).
Antagonism at 5-HT2C receptor causes a postulated increase in
frontal dopamine transmission in animal models (Millan 2003).
Agomelatine has shown some antidepressant-like activity in animal models of depression (Popoli 2009). It has been studied for
major depression in adults at doses of 25 mg to 50 mg/day given
in the evenings (Popoli 2009).
Why it is important to do this review

Agomelatine is a unique antidepressant drug that has been found
to be effective when compared with placebo and other antidepressant drugs (Kasper 2008). Its efficacy and tolerability compared
to other antidepressants have been assessed in a recent meta-analyses of published trials (Singh 2011), and a pooled analysis of selected trials (Kasper 2013). Another systematic review of placebo
controlled trials (Koesters 2013), questioned whether there is a
clinically important difference between agomelatine and placebo.
However, as shown by Howland 2011 and Koesters 2013, published evidence for agomelatine may be influenced by publication
bias. Therefore, there is good reason to conduct a systematic quantitative review using both published and unpublished evidence for
its comparative efficacy, and adverse effects, against other 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.
METHODS
Criteria for considering studies for this review
Types of studies
We included all randomised controlled trials using a parallel
group design that compared agomelatine with other antidepressant agents as monotherapies. For cross-over trials we included
only the results from the first randomised period.
Comparator interventions
1. Selective serotonin reuptake inhibitors (SSRIs; fluoxetine,

fluvoxamine, citalopram, paroxetine, escitalopram)
2. Serotonin-norepinephrine reuptake inhibitors (SNRIs;
venlafaxine, duloxetine, milnacipran)
3. Other antidepressive agents (tricyclic or heterocyclic
antidepressants; monoamine oxidase inhibitors (MAOIs); newer
agents (mirtazapine, bupropion, reboxetine); atypical
antipsychotics in monotherapy (risperidone, paliperidone,
olanzapine, quetiapine, aripiprazole, amisulpride, ziprasidone);
non-conventional (herbal products such as Hypericum).
In future updates, if studies become available, we will group the
other antidepressants according to classes in further comparisons.
We applied no restrictions regarding dose, frequency, intensity or
duration.
We excluded trials in which agomelatine was used as an augmentation strategy.
Types of outcome measures
Types of participants
1. Participants of both sexes, aged 18 years or older, with a
primary diagnosis of major depression.
2. We included studies that used any standardised criteria to
define unipolar major depression. We expected that most studies
would use DSM-IV (APA 1994), DSM- IV-TR (APA 2000), or
ICD-10 (WHO 1992). Older studies might have used ICD-9
(WHO 1978), DSM-III (APA 1980), DSM- III-R (APA 1987),
or other diagnostic systems. We excluded studies that used ICD9 because it does not have operationalised criteria, but only
disease names and no diagnostic criteria. However, we included
studies that used Feighner criteria (Feighner 1972), or Research
Diagnostic Criteria (Spitzer 1978).
3. We included studies in which less than 20% of participants
were suffering from bipolar depression, but we examined the
validity of the decision in a sensitivity analysis.
4. We did not consider a concurrent secondary diagnosis of
another psychiatric disorder as a criterion for exclusion, though
we did consider a concurrent primary diagnosis of Axis I or II
disorders as an exclusion criterion. We excluded participants
with a concurrent DSM-IV diagnosis of schizophrenia,
delusional disorder, or a psychosis not otherwise specified. We
excluded antidepressant trials in depressive participants with a
serious concomitant medical illness.
Types of interventions
Experimental intervention
1. Agomelatine
Primary outcomes
Our primary outcome measure for efficacy was:

1. the number of participants who responded to treatment,
showing a reduction of at least 50% on the Hamilton Rating
Scale for Depression (HAM-D) (Hamilton 1960), the
Montgomery Asberg Depression Rating Scale (MADRS)
(Montgomery 1979), or any other depression scale (e.g. the Beck
Depression Inventory (Beck 1987), or the CES-D scale (Radloff
1977)); or were much or very much improved (score 1 or 2) on
the Clinical Global Impression-Improvement (CGI-I) (Guy
1976).
Secondary outcomes
Our secondary outcome measures included:

1. the number of participants who achieved remission as
defined by: a score of 7 or less on the 17-item HAM-D, or 8 or
less on the longer version of HAM-D; 10 or less on the MADRS;
not ill or borderline mentally ill on the CGI-S (Guy 1976); or
any other equivalent value on a depression scale defined by the
authors. We preferred remission rates defined by the HAM-D or
MADRS scores.
2. group mean scores at endpoint on HAM-D, MADRS,
CGI-S or any other depression rating scale score.
Acceptability was evaluated using the following outcome measures:
1. total drop-out rate: i.e. total number of participants who
dropped out during the trial as a proportion of the total number
of randomised participants.
2. drop-out rates due to inefficacy: i.e. number of participants
who dropped out due to inefficacy during the trial as a
proportion of the total number of randomised participants.

3. drop-out rates due to side effects: i.e. number of

participants who dropped out due to side effects during the trial
as a proportion of the total number of randomised participants.
Tolerability was evaluated using the following outcome measures:
1. total number of participants experiencing at least some side
effects.
2. total number of participants experiencing the following
specific side effects:
i) sleepiness or drowsiness;
ii) insomnia;
iii) dry mouth;
iv) constipation;
v) dizziness;
vi) hypotension;
vii) agitation or anxiety;
viii) suicide wishes, gestures or attempts;
ix) completed suicide;
x) vomiting or nausea;
xi) diarrhoea;
xii) sexual dysfunction;
xiii) abnormal liver function tests;
xiv) weight gain;
xv) hypertension.
In order not to miss any relatively rare or unexpected yet important
side effects, in the data extraction phase we collected all side-effect
data reported in the literature and discussed ways to summarize
them later.
International Clinical Trials Registry Platform (ICTRP)), pharmaceutical companies, the handsearching of key journals, conference proceedings and other (non-Cochrane) systematic reviews
and meta-analyses.
Details of CCDANs generic search strategies (used to identify
RCTs) can be found on the Groups website.
Electronic searches
1. The CCDANCTR-Studies Register was searched using the
following terms: Diagnosis = depress* and Intervention =
agomelatine and Age group = (adult or aged or unclear or not
stated)
2. The CCDANCTR-References Register was searched using
free-text terms to identify additional untagged/uncoded reports
of RCTs: (depress* and agomelatine)
3. International trial registers were searched via the WHO
International Clinical Trials Registry Platform (ICTRP), which
includes access to Controlled-Trials.com where Servier
Laboratories (developers of agomelatine) register their trial
protocols. The following search terms were used: (agomelatine or
valdoxan or thymanax)
The literature search was last updated on 31 July 2013.
Searching other resources
Personal communication
Search methods for identification of studies
The Cochrane Depression, Anxiety and Neurosis

Review Groups Specialised Register (CCDANCTR)
The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) maintains two clinical trials registers at the editorial base in
Bristol, UK: a references register and a studies-based register. The
CCDANCTR-References Register contains over 31,500 reports
of RCTs in depression, anxiety and neurosis. Approximately 65%
of these references have been tagged to individual, coded trials.
The coded trials are held in the CCDANCTR-Studies Register
and records are linked between the two registers through the use
of unique Study ID tags. Coding of trials is based on the EU-Psi
coding manual, using a controlled vocabulary (please contact the
CCDAN Trials Search Co-ordinator for further details). Reports
of trials for inclusion in the Groups registers are collated from
routine (weekly), generic searches of MEDLINE (1950 onwards),
EMBASE (1974 onwards) and PsycINFO (1967 onwards); quarterly searches of the Cochrane Central Register of Controlled Trials
(CENTRAL) and review-specific searches of additional databases.
Reports of trials are also sourced from international trials registers
c/o the World Health Organizations (WHO) trials portal (the
We contacted experts in the field for information on unpublished

or ongoing studies, or to request additional trial data.
We contacted Servier Laboratories directly in Slough (UK) and
Paris (France), but they failed to respond to our request for additional data.
Reference checking
We checked the reference lists of all included studies, relevant

reviews and regulatory agency reports to identify additional studies
missed from the original electronic searches, and also conducted
a cited reference search on the Web of Science.
Data collection and analysis

Selection of studies
The selection of trials for inclusion in this systematic review was
done by two of the review authors.
Both review authors inspected the search hits by reading the titles
and the abstracts to see if they met the inclusion criteria. Possible
doubts were resolved by consultation with each other. We obtained
each potentially relevant study located in the search as a full article,

then two review authors independently assessed each for inclusion,

and, if there was disagreement sought resolution through discussion between review authors. The discordance in the selection of
studies was calculated using Cohens Kappa (k) (Cohen 1960), a
more robust measure than a simple per cent agreement calculation
since it takes into account the agreement between review authors
that occurs by chance. Where it was not possible to evaluate the
study because of language problems or missing information, we
have classified the study as a study awaiting classification until we
can obtain either a translation or further information. We have
reported the reasons for exclusion of trials in the Characteristics
of included studies table.
Data extraction and management
Two review authors independently used a data extraction form
to extract the data from included studies concerning participant
characteristics (age, sex, severity of depression, study setting), intervention details (dosage, duration of study, sponsorship), study
characteristics (blinding, allocation etc.) and outcome measures of
interest. Again, any disagreement was resolved by consensus or by
the third member of the review team. If necessary, we contacted
authors of studies to obtain clarification.
Main comparisons
1. Agomelatine versus SSRIs

2. Agomelatine versus SNRIs
3. Agomelatine versus other antidepressive agents (see Types
of interventions)
Where sufficient data were available, we presented the results
grouped by substance as well.
in order to obtain further information. We agreed to report nonconcurrence in quality assessment.

Measures of treatment effect
The main outcome result was response to treatment. The improvement is usually presented as either a change in a depression scale(s)
(mean and standard deviation), or as a dichotomous outcome (responder or non-responder, remitted or not-remitted), or both.
(1) Binary or dichotomous data
For binary outcomes we calculated a standard estimation of the

random-effects model risk ratio (RR) and its 95% confidence interval (CI). It has been shown that RR is more intuitive than odds
ratio (Boissel 1999), and odds ratios tend to be interpreted as RR
by clinicians (Deeks 2000). This misinterpretation then leads to
an overestimation of the impression of the effect. For statistically
significant results we calculated the number needed to treat to
benefit or harm statistic (NNTB or NNTH) and its 95% CI using Visual Rx (http://www.nntonline.net/), taking account of the
event rate in the control group.
(2) Continuous data
(a) Summary statistics

It was likely that different studies would use a variety of depression rating scales; therefore we used standardised mean difference
(SMD). If all included studies had used the same instrument, we
would have used mean differences (MD).
Assessment of risk of bias in included studies

Again working independently, two authors assessed risk of bias
using the tool described in the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2011). This tool encourages consideration of how the sequence was generated, how allocation was
concealed, the integrity of blinding at outcome assessment, the
completeness of outcome data, selective reporting and other biases. We also considered sponsorship bias.
The risk of bias, in each domain and overall, was assessed and
categorised as either:
1. low risk of bias, i.e. plausible bias unlikely to seriously alter
the results; or
2. high risk of bias, i.e. plausible bias that seriously weakens
confidence in the results; or
3. unclear risk of bias, i.e. plausible bias that raises some doubt
about the results.
If the assessors disagreed, the final rating was made by consensus
or with the involvement of another member of the review group.
Where insufficient details of randomisation and other characteristics of trials were provided, we contacted authors of the studies
(b) Endpoint versus change data

We preferred to use scale endpoint data, which typically cannot
have negative values and are easier to interpret from a clinical point
of view. When endpoint data were unavailable, we used the change
data. If we used MD, we pooled results based on change data and
endpoint data in the same analysis.
Unit of analysis issues
(1) Cross-over trials
Cross-over trials are trials in which all participants receive both the
control and intervention treatment but not in the same order. The
major problem with this design of trial is a carry-over effect from
the first phase to the second phase of the study, especially if the
condition of interest is unstable (Elbourne 2002). As this is the
case with depression, randomised cross-over studies were eligible,
but we would only use data up to the point of first cross-over.

10
(2) Studies with multiple treatment groups
Where a study involved more than two agomelatine arms, especially two appropriate dose groups of an antidepressant drug,
the different dose arms were pooled and considered to be one.
For dichotomous outcomes sample sizes and the event numbers
were summed across groups. For continuous outcomes, means and
standard deviations were grouped using the methods described in
Chapter 7 (Section 7.7.3.8) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). In three-armed trials
with placebo groups, we only considered data from active treatments.
without these studies. If the data had been log-transformed for

analysis, and the geometric means were reported, skewness was
reduced. This is the recommended method of analysis of skewed
data. If papers used non-parametric tests and described averages
using medians, they could not be pooled formally in the analysis.
We followed the recommendation made by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) that
results of these studies are reported in a table in our review, along
with all other papers. This meant that the data were not lost from
the review and these results could be considered when drawing
conclusions, even if they could not be pooled formally in the analyses.
Dealing with missing data

We tried to contact the authors for all relevant missing data.
(1) Dichotomous outcomes
Response, or remission on treatment, was calculated using an intention-to-treat analysis (ITT). We followed the principle once
randomised always analyse. In trials where participants left the
study before the intended endpoint, it was be assumed that they
would have experienced a negative outcome. The validity of
the above assumption was tested by sensitivity analysis, applying
worst-case and best-case scenarios. When dichotomous outcomes
were not reported, but the baseline mean and standard deviation
on a depression scale were reported, we calculated the number of
responding or remitted participants according to a validated imputation method (Furukawa 2005). We analysed the validity of
the above approach by sensitivity analysis.
(2) Continuous outcomes
The Cochrane Handbook for Systematic Reviews of Interventions recommends avoiding imputations of continuous data and suggests
that the data must be used in the form they were presented by the
original authors. We preferred ITT data, when available, to perprotocol analysis.
(3) Skewed or qualitative data
We presented skewed and qualitative data descriptively.

We considered several strategies for skewed data. If papers reported
a mean and standard deviation, and there was also an absolute
minimum possible value for the outcome, we divided the mean by
the standard deviation. If this was less than two, then we concluded
that there was some indication of skewness. If it was less than one
(that is the standard deviation was bigger than the mean) then
skewness was almost certainly present. If papers had not reported
the skewness and simply reported means, standard deviations and
sample sizes, these numbers were used. We did this because there
was a possibility that these data may not have been properly analysed, and can also be misleading; we conducted analyses with and
(4) Missing statistics
When only P or standard error (SE) values were reported, we calculated standard deviations (SDs) (Altman 1996). In the absence
of supplementary data after requests to the authors, we calculated
the SDs according to a validated imputation method (Furukawa
2006). We examined the validity of these imputations in the sensitivity analyses. We applied ITT analyses, in which all the drop
outs not included in the analyses were considered to be non-responders. We examined the validity of this decision in the sensitivity analyses by applying worst-case and best-case scenarios. We
presented symptom levels as either continuous (mean SD) or
dichotomous outcomes (improved or not improved).
Assessment of heterogeneity
We followed the Cochrane Handbook for Systematic Reviews of Interventions recommendations (I2 statistic values 0% to 40%: might
be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75%
to 100%: represent considerable heterogeneity). We also used Chi
2 and its P value to determine the direction and magnitude of
the treatment effects. In a meta-analysis of few trials, Chi2 will
be underpowered to detect heterogeneity, if it exists. Therefore, a
P value of less than 0.10 was used as the threshold for statistical
significance (Higgins 2011).
Assessment of reporting biases

Reporting biases arise when the dissemination of research findings
is influenced by the nature and direction of results. These are
described in section 10.1 of the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2011). A funnel plot is usually
used to investigate publication bias. However, it has a limited
role when there are only a few studies of similar size. Secondly,
asymmetry of a funnel plot does not always reflect publication
bias. We did not use funnel plots for outcomes if there were 10 or
fewer studies, or if all studies were of similar size.

11
Data synthesis
We used a random-effects model to calculate the treatment effects.
We preferred the random-effects model as it takes in to account
differences between studies even when there is no evidence of
statistical heterogeneity. It gives a more conservative estimate than
the fixed-effect model. We note that the random-effects model
gives added weight to small studies, which can either increase or
decrease the effect size. We also did the analysis using a fixed-effect
model to see whether it changed the effect size markedly.
Subgroup analysis and investigation of heterogeneity

We note that subgroup analyses are often exploratory in nature and
should be interpreted very cautiously: firstly, because they often
involve multiple analyses and this can lead to false positive results;
and secondly, because these analyses lack power and are more likely
to result in false positive results. Bearing the above reservations in
mind, we performed the following subgroup analyses.
1. Agomelatine dosing (fixed low dosage: 25 mg/day; fixed
high dosage: 50 mg and above; flexible high dose and flexible low
dose). The standard dose of agomelatine is 25 mg to 50 mg per
day. There is evidence to suggest that low dose antidepressants
may be associated with better outcomes both in terms of
effectiveness and tolerability (Bollini 1999). Similarly, fixed
versus flexible dose can also affect the estimate of treatment
effectiveness (Khan 2003).
2. Severity of depression (mild, moderate, severe depression).
This analysis might have been useful in assessing the efficacy of
agomelatine in different subpopulations of participants divided
by severity.
3. Treatment settings (primary care, psychiatric inpatients, or
psychiatric outpatients). This analysis might have been useful in
identifying whether agomelatine could have been more or less
effective in different treatment settings.
4. Older participants (participants aged 65 years or more)
separately from other adult participants. This analysis might
have been useful for finding out whether agomelatine could have
more or less efficacy among older participants.
5. Examination of wish bias by comparing agomelatine as
the investigational drug versus agomelatine as the comparator, as
there is evidence to suspect that a new antidepressant might
perform worse when used as a comparator than when used as an
experimental agent (Barbui 2004).
6. Examination of publication bias by assessing response to
agomelatine in unpublished studies versus response to
agomelatine in published studies. This analysis might be useful
in determining whether there is a significant difference in
reported outcome in published studies versus unpublished
studies, in order to be able to assess publication bias.
If groups within any of the subgroups were found to be significantly different from one another, we planned to run meta-regressions for exploratory analyses of additive or multiplicative influ-
ences of the variables in question.

Sensitivity analysis
The following sensitivity analyses were planned a priori. By limiting the included studies to those of higher quality, we examined
whether the results changed, and checked for the robustness of the
observed findings.
1. Excluding trials with unclear concealment of random
allocation or unclear double blinding, or both; and trials with
inadequate concealment of random allocation.
2. Excluding trials with drop-out rates greater than 20%.
3. Performing the worst-case scenario ITT (i.e. all the
participants in the experimental group experienced the negative
outcome and all those allocated to the comparison group
experienced the positive outcome) and the best-case scenario
ITT (i.e. all the participants in the experimental group
experienced the positive outcome and all those allocated to the
comparison group experienced the negative outcome).
4. Excluding trials for which the response rates had to be
calculated via the imputation method (Furukawa 2005), and
those for which the SD had to be borrowed from other trials
(Furukawa 2006).
5. Excluding all cross-over trials.
6. Excluding studies funded by the pharmaceutical company
marketing agomelatine (Servier). This sensitivity analysis is
particularly important in view of the repeated findings that
funding strongly affects the outcomes of research studies
(Als-Nielsen 2003; Bhandari 2004; Lexchin 2003), and because
industry sponsorship and authorship of clinical trial reports has
increased over the last 20 years (Buchkowsky 2004).
7. Excluding studies in which there were any participants
diagnosed with bipolar depression.
Our routine application of random-effects and fixed-effect models, as well as our secondary outcomes of remission rates and continuous severity measures, might be considered to be additional
forms of sensitivity analyses.
Summary of findings table
A Summary of findings (SoF) table was made for each comparison (agomelatine versus SSRI and agomelatine versus SNRI). Six
outcomes were chosen to build the two tables, based on their importance (response rate, remission rates, total drop outs, drop out
due to inefficacy, drop outs due to side effects, total number of
participants experiencing at least one side effect). The SoF table is
based on the GRADE (Grading of Recommendations Assessment
Development and Evaluation) system (Rosenbaum 2010). The
GRADE system is a formal way of evaluating the quality of evidence, using several parameters, in order to achieve transparency
and simplicity (Guyatt 2008). Initially, evidence for each RCT is
considered as high, and then downgraded for a variety of reasons,
including study limitations, inconsistency of results, indirectness

12
of evidence, imprecision and reporting bias. On the basis of these

criteria, the evidence can be downgraded to moderate, low or very
low (Guyatt 2008). The inclusion of SoF tables in Cochrane reviews improves understanding and rapid retrieval of key findings
(Rosenbaum 2010).
RESULTS
Description of studies
See Characteristics of included studies; Characteristics of

excluded studies; Characteristics of studies awaiting classification;
Characteristics of ongoing studies.
Results of the search
Initially, we identified 120 references, 88 through database searching and 32 through other sources. These included 28 duplicates
that were excluded, and a further 44 records were excluded after
screening of abstracts. We retrieved full-text copies of the remaining 48 references for more detailed evaluation. Thirty-five studies
were excluded for a variety of reasons. In the end, 13 studies were
included in the qualitative and quantitative synthesis. The literature search was last updated in July 2013.
See Figure 1 for more details on the result of the search.

13
Figure 1. Study flow diagram

14
Included studies
A total of 13 studies was included in this systematic review. Four
of these were unpublished trials carried out by a pharmaceutical
company (Servier; CAGO2303; CL3-022; CL3-023; CL3-024).
Attempts to contact the pharmaceutical company (Servier) for additional information on all unpublished studies were unsuccessful.
With the exception of one study (Martinotti 2012), requests to
authors concerning missing data were also unsuccessful.
Design
All the included studies were randomised trials. Eleven were reported to be double blind, and one study used an open label parallel group design (Martinotti 2012). Five studies were
three-armed with agomelatine, an active comparator and placebo
(CAGO2303; CL3-022; CL3-023; CL3-024; Loo 2002a). Seven
studies were two-armed with agomelatine versus another antidepressant (Corruble 2013; Hale 2010; Kasper 2010; Kennedy 2008;
Lemoine 2007; Martinotti 2012; Quera-Salva 2011).
Sample sizes
Overall, the studies included 4495 participants in active treatment

arms. Of these, 2457 were randomised to agomelatine. Of the
remaining 2048 participants, 1701 were randomised to SSRIs:
862 to fluoxetine, 453 to paroxetine,159 to sertraline and 227 to
escitalopram. The remaining 337 participants were randomised
to an SNRI, venlafaxine. The mean sample size per arm was 156
participants (range 30 to 314). Only one study recruited fewer
than 100 participants overall (Martinotti 2012).
Setting
All studies were multicentre trials. Three studies were conducted in a single nation, namely, the USA (CAGO2303), France
(CL3-022), and Italy (Martinotti 2012). One study was conducted
in France and Spain (Lemoine 2007). One multinational study
recruited Asian participants only (Shu 2013). The other studies
were multinational across continents.
Three studies enrolled both inpatients and outpatients (CL3022; CL3-023; CL3-024). Eight studies recruited outpatients (
Corruble 2013; Hale 2010; Kasper 2010; Kennedy 2008; Lemoine
2007; Martinotti 2012; Quera-Salva 2011; Shu 2013). Two studies did not report the setting (CAGO2303; Loo 2002a).
Participants
All studies included participants with a diagnosis of major depressive disorder (MDD). One study also included participants with
bipolar II depression (Loo 2002a), although the proportion suffering from this condition was no more than 3%. As per our protocol
for the review, Loo 2002a was included in the present review as
less than 20% of the participants in the study had bipolar disorder.
All studies randomised participants from 18 years of age, but the
age ranges recruited varied: two studies recruited participants up
to 70 years of age (CAGO2303; Corruble 2013); three studies
recruited between the ages of 18 to 59 years (CL3-022; CL3023; CL3-024); four studies recruited between the ages of 18 to
60 (Kasper 2010; Kennedy 2008; Martinotti 2012; Quera-Salva
2011); and the final four studies recruited between the ages of 18
to 65 (Hale 2010; Lemoine 2007; Loo 2002a; Shu 2013).
Interventions and comparators
Most studies compared agomelatine to SSRIs: three compared

agomelatine to paroxetine (CAGO2303; CL3-023; Loo 2002a);
four compared agomelatine to fluoxetine (CL3-022; CL3-024;
Hale 2010; Shu 2013); two compared agomelatine to escitalopram
(Corruble 2013; Quera-Salva 2011); and one compared agomelatine to sertraline (Kasper 2010). Three studies compared agomelatine to an SNRI, venlafaxine (Kennedy 2008; Lemoine 2007;
Martinotti 2012).
Outcomes
Efficacy data (either as dichotomous or as continuous outcome)

and tolerability/acceptability data were available for all 13 included
studies and could be entered into a meta-analysis.
All but one study used HAM-D as rating scale for primary or
secondary outcome measures; Kennedy 2008 used MADRS instead. Ten studies reported response rates: data for one study was
provided by the authors upon request (Martinotti 2012), and we
imputed response rates for the remaining two studies from continuous data (CL3-023; CL3-024). Seven studies reported remission rates: data for one study was provided by the authors upon
request (Martinotti 2012), and we imputed remission rates for the
remaining five studies from continuous data (CL3-023; CL3-024;
Lemoine 2007; Quera-Salva 2011; Shu 2013).
All but one study reported drop outs due to any reason (Kennedy
2008). Nine studies reported drop outs due to side effects
(CAGO2303; CL3-022; CL3-023; Corruble 2013; Hale 2010;
Kasper 2010; Loo 2002a; Quera-Salva 2011; Shu 2013), and the
same nine also reported drop outs due to inefficacy. Six studies reported the total number of participants who experienced
side effects (CAGO2303; Hale 2010; Kasper 2010; Loo 2002a;
Quera-Salva 2011; Shu 2013).

15
Excluded studies
Overall, we excluded 20 studies from the systematic review because
of the inclusion criteria. Nineteen of these did not have an active
control group and one trial was withdrawn prior to enrolment (see
Characteristics of excluded studies and Figure 1).
Ongoing studies
We identified six ongoing studies (see Characteristics of ongoing
studies) (CL3-060; CL3-074; CL3-083; GENRAS; Lundbeck
2011; NCT01483053).
trials were either published (Karaiskos 2013; Montgomery

2004), included in EMEA documents (CL3-027; CL3-048;
CL3-062; CL3-073), retreived from Clinical Trial Registry India
(CRSC11003; CTRI/2011/04/001659) or retreived from conference proceedings (Vasile 2011). One of the published studies was
designed to examine withdrawal symptoms (Montgomery 2004);
data for the first 12 weeks of the study, comparing agomelatine
(25 mg/day) and paroxetine (20 mg/day) were not adequately
reported to be included (see: Characteristics of studies awaiting
classification). The other published study was rated as awaiting
classification because it was unclear whether the trial was randomised (Karaiskos 2013); a request to the authors remains unanswered.
Studies awaiting classification

We classified nine studies as awaiting classification (CL3-027;
CL3-048; CL3-062; CL3-073; CRSC11003; CTRI/2011/04/
001659; Karaiskos 2013; Montgomery 2004; Vasile 2011. Those
Risk of bias in included studies

See: Characteristics of included studies, Figure 2, Figure 3.
Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies

16
Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included
study

17
The overall methodological quality of the studies was not very

good; every study judged as having high or unclear risk of bias in at
least one domain (see Figure 2 and Figure 3 for summary graphs).
Almost all of the studies were sponsored by the pharmaceutical
company that manufactures agomelatine (Servier), and some of
them were unpublished. This last source of bias should be taken
into account when interpreting the results.
Allocation
Ten studies reported no details about the randomisation procedure
and so were judged as having unclear risk of bias (CAGO2303;
CL3-022; CL3-023; CL3-024; Hale 2010; Kasper 2010; Kennedy
2008; Lemoine 2007; Loo 2002a; Shu 2013). One study reported
that randomisation was non-adaptive, balanced, and stratified on
the centre and that an interactive computer-based system allocated
a therapeutic unit number (Martinotti 2012). One study reported
that randomisation was balanced but, did not provide any more
details on the sequence generation (Quera-Salva 2011).
Blinding
All RCTs apart from Martinotti 2012 were reported as double
blind and so were deemed to have low risk of bias. Martinotti
2012, which was an open-label parallel group trial, was judged as
having a high risk of bias in this domain. All but two double-blind
studies reported details of measures employed to ensure successful
blinding (CAGO2303; Loo 2002a).
as having a high risk of bias in this domain. The risk of bias in

Shu 2013 was assessed as unclear, and the remaining studies were
deemed as having low risk of bias.
Other potential sources of bias

All but two of the included RCTs were sponsored by the company
that manufactures agomelatine (Servier) and so were assessed as
having high risk of bias. Martinotti 2012 was funded by a research
department without industry support and it was unclear whether
Loo 2002a was sponsored or not, so these two studies were assessed
as having unclear risk of bias in this domain.
Effects of interventions
See: Summary of findings for the main comparison
Agomelatine compared to SSRI for major depression; Summary
of findings 2 Agomelatine compared to SNRI for major
depression
We have reported the results of the present systematic review by
grouping the comparators into three classes: SSRIs, SNRIs and
other antidepressive agents. Where possible, each comparator is
presented in subgroups.
Comparison one: agomelatine versus other SSRIs
Incomplete outcome data
Primary outcome
Overall, the drop out rate was around 18% for agomelatine and
19% for the control medication; this ranged from 10% in QueraSalva 2011 to 22% in CAGO2303. Three studies had a drop-out
rate of more than 20% (CAGO2303; CL3-024; Loo 2002a).
1.1 Efficacy - number of participants who responded to

treatment
Selective reporting
Study protocols were not available for all the studies. Data from
CL3-022; CL3-023; CL3-024 were limited, as we could not gain
access to the full dataset because the studies were unpublished;
attempts to obtain data from the pharmaceutical company manufacturing agomelatine (Servier) were unsuccessful. Loo 2002a,
CL3-022, CL3-023 and CL3-024 were not registered, thus increasing risk of selective reporting, and Martinotti 2012 did not
report full data on adverse events. CL3-022, CL3-023, CL3-024,
Loo 2002a, Martinotti 2012 and Corruble 2013 were all judged
There was no evidence that agomelatine was less or more effective

than SSRIs as a whole (Mantel-Haenszel risk ratio (RR) 1.01,
95% confidence interval (CI) 0.95 to 1.08, P value 0.75; 10 trials,
3826 participants), statistical heterogeneity was moderate (I =
31%). Considering each comparator, there was no evidence that
agomelatine was less or more effective than: paroxetine (RR 0.92,
95% CI 0.77 to 1.09, P value 0.33, I = 56%; three trials, 1189
participants); fluoxetine (RR 1.01, 95% CI 0.92 to 1.11, P value
0.80, I = 31%; four trials, 1862 participants); sertraline (RR 1.11,
95% CI 0.94 to 1.30, P value 0.23, one trial, 313 participants); or
escitalopram (RR 1.05, 95% CI 0.95 to 1.16, P value 0.33, I =
0%; two trials, 462 participants) (see Analysis 1.1 and Figure 4).

18
Figure 4. Forest plot of comparison: 1 Agomelatine vs SSRI, outcome: 1.1 Response rates
Secondary outcomes
1.2 Efficacy - number of participants who achieve remission

There was no significant difference in the number of participants
who achieved remission between agomelatine and SSRIs as a whole
(RR 0.83, 95% CI 0.68 to 1.01, P value 0.07; ten trials, 3826
participants). Heterogeneity was substantial between studies (I
= 78%). There was no significant difference in the number of

participants who achieved remission between: agomelatine and
paroxetine (RR 0.61, 95% CI 0.32 to 1.18, P value 0.14, I = 84%;
three trials, 1189 participants); fluoxetine (RR 0.76, 95% CI 0.55
to 1.05, P value 0.10, I = 84%; four trials, 1862 participants);
sertraline (RR 1.12, 95% CI 0.80 to 1.58, P value 0.50; one trial,
313 participants); and escitalopram (RR 1.13, 95% CI 0.94 to
1.35, P value 0.20, I = 0%; two trials, 462 participants) (see
Analysis 1.2 and Figure 5).

19
Figure 5. Forest plot of comparison: 1 Agomelatine vs SSRI, outcome: 1.2 Remission rates
1.3 Acceptability - total drop-out rate

There was no evidence that agomelatine was associated with a
lower or higher total drop-out rate than SSRIs as a whole (RR
0.95, 95% CI 0.83 to 1.09, P value 0.44, I = 0%; ten trials,
3826 participants). There was no evidence that agomelatine was
associated with a higher total drop-out rate than: paroxetine (RR
1.01, 95% CI 0.80 to 1.28, P value 0.94; three trials, 1189 participants); fluoxetine (RR 0.96, 95% CI 0.74 to 1.26, P value 0.78,
I = 43%; four trials, 1862 participants); sertraline (RR 0.72, 95%
CI 0.43 to 1.21, P value 0.21; one trial, 313 participants); and
escitalopram (RR 0.81, 95% CI 0.50 to 1.32, P value 0.76, I =
0%; two trials, 462 participants) (see Analysis 1.3 and Figure 6).

20
Figure 6. Forest plot of comparison: 1 Agomelatine vs SSRI, outcome: 1.3 Total drop outs
1.4 Acceptability - drop-out rates due to inefficacy

higher drop-out rate due to inefficacy than SSRIs as a whole (RR
0.99, 95% CI 0.71 to 1.37, P value 0.95, I = 0%; nine trials,
3377 participants). There was no evidence that agomelatine was
associated with a lower or higher drop-out rate due to inefficacy
than: paroxetine (RR 1.07, 95% CI 0.64 to 1.80, P value 0.80,
I = 0%; three trials, 1189 participants); fluoxetine (RR 0.97,
95% CI 0.57 to 1.65, P value 0.91, I = 17%; three trials, 1413
participants); sertraline (RR 0.52, 95% CI 0.16 to 1.68, P value
0.27; one trial, 313 participants); or escitalopram (RR 1.34, 95%
CI 0.43 to 4.21, P value 0.61, I = 0%; two trials, 462 participants)
(see Analysis 1.4).
1.5 Acceptability - drop-out rates due to side effects

There was evidence that fewer participants dropped out due to side
effects when treated with agomelatine compared to other SSRIs as
a whole (RR 0.68, 95% CI 0.51 to 0.91, P value 0.009, I = 0%;
nine studies, 3377 participants, NNTH = 47).
There was no evidence that fewer or more people dropped out due
to side effects when treated with agomelatine compared to: paroxetine (RR 0.83, 95% CI 0.49 to 1.41, P value 0.49, I = 0%; three
studies, 1189 participants); fluoxetine (RR 0.74, 95% CI 0.50 to
1.09, P value 0.13, I = 0%; three studies, 1413 participants); and
escitalopram (RR 0.40, 95% CI 0.15 to 1.06, P value 0.07; two
studies, 462 participants). There was some evidence (albeit with
a small effect size) that agomelatine was associated with a lower
drop-out rate due to side effects compared to sertraline (RR 0.37,

21
95% CI 0.14 to 1.00, P value 0.05; one study, 313 participants,

NNTH = 18) (see Analysis 1.5).
1.6 Tolerability - total number of participants experiencing

at least some side effects
There was evidence (albeit with a small effect size) that fewer participants experienced side effects when treated with agomelatine
than when treated with other SSRIs as a whole (RR 0.91, 95%
CI 0.84 to 0.98, P value 0.01, I = 28%; six studies, 2490 participants, NNTH = 23).
There was evidence that fewer participants experienced at least
some side effects when treated with agomelatine compared to
paroxetine (RR 0.86, 95% CI 0.78 to 0.94, P value 0.0010, I
= 0%; two studies, 905 participants, NNTH = 7). There was no
evidence that fewer or more participants experienced at least some
side effects when treated with agomelatine compared to either fluoxetine (RR 1.00, 95% CI 0.89 to 1.11, P value 0.95, I = 0%;
two studies, 1141 participants) or sertraline (RR 0.98, 95% CI
0.78 to 1.23, P value 0.86; one study, 307 participants). There
was some evidence (albeit with a small effect size) that agomelatine was associated with a lower rate of participants experiencing
side effects compared to escitalopram (RR 0.81, 95% CI 0.66 to
0.99, P value 0.04; one study, 137 participants, NNTH = 6). See
Analysis 1.6.
We also analysed the six outcomes above using a fixed-effect model;
this produced no change in significance levels and only negligible
changes in effect sizes.

specific side effects
(a) Sleepiness or drowsiness

lower or higher rate of participants experiencing sleepiness or
drowsiness compared to all other SSRIs as a group (RR 0.96, 95%
CI 0.43 to 2.15, P value 0.92, I = 68%; five studies, 1868 participants).
lower or higher rate of participants experiencing sleepiness or
drowsiness than: paroxetine (RR 0.63, 95% CI 0.32 to 1.21, P
value 0.16; two studies, 905 participants); fluoxetine (RR 1.75,
95% CI 0.78 to 3.93, P value 0.17; one study, 513 participants);
or escitalopram (RR 0.19, 95% CI 0.02 to 1.55, P value 0.12; one
study, 137 participants). There was evidence that agomelatine was
associated with a higher rate of participants experiencing sleepiness or drowsiness compared to sertraline (RR 4.65, 95% CI 1.02
to 21.16, P value 0.05; one study, 313 participants, NNTH = 22)
(see Analysis 1.7).
(b) Insomnia
lower or higher rate of participants experiencing Insomnia compared to other SSRIs as a group (RR 0.78, 95% CI 0.38 to 1.59,
P value 0.49, I = 14%; two studies, 1192 participants).
lower or higher rate of participants experiencing insomnia than
paroxetine (RR 0.54, 95% CI 0.21 to 1.38, P value 0.20; one
study, 572 participants) or fluoxetine (RR 1.13, 95% CI 0.44
to 2.88, P value 0.81; one study, 620 participants) (see Analysis
1.8). No data were available for sertraline or escitalopram for this
outcome.
(c) Dry mouth

lower or higher rate of participants experiencing dry mouth compared to all other SSRIs as a group (RR 0.94, 95% CI 0.64 to
1.40, P value 0.77, I = 0%; five studies, 2349 participants).
higher rate of participants experiencing dry mouth than: paroxetine (RR 0.90, 95% CI 0.51 to 1.57, P value 0.71; two studies,
905 participants); fluoxetine (RR 0.96, 95% CI 0.49 to 1.89, P
value 0.92, I = 0%; two studies, 1133 participants); or sertraline
(RR 1.05, 95% CI 0.40 to 2.72, P value 0.93; one study, 311
participants) (see Analysis 1.9). No data were available for escitalopram for this outcome.
(d) Constipation
higher rate of participants experiencing constipation than fluoxetine (RR 2.81, 95% CI 0.75 to 10.46, P value 0.12; one study,
513 participants). See Analysis 1.10. No data were available for
paroxetine, sertraline and escitalopram for this outcome.
(e) Dizziness
lower or higher rate of participants experiencing dizziness compared to all other SSRIs as a group (RR 1.00, 95% CI 0.64 to
1.55; P value 0.99, I = 3%; four studies, 1603 participants).
lower or higher rate of participants experiencing dizziness than:
study, 333 participants); fluoxetine (RR 1.17, 95% CI 0.71 to
1.94, P value 0.54; I = 0%; two studies, 1133 participants); or
escitalopram (RR 0.23, 95% CI 0.03 to 2.03, P value 0.19; one
study, 137 participants) (see Analysis 1.11). No data were available
for sertraline for this outcome.

22
None of the included studies reported data for this outcome.
value 0.35; one study, 137 participants) (see Analysis 1.15). No

data were available for sertraline for this outcome.
(g) Agitation or anxiety
(k) Diarrhoea
(f) Hypotension

lower or higher rate of participants experiencing agitation or anxiety compared to other SSRIs as a group (RR 1.02, 95% CI 0.46
to 2.27, P value 0.97, I = 0%; two studies, 1192 participants).
higher rate of participants experiencing agitation and anxiety than
study, 572 participants) or fluoxetine (RR 0.83; 95% CI 0.26
to 2.70, P value 0.76; one study, 620 participants) (see Analysis
1.12). No data were available for sertraline and escitalopram for
this outcome.

lower or higher rate of participants experiencing diarrhoea compared to all other SSRIs as a group (RR 0.80, 95% CI 0.46 to
1.40, P value 0.43, I = 0%; four studies, 1533 participants).
lower or higher rate of participants experiencing diarrhoea than:
paroxetine (RR 0.52, 95% CI 0.19 to 1.43, P value 0.21; one study,
572 participants); fluoxetine (RR 1.05, 95% CI 0.37 to 2.96, P
value 0.92; one study, 513 participants); sertraline (RR 0.70, 95%
CI 0.25 to 1.91, P value 0.48; one study, 311 participants); or
escitalopram (RR 1.86, 95% CI 0.35 to 9.82, P value 0.47; one
study, 137 participants) (see Analysis 1.16).
(h) Suicide wishes, gestures or attempts

higher rate of participants experiencing suicide wishes, gestures or
attempts than paroxetine (RR 0.86, 95% CI 0.17 to 4.41, P value
0.86; one study, 572 participants) (see Analysis 1.13). No data
were available for fluoxetine, sertraline and escitalopram for this
outcome.
(l) Sexual dysfunction

There was evidence that agomelatine was associated with a lower
rate of participants experiencing sexual dysfunction than paroxetine (RR 0.14, 95% CI 0.04 to 0.47, P value 0.001; one study,
333 participants, NNTH = 9) (see Analysis 1.17). No data were
available for fluoxetine, sertraline and escitalopram for this outcome.
(i) Completed suicide

higher rate of participants completing suicide than paroxetine (RR
0.35 , 95% CI 0.02 to 5.49, P value 0.45; one study, 572 participants) (see Analysis 1.14). No data were available for fluoxetine,
sertraline and escitalopram for this outcome.
(j) Vomiting or nausea

lower rate of participants experiencing vomiting or nausea compared to all other SSRIs as a group (RR 0.70, 95% CI 0.33 to
1.45, P value 0.34, I = 83%; five studies, 2175 participants).
rate of participants experiencing vomiting or nausea than paroxetine (RR 0.34, 95% CI 0.23 to 0.52, P value < 0.00001, I = 0%;
two studies, 905 participants, NNTH = 9) There was no evidence
that agomelatine was associated with a lower rate of participants
experiencing vomiting or nausea compared to fluoxetine (RR 1.54,
95% CI 0.30 to 7.90, P value 0.60, I = 90%; two studies, 1133
participants) or escitalopram (RR 0.65, 95% CI 0.26 to 1.61, P
(m) Abnormal liver function tests

There was no statistically significant higher rate of abnormal liver
function tests in participants treated with agomelatine compared
to all other SSRIs as a group (RR 3.04, 95% CI 0.90 to 10.22, P
value 0.07, I = 0%; four studies, 1755 participants).
There was no statistically significant higher rate of abnormal liver
function tests in participants treated with agomelatine compared
to: paroxetine (RR 3.04, 95% CI 0.32 to 28.89, P value 0.33;
one study, 318 participants); fluoxetine (RR 3.02, 95% CI 0.60
to 15.17, P value 0.18; two studies, 1124 participants); or sertraline (RR 3.10, 95% CI 0.13 to 75.44, P value 0.49; one study,
313 participants). See Analysis 1.18. No data were available for
escitalopram for this outcome.
(n) Weight gain

No data reported for this outcome.

23
No data reported for this outcome.
vantage of agomelatine compared to sertraline (SMD -0.23; 95%

CI -0.46 to -0.01, P value 0.04; one study, 306 participants) (see
Analysis 1.19).
1.8 Continuous outcome - depression scale endpoint score
Comparison two: agomelatine versus other SNRIs
(o) Hypertension

statistically significant difference compared to the other SSRIs as
a group (SMD 0.00; 95% CI -0.11 to 0.12, P value 0.94, I =
66%; ten studies, 3457 participants). There was no evidence that
agomelatine was associated with a lower or higher depression endpoint score compared to: paroxetine (SMD 0.16; 95% CI -0.11
to 0.43, P value 0.24, I = 75%; three studies, 882 participants);
fluoxetine (SMD -0.01; 95% CI -0.15 to 0.13, P value 0.87, I
= 54%; four studies, 1816 participants); or escitalopram (SMD 0.08; 95% CI -0.26 to 0.11, P value 0.42, I = 0%; two studies,
453 participants).There was a small but statistically significant ad-
Primary outcome
2.1 Efficacy - number of participants who responded to

treatment
There was no evidence that agomelatine was less or more effective
than venlafaxine (RR 1.06, 95% CI 0.98 to 1.16, P value 0.16, I
= 0%; three trials, 669 participants) (see Analysis 2.1 and Figure
7).
Figure 7. Forest plot of comparison: 2 Agomelatine vs SNRI, outcome: 2.1 Response rates
Secondary outcomes
2.2 Efficacy - number of participants who achieved remission

There was no significant difference in the number of participants
who achieved remission between agomelatine and venlafaxine (RR
1.08, 95% CI 0.94 to 1.24, P value 0.26, I = 0%; three trials,
669 participants) (see Analysis 2.2 and Figure 8).

24
Figure 8. Forest plot of comparison: 2 Agomelatine vs SNRI, outcome: 2.2 Remission rates
2.3 Acceptability - total drop-out rate

total drop-out rate than venlafaxine (RR 0.40, 95% CI 0.24 to
0.67, P value 0.0005, I = 0%; two trials, 392 participants, NNTB
= 2) (See Analysis 2.3 and Figure 9).
Figure 9. Forest plot of comparison: 2 Agomelatine vs SNRI, outcome: 2.3 Total drop outs
2.4 Acceptability - drop-out rates due to inefficacy

lower or higher drop-out rate due to inefficacy compared to venlafaxine (RR 1.01, 95% CI 0.21 to 4.94, P value 0.99; one trial,
332 participants) (see Analysis 2.4).
2.5 Acceptability - drop-out rates due to side effects

drop-out rate due to side effects compared to venlafaxine (RR
0.30, 95% CI 0.15 to 0.59, P value 0.0006, I = 0%; two trials,

608 participants, NNTH = 13) (see Analysis 2.5).
at least some side effects
There was no evidence that fewer or more participants experienced
at least some side effects compared to venlafaxine (RR 0.72, 95%
CI 0.44 to 1.18, P value 0.19, I = 80%; two trials, 611 participants) (see Analysis 2.6).

25
We also analysed the six outcomes above using a fixed-effect model

and noted no change in significance levels and only negligible
changes in effect sizes.

specific side effects
(g) Agitation or anxiety

No data were available for the comparison of agomelatine and
venlafaxine for this outcome.
(h) Suicide wishes, gestures or attempts

(a) Sleepiness or drowsiness

higher rate of participants experiencing sleepiness or drowsiness
than venlafaxine (RR 0.76, 95% CI 0.27 to 2.14, P value 0.60;
one study, 334 participants) (see Analysis 2.7).
(i) Completed suicide

(b) Insomnia
higher rate of participants experiencing insomnia than venlafaxine
participants) (see Analysis 2.8).
(j) Vomiting or nausea

higher rate of participants experiencing vomiting and nausea than
venlafaxine (RR 0.42, 95% CI 0.17 to 1.08, P value 0.07, I =
80%; two studies, 609 participants) (see Analysis 2.12).
(c) Dry mouth

higher rate of participants experiencing dry mouth than venlafaxine (RR 0.51, 95% CI 0.13 to 1.99, P value 0.33; one study, 332
(k) Diarrhoea
higher rate of participants experiencing diarrhoea than venlafaxine
(d) Constipation
higher rate of participants experiencing constipation than venlafaxine (RR 0.87, 95% CI 0.30 to 2.53, P value 0.79; one study,
(l) Sexual dysfunction

(e) Dizziness
rate of participants experiencing dizziness than venlafaxine (RR
0.19, 95% CI 0.06 to 0.64, P value 0.007, one study, 332 participants, NNTH = 13) (see Analysis 2.11).
(m) Abnormal liver function tests
(f) Hypotension
(n) Weight gain




26
(o) Hypertension
2.8 Continuous outcome - depression scale endpoint score

statistically significant difference compared to venlafaxine (SMD
-0.07; 95% CI -0.22 to 0.08, P value 0.37, I = 0%; three studies,
0.18; two studies, 392 participants) or moderate depressed participants (RR 1.04, 95% CI 0.93 to 1.17, P value 0.50; one study,
(c) Treatment settings (primary care, psychiatric inpatients,

or psychiatric outpatients)
No study was conducted in a primary care or inpatient setting only. One study did not report detailed setting information
(CAGO2303). All other studies included outpatients only or inand outpatients without separating the two groups. Therefore, it
was not meaningful to carry out this subgroup-analysis.
Comparison three: agomelatine versus other

antidepressive agents
No studies were found comparing agomelatine with tricyclic or
heterocyclic antidepressants, MAOIs, newer agents (mirtazapine, bupropion, reboxetine), atypical antipsychotics in monotherapy (risperidone, paliperidone, olanzapine, quetiapine, aripiprazole, amisulpride, ziprasidone) or non-conventional antidepressive agents (herbal products such as Hypericum).
Subgroup analyses
Where possible, the pre-planned subgroup analyses were conducted for the primary outcome. Results were interpreted with
caution, because of the small number of studies included. Furthermore, multiple comparisons could lead to false positive conclusions (Oxman 1992).
(a) Agomelatine dosing (fixed low dosage: 25 mg/day; fixed

high dosage: 50 mg and above; flexible high and flexible low)
Subgroup analyses of fixed versus flexible dosages were performed

for the comparisons of agomelatine with SSRIs (Analysis 1.20),
and agomelatine with venlafaxine (Analysis 2.15). There was no
evidence for a difference between flexible or fixed dosage schemes
for the former comparison (P value 0.42) or the latter (P value
0.74).
(d) Older participants (participants aged 65 years or more)

versus other adult participants
None of the included studies specifically recruited older participants. Only one study recruited participants up to 70 years of age
(CAGO2303), all others included participants under 65 years of
age. Therefore, this subgroup analysis could not be performed.
(e) Examination of wish bias by comparing agomelatine as

the investigational drug versus agomelatine as the
comparator
Only one study that used agomelatine as the investigational

drug was not conducted by the manufacturer of agomelatine
(Martinotti 2012). Accordingly, it was not considered meaningful
to perform this subgroup analyses.
(f) Examination of publication bias by assessing response to

agomelatine in unpublished studies versus response to
agomelatine in published studies
Four unpublished studies were included in the review, all comparing agomelatine to SSRIs (see CAGO2303, CL3-022, CL3-023,
CL3-024 and Analysis 1.30). This analysis showed a significant
difference between published and unpublished trials (P value
0.009), with a better outcome for participants in the published
trials who were treated with agomelatine.
(b) Severity of depression (mild, moderate, severe

depression)
Mean HAM-D scores of the agomelatine groups ranged from 25.7

(CL3-023), to 28.7 (Martinotti 2012). Kennedy 2008 reported a
mean MADRS score of 17.9 at baseline. We defined severe depression at a threshold of 25 or more for HAM-D and 31 or more
on MADRS (Mller 2003); this meant that all the trials, except
for one (Kennedy 2008), were rated as trials in severe depression.
The subgroup analysis was conducted, therefore, for agomelatine
versus SNRIs only. There was no evidence (P value 0.59) of a difference in response rates of agomelatine compared to venlafaxine
for severely depressed (RR 1.09, 95% CI 0.96 to 1.23, P value
Sensitivity analyses
(a) Excluding trials with unclear concealment of random

allocation or unclear double blinding, or both; and trials with
inadequate concealment of random allocation
We rated all but two studies as having an unclear risk of bias

for allocation concealment (Martinotti 2012; Quera-Salva 2011).
Martinotti 2012 compared agomelatine to venlafaxine (an SNRI),
and Quera-Salva 2011 compared agomelatine to escitalopram (an

27
SSRI). Consequently, it was not considered meaningful to conduct

this sensitivity analysis.
Four studies reported overall drop-out rates of more than 20% and
were excluded (CAGO2303; CL3-024; Loo 2002a; Shu 2013).
Kennedy 2008 did not report drop-out rates and was also excluded. Martinotti 2012 reported drop-out rates of exactly 20%.
Excluding the studies with drop-out rates over 20%, results from
the sensitivity analysis changed the findings only marginally (see
Analysis 1.21 and Analysis 2.17).
Shu 2013), and one study that compared agomelatine to an SNRI

(Lemoine 2007). The exclusion of these studies did not change the
results of the overall estimates comparing agomelatine with SSRIs as a group or SNRIs substantially (Analysis 1.23 and Analysis
2.18). However, exclusion of one study, CL3-023, led to a significant difference in the number of participants who achieved remission between agomelatine and paroxetine, with a lower number of
remitters when treated with agomelatine (RR 0.90, 95% CI 0.67
to 1.21, P value 0.02; I = 78%; two trials, 909 participants).
Post test SDs were imputed for one study (Corruble 2013). Exclusion of this study did not change the results significantly (see
Analysis 1.24).
(c) Worst-case scenario and best-case scenario ITT analyses
(e) Excluding all cross-over trials
All studies calculated response and remission rates based on ITT

population as defined by the authors. Therefore, participants who
terminated their participation in the study early by dropping out
could also be responders or remitters. Accordingly, we calculated
the best- and worst-case scenarios only for participants who were
not included in the ITT analysis. Two studies did not report difference between ITT samples and randomised participants and were
left unchanged (Lemoine 2007; Martinotti 2012). One study did
not report the number of participants included in the ITT analysis and was also left unchanged (Corruble 2013). Although the
analyses did not differ significantly from the main analyses (see
Analysis 1.25; Analysis 1.26; Analysis 1.27; Analysis 1.28; Analysis
2.19; Analysis 2.20; Analysis 2.21; Analysis 2.22), the worst-case
scenario for remission rates showed a small but significant effect
in favour of SSRIs (RR 0.73, 95% CI 0.57 to 0.94, P value 0.01,
I = 76%; ten studies, 3502 participants, see Analysis 1.28).
This review did not include any cross-over trials.
(b) Excluding trials with drop-out rates greater than 20%
(d) Excluding trials for which the response or remission rates

had to be calculated based on the imputation method and
those for which the SD had to be borrowed from other trials
Response rates were imputed for two SSRI studies (CL3-023;

CL3-024). The exclusion of these trials changed the results only
marginally (Analysis 1.22). No response rates were imputed in
studies that compared agomelatine to SNRIs.
Remission rates were imputed for four studies that compared
agomelatine to SSRIs (CL3-023; CL3-024; Quera-Salva 2011;
(f) Excluding studies funded by the pharmaceutical company

that manufactures agomelatine
Only one of the included studies was not conducted by Servier,

the manufacturer of agomelatine (Martinotti 2012), so it was not
considered meaningful to conduct this sensitivity analysis.
(g) Excluding studies in which there were any participants

diagnosed with bipolar depression
Only one study allowed the inclusion of bipolar participants (Loo

2002a). Exclusion of this study showed no difference between
agomelatine and paroxetine (RR 0.84, 95% CI 0.70 to 1.03, P
value 0.09, I = 32%; two studies, 617 participants) (see Analysis
1.29).
Reporting bias
We did not use funnel plots to investigate publication bias, because
none of the comparisons contained more than 10 studies. The
review included four unpublished trials (CAGO2303; CL3-022;
CL3-023; CL3-024), but the Studies awaiting classification section lists further unpublished trials. We added an additional
subgroup analyses to compare published and unpublished trials
(Analysis 1.30).

28

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Agomelatine compared to SNRI for major depression

Patient or population: patients with major depression
Settings: inpatients and outpatients
Intervention: agomelatine
Comparison: SNRI
Outcomes
Response rates
showing a reduction of at
least 50% on the Hamilton
Depression Rating Scale
for Depression, the Montgomery-Asberg Depression Rating Scale or any
other depression scale
Illustrative comparative risks* (95% CI)
Assumed risk
Corresponding risk
SNRI
Agomelatine
Study population
727 per 1000
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
RR 1.06
(0.98 to 1.16)
669
(3 studies)

very low1,2
RR 1.08
(0.94 to 1.24)
669
(3 studies)

very low1,2
771 per 1000

(712 to 843)
Moderate
707 per 1000
29
Remission rates
Study population
The number of participants who achieved remission as defined by:
a score of 7 or less
on the 17-item Hamilton
Depression Rating Scale;
10 or less on the Montgomery-Asberg Depression Rating Scale; not ill
or borderline mentally ill
749 per 1000

(693 to 820)
Comments

on the Clinical Global Impression - Severity; or any

other equivalent value on
454 per 1000
a depression scale defined by the authors
Moderate
333 per 1000
Total drop outs

Total number of participants who dropped out
during the trial as a proportion of the total number of randomised participants
Study population
Drop out due to inefficacy

inefficacy during the trial,
as a proportion of the total number of randomised
participants
Follow-up: 6 weeks
Study population
228 per 1000
490 per 1000

(427 to 563)
360 per 1000

(313 to 413)
RR 0.4
(0.24 to 0.67)
392
(2 studies)

very low1,2
RR 1.01
(0.21 to 4.94)
332
(1 study)

very low1,2
RR 0.3
(0.15 to 0.59)
608
(2 studies)

very low1,2
91 per 1000
(55 to 153)
Moderate
258 per 1000
18 per 1000
103 per 1000

(62 to 173)
18 per 1000
(4 to 89)
Moderate
18 per 1000
Drop outs due to side ef- Study population

fects
side effects during the
trial, as a proportion of
18 per 1000
(4 to 89)
30

the total number of randomised participants

111 per 1000
33 per 1000
(17 to 66)
Moderate
109 per 1000
Total number of patients Study population

with side effects
Total number of par- 481 per 1000
ticipants experiencing at
least one side effect
Moderate
471 per 1000
33 per 1000
(16 to 64)
RR 0.72
(0.44 to 1.18)
611
(2 studies)

very low1,2,3
346 per 1000

(211 to 567)
339 per 1000

(207 to 556)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: we are very uncertain about the estimate
1
2
3
The studies included in our review were conducted in inpatient and outpatient settings. Results may not be generalisable for a primary
care setting
Most studies were funded by the pharmaceutical company that manufactures agomelatine (Servier)
There is high heterogeneity
31
DISCUSSION
Summary of main results
A total of 13 studies (4495 participants) were included in this
review. Agomelatine does not seem to have any clinically significant advantage over other antidepressants, in terms of efficacy,
for response or remission, for the acute phase treatment of major depression. It may even have some disadvantages compared
to other antidepressants, in terms of remission. Overall, agomelatine appeared to be slightly better tolerated than venlafaxine, and
showed the same level of tolerability as the other SSRIs examined
(fluoxetine, sertraline, paroxetine and escitalopram). Agomelatine
was associated with a lower rate of dizziness than venlafaxine, and
a lower rate of vomiting and nausea than paroxetine. Agomelatine also appeared to be associated with less sexual dysfunction
than paroxetine, although only one study was included in that
analysis. With regard to liver function test abnormalities, the evidence for agomelatine compared to paroxetine, fluoxetine or sertraline, is inconclusive. Although our analysis did not reach statistical significance, all comparisons showed a risk ratio greater than
3, indicating an increased risk of liver function abnormalities in
people treated with agomelatine, but only four studies could be
included in these analyses. In the light of the recently updated
contraindication for people with increased transaminase levels due
to reports of liver injuries and hepatic failures (Servier 2013), it
seems likely that these elevations are clinically relevant and masked
in our review due to a reporting bias. Unfortunately, agomelatine
was compared to a limited number of antidepressants, only SSRIs
and venlafaxine, which limits the generalisability of the results.
We found no clear evidence that agomelatine has advantages over
other antidepressants. There is limited evidence that agomelatine
could be more tolerable than venlafaxine, but this is based only on
two studies with a limited number of events.
Please see Summary of findings for the main comparison and
Summary of findings 2 for more details.
surveillance data from the French national monitoring system, EU

periodic safety update reports (PSURs), and the European pharmacovigilance database concluded that the harms associated with
agomelatine may outweigh its benefits (Prescrire 2013). Thus, the
evidence is insufficient to guide treatment decisions based on considerations of side effects. Furthermore, the number of studies for
each comparator was quite small, limiting the applicability of the
findings. Indeed, only one trial included participants over 70 years
of age, and no study was conducted in a primary care setting, which
further limits the generalisability of the evidence. It may also be
possible that the population selected, given the stringent exclusion
criteria employed in the studies, may not have been representative
of the real world population. Often, real patients with depressive
disorder have several co-morbidities (physical or psychiatric), and
this may not be accurately reflected in the severity of the condition
evident in participants in the RCTs.

We chose six outcomes for assessing the quality of evidence and to
construct the Summary of findings tables (the chosen outcomes
being response rates; remission rates; total drop outs; drop outs
due to inefficacy; drop outs due to side effects; total number of
participants with side effects). We constructed two separate Summary of findings tables: one for agomelatine compared to SSRIs (Summary of findings for the main comparison), and one for
agomelatine compared to SNRIs (Summary of findings 2). The
quality of the evidence was low and outcomes may have been selectively reported, particularly in the unpublished material, which
limits the generalisability of our findings. Ten out of 11 studies
were sponsored by the pharmaceutical company that manufactures
agomelatine (Servier). Evidence shows that sponsored trials may
be associated with a more favourable outcome (Lundh 2012), so
the results in this review should be considered with caution.
Study limitations (risk of bias)
Overall completeness and applicability of

evidence
The present review focused on the comparison between agomelatine and other antidepressants. This may limit the applicability of the findings as, ideally, an agent should be assessed against
placebo. Data from seven unpublished studies were included in
our review, but, given the number of completed studies awaiting
assessment, we can not be sure that all unpublished material has
been included. Furthermore, there was a high chance of selective
reporting bias, especially for analysis of side effects. For example,
data from placebo-controlled studies submitted to the European
Medicines Agency showed that agomelatine was consistently associated with a significantly higher incidence of abnormal liver
function tests than placebo. Moreover, a recent review based on
We judged that the studies have a moderate risk of bias for all
outcomes. There were several unpublished studies in our review,
which may not have reported all the outcomes. Also, unpublished
studies may not have been subject to peer review. We decided to
downgrade the quality of evidence by one level accordingly.
Consistency of effect
Studies showed some heterogeneity, and our additional analysis revealed a significant difference between published and unpublished
studies in the response rates outcome; we decided to downgrade
the quality of evidence by one level for this outcome. The other
outcomes did not show any significant evidence of heterogeneity
and, therefore, we did not downgrade the level of evidence.

32
Indirectness
The studies included in our review were conducted in inpatient
and outpatient settings, so results may not be generalisable to
the primary care setting. Therefore we downgraded the quality of
evidence for all the outcomes, by one level.
Imprecision
The results on efficacy showed a variable level of precision depending on the outcome. With regard to the efficacy outcomes, the response rates and remission rates showed sufficient precision. The
tolerability outcomes, on the other hand, were mostly imprecise.
The total drop outs and drop outs due to inefficacy outcomes
had large CIs. The drop outs due to side effects outcome had a
narrow confidence interval but the event rate was low. We decided
to the downgrade for imprecision, based on the tolerability outcomes. The total number of participants with side effects outcome, showed a narrow confidence interval in addition to a high
event rate, so we did not downgrade it for imprecision.
Agreements and disagreements with other

studies or reviews
A recent pooled analysis on agomelatine compared to SSRIs and
SNRIs has been published (Kasper 2013). This review is very similar in scope to our review, but the authors did not conduct a systematic literature review and only included trials without placebo
control groups. The authors concluded that agomelatine can be
used as first-line treatment for depression, however, the study included only six of the studies that are analysed in the present review. Moreover, only one unpublished study was included, which
could mean that Kasper 2013 is at greater risk of having publication bias than this systematic review. Another systematic review of
published trials comparing agomelatine to placebo and SSRIs and
SNRIs concluded that agomelatine had a marginal superior effect
compared to other antidepressants (Singh 2011). Although the
review included published trials only, the authors judged the effect
to be fragile and not clinically relevant. The review included only
five of the studies included in our review and combined SSRIs and
SNRIs as comparators.
Publication bias
In accordance with the protocol, publication bias was not formally
assessed by funnel plot analyses, because all analyses included fewer
than 10 studies. Our review included unpublished studies and we
think that this reduced the impact of publication bias. Our additional subgroup analysis showed a clear difference between published and unpublished trials, and we are aware of a number of unpublished studies that we were not able to include. Therefore, our
results may still be biased to some extent. Furthermore, these studies may raise further doubts with regard to the generalisabilty of
the results. For example, one unpublished study compared agomelatine to paroxetine in older people (CL3-048), and according to
data from this study included in a pooled analysis (Kasper 2013),
agomelatine was not more effective than paroxetine in this study.
Overall the quality of the evidence was quite low.
Potential biases in the review process

Some biases and limitations can be noted.
1. We tried to perform a thorough article search, however, it is
possible that we missed some relevant studies. Some of the data
from this review come from unpublished material, and it may be
possible that more unpublished studies have not been identified.
2. Some of the included studies were not designed to test
efficacy of agomelatine as a primary outcome (Lemoine 2007;
Martinotti 2012; Quera-Salva 2011), but focused on sleep
(Lemoine 2007; Quera-Salva 2011), and anhedonia (Martinotti
2012), though they did include data for efficacy and tolerability.
This means that the applicability of the results may be limited,
because the studies may not have been sufficiently powered to
detect differences in depressive symptoms.
AUTHORS CONCLUSIONS
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

33
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.
CRG Funding Acknowledgement

The National Institute for Health Research (NIHR) is the largest
single funder of the Cochrane Depression, Anxiety and Neurosis
Group.
Disclaimer: the views and opinions expressed herein are those of
the authors and do not necessarily reflect those of the NIHR, NHS
or the Department of Health.
ACKNOWLEDGEMENTS
REFERENCES
References to studies included in this review

CAGO2303 {unpublished data only}
Novartis Pharmaceuticals. A placebo- and paroxetinecontrolled study of the efficacy, safety and tolerability
of agomelatine (25 or 50 mg) in the treatment of
major depressive disorder (MDD) [NCT00463242].
ClinicalTrials.gov [www.clinicaltrials.gov] [accessed 10
November 2012] 2009.
Novartis Pharmaceuticals. An 8-week, multicenter,

randomized, double-blind, placebo-and paroxetinecontrolled study of the efficacy, safety and tolerability
of agomelatine 25 or 50 mg given once daily in the
treatment of Major Depressive Disorder (MDD). http:
//www.novctrd.com/ctrdWebApp/clinicaltrialrepository/
displayFile.do?trialResult=2659 [accessed 10 November
2012] 2009.
CL3-022 {unpublished data only}
European Medicines Agency. CHMP Assessment
report for Thymanax [Procedure No. EMEA/H/
C/000916, Doc. Ref. EMEA/97539/2009].http://
www.ema.europa.eu/docs/enGB/documentlibrary/
EPAR-Publicassessmentreport/human/000915/
WC500046226.pdf. [Accessed 22 October 2012] 2008.

report for Valdoxan [Procedure No. EMEA/H/C/
656, Doc. Ref. EMEA/CHMP/87018/2006].http:/
/www.ema.europa.eu/docs/enGB/documentlibrary/
WC500070527.pdf. [Accessed 22 January 2013] 2006.


Corruble 2013 {published data only}
Corruble E, Belaidi C, Goodwin GM. Agomelatine versus
escitalopram in major depressive disorders. European
Psychiatry [abstracts from the 19th European Congress of
Psychiatry, EPA 2011 Mar 12-15; Vienna, Austria] 2011;26
(S1):619.
Corruble E, de Bodinat C, Belaidi C, Goodwin GM.

Efficacy of agomelatine and escitalopram on depression,

34
subjective sleep and emotional experiences in patients

with major depressive disorder: a 24-wk randomized,
controlled, double-blind trial. International Journal of
Neuropsychopharmacology 2013:1-16 [epub ahead of print].
Hale 2010 {published data only (unpublished sought but not used)}
Hale A. Efficacy and safety of agomelatine (25 mg/day
with potential adjustment to 50 mg) given orally for eight
weeks in out-patients with severe major depressive disorder:
a randomised double-blind, parallel groups, international
study versus selective serotonin reuptake inhibitor
(SSRI) with a double-blind extension period of 16 weeks.
Controlled-Trials.com 2008 (http://www.controlledtrials.com/ISRCTN19313268/servier).
Hale A, Corral RM, Mencacci C, Ruiz JS, Severo

CA, Gentil V. Superior antidepressant efficacy results of
agomelatine versus fluoxetine in severe MDD patients: a
randomized, double-blind study. International Clinical
Psychopharmacology 2010;25(6):30514.
Kasper 2010 {published data only (unpublished sought but not used)}
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 [ISRCTN49376288]. Journal of
Clinical Psychiatry 2010;71(2):10920.
Kennedy 2008 {published data only (unpublished sought but not
used)}
Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A doubleblind comparison of sexual functioning, antidepressant
efficacy, and tolerability between agomelatine and
venlafaxine XR. Journal of Clinical Psychopharmacology
2008;28(3):32933.
Lemoine 2007 {published data only (unpublished sought but not used)}
Lemoine P, Guilleminault C, Alvarez E. Improvement in
subjective sleep in major depressive disorder with a novel
antidepressant, agomelatine: randomized, double-blind
comparison with venlafaxine. Journal of Clinical Psychiatry
2007;68(11):172332.
Loo 2002a {published data only}
Loo H, Hale A, Dhaenen 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.
International Clinical Psychopharmacology 2002;17(5):
23947.
Martinotti 2012 {published data only}
Martinotti G, Sepede G, Di Nicola M, Di Iorio G, Gambi
F, De Risio L, et al.Agomelatine versus venlafaxine in the
treatment of anhedonia in major depressive subjects: A pilot
study [oral presentation]. European Psychiatry [abstracts of
the 20th European Congress of Psychiatry, EPA. 2012 Mar 36; Prague Czech Republic] 2012;27(Suppl 1):O35.
Martinotti G, Sepede G, Gambi F, Di Iorio G, De Berardis

D, Di Nicola M, et al.Agomelatine versus venlafaxine XR in
the treatment of anhedonia in major depressive disorder: A
pilot study. Journal of Clinical Psychopharmacology 2012;32

(4):48791.
Quera-Salva 2011 {published data only (unpublished sought but not
used)}
Quera-Salva M-A, Hajak G, Philip P, Montplaisir

J, Keufer-Le Gall S, Laredo J, et al.Comparison of
agomelatine and escitalopram on nighttime sleep and
daytime condition and efficacy in major depressive disorder
patients. International Clinical Psychopharmacology 2011;26
(5):25262.
Quera-Salva M-A, Servier Laboratories. Effects of
agomelatine on sleep electroencephalogram parameters
compared to selective serotonin reuptake inhibitors in
patients with major depressive disorder: a six-week
randomised, double-blind parallel group study versus
comparator, followed by a double-blind optional treatment
extension period up to six months [ISRCTN44737909;
CL3-20098-056; EUCTR2006-004716-48]. ControlledTrials.com [www.controlled-trials.com] 2007.
Shu 2013 {published data only}
Shu L, Sulaiman AH, Huang YS, et al.Comparable

efficacy and safety of 8 weeks treatment with agomelatine
25-50mg or fluoxetine 20-40mg in Asian out-patients with
major depressive disorder. Asian Journal of Psychiatry 2013;
(in press). [DOI: 10.1016/j.ajp.2013.09.009]
Shu L, Zhang Y, Servier Laboratories. Efficacy and safety of
agomelatine with flexible dose (25 mg/day with potential
adjustment at 50 mg) given orally for 8 weeks in out-patients
with Major Depressive Disorder. A randomised flexible
dose double-blind international multicentric study with
parallel groups, versus fluoxetine (20 mg/day with potential
adjustment at 40 mg) [ChiCTR-TRC-11001668]. Chinese
Clinical Trial Registry [http://www.chictr.org/en] 2011.
References to studies excluded from this review

CAGO2301 {published data only}
Novartis Pharmaceuticals. An 8-week, randomized,
double-blind, placebo-controlled, parallel-group, multicenter study of the efficacy and safety of agomelatine
0.5 mg and 1 mg sublingual tablets administered once
daily in patients with major depressive disorder (MDD)
[NCT01110889; CAGO178C2301]. ClinicalTrials.gov
[www.clinicaltrials.gov] 2010.
Novartis Pharmaceuticals. A 8-week, randomized,
double-blind, placebo-controlled, parallel-group, multicenter study of the efficacy and safety of agomelatine
0.5 mg and 1 mg sublingual tablets administered once
daily in patients with major depressive disorder (MDD)
[NCT01110902; CAGO178C2302]. ClinicalTrials.gov
Novartis Pharmaceuticals. A 52-week, randomized,
double-blind, placebo-controlled, multi-center, parallelgroup study of the long-term efficacy, tolerability
and safety of agomelatine 25 and 50 mg in the

35
prevention of relapse of major depressive disorder

(MDD) following open-label treatment of 16-24 weeks
[NCT00467402; CAGO178A2304]. ClinicalTrials.gov
CL2-009 {published data only}
Servier Laboratories. Efficacy and safety of 3 doses (0.25,
0.5 and 1mg/day) of agomelatine sublingual administration
over an 8-week treatment period, in out-patients with Major
Depressive Disorder. An 8-week randomised, double-blind,
fixed dose, international multicentre, placebo-controlled
study with parallel groups, followed by an extension doubleblind treatment period of 16 weeks [CL2-90098-009;
EUCTR2009-014045-92]. EU Clinical Trials Register
[.www.clinicaltrialsregister.eu] 2009.
WC500046226.pdf [Accessed 22 October 2012] 2008.



Corral 2009 {published data only}
Corral RM, Servier Laboratories. Efficacy and safety
of three dose regimens of agomelatine (10, 25, 25 - 50
mg) versus placebo given once a day for 6 weeks in outpatients suffering from moderate to severe major depressive
disorder: a 6-week randomised, double-blind, placebocontrolled, parallel groups study followed by a double-blind
optional 18-week extension period [ISRCTN10845256;
CL3-20098-069; EUCTR2009-011238-84]. ControlledTrials.com [www.controlled-trials.com] 2009.
Goodwin 2009 {published data only}
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 [ISRCTN53193024].
Journal of Clinical Psychiatry 2009;70(8):112837.
Heun 2013 {published data only}
Heun R, Ahokas A, Boyer P, Gimenez-Montesinos N,

Pontes-Soares F, Olivier V. The efficacy of agomelatine in
elderly patients with recurrent major depressive disorder:
a placebo-controlled study. Journal of Clinical Psychiatry
2013;74(6):58794.
Heun R, Servier Laboratories. Efficacy and safety of
agomelatine oral administration (25 to 50 mg/day) in
elderly patients suffering from major depressive disorder: an
8-week, randomised, double-blind, flexible-dose, parallel
groups, placebo-controlled, international, multicentre
study followed by an extension double-blind treatment
period of 16 weeks [ISRCTN57507360; CL3-20098070; EUCTR2009-011795-29]. Controlled-Trials.com
[www.controlled-trials.com] 2010.
Kennedy 2006 {published data only}
Kennedy SH, Emsley R. Placebo-controlled trial of
agomelatine in the treatment of major depressive disorder.
European Neuropsychopharmacology 2006;16(2):93100.
Loo 2002b {published data only}
Loo H, Dalery J, Macher JP, Payen A. Pilot study comparing
in blind the therapeutic effect of two doses of agomelatine,
melatoninergic agonist and selective 5ht2c receptors
antagonist, in the treatment of major depressive disorders.
LEncephale 2002;28(4):35662.
Olie 2007 {published data only}
Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2
receptor agonist with 5-HT2C antagonistic properties,
in major depressive disorder. International Journal of
Neuropsychopharmacology 2007;10(5):66173.
Rouillon 2008 {published data only}
Rouillon F, Servier Laboratories. Efficacy and safety
of two doses of S 90098 (1 and 2 mg/day), sublingual
formulation for 8 weeks in out-patients with major
depressive disorder: An 8-week randomised, double-blind,
fixed dose, international, multicentre, placebo-controlled
study with parallel groups, followed by an extension doubleblind treatment period for 16 weeks [ISRCTN38378163;
CL2-90098-005]. Controlled-Trials.com [www.controlledtrials.com] 2008.

36
Saletu 2011 {published data only}

Saletu M, Saletu-Zyhlarz GM, Anderer P, RosalesRodriguez S, Saletu B. On the acute effect of agomelatine
on sleep and awakening in major depression: controlled
polysomnographic and psychometric studies [abstract].
Somnologie [abstracts of the 19th Jahrestagung der DGSM;
2011 Nov 10-12; Mannheim Germany] 2011.
Save 2011 {published data only}
Save D, Precise Chemipharma Pvt Ltd. A multicentric,
open-label, randomized, comparative, parallel-group, activecontrolled Phase III clinical trial of the efficacy and safety of
agomelatine oral tablets in patients with major depressive
disorder [CTRI/2011/08/001946]. Clinical Trials Registry
- India [http://ctri.nic.in] 2011.
Serfaty 2010 {published data only}
Serfaty MA, Osborne D, Buszewicz MJ, Blizard R, Raven
PW. A randomized double-blind placebo-controlled trial of
treatment as usual plus exogenous slow-release melatonin
(6 mg) or placebo for sleep disturbance and depressed
mood. International Clinical Psychopharmacology 2010;25
(3):13242.
Stahl 2010 {published data only}
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 [NCT00411242]. Journal of Clinical Psychiatry 2010;
71(5):61626.
Tseng 2007 {published data only}
Tseng M-C. The effect of agomelatine or fluoxentine
on heart rate variability in patients with major
depressive disorder [NCT00451490]. ClinicalTrials.gov
Zajecka 2010 {published data only}
Zajecka J, Schatzberg A, Stahl S, Shah A, Caputo A, Post
A. Efficacy and safety of agomelatine in the treatment
of major depressive disorder: a multicenter, randomized,
double-blind, placebo-controlled trial. Journal of Clinical
References to studies awaiting assessment

Bougerol T, Servier Laboratories. Efficacy of agomelatine
given orally on the quality of remission in elderly depressed
patients, after a 12-week treatment period. A randomised,
double-blind, flexible-dose international multicentre
study with parallel groups versus SSRI drug. Twelveweek treatment plus optional continuation for 12 weeks
[ISRCTN68222771; CL3-20098-048; EUCTR2005-
002388-95]. Controlled-Trials.com [www.controlledtrials.com] 2006.

Marey C, Servier Laboratories. Evaluation of efficacy and
clinical benefit of agomelatine in patients with major
depressive disorder compared to serotonin-norepinephrine
reuptake inhibitor (SNRI) [ISRCTN96725312; CL320098-062; EUCTR2008-004642-92]. ControlledTrials.com [www.controlled-trials.com] 2009.
Lejoyeux M, Servier Laboratories. Initiation of agomelatine
after antidepressant treatment in outpatients suffering major
depressive disorder [ISRCTN97599615; CL3-20098073; EUCTR2010-019556-44]. Controlled-Trials.com
[www.controlled-trials.com] 2010.
CRSC11003 {published data only}
Cadila Pharmaceuticals Limited. A randomized, multicenter, double blind, controlled, comparative study of
the efficacy and safety of agomelatine 25 mg (or 50 mg)
and paroxetine 20mg (or 30 mg) in patients with major
depressive disorder (MDD) [CTRI/2012/03/002480;
CRSC11003]. Clinical Trials Registry - India [http://
ctri.nic.in] 2012.
CTRI/2011/04/001659 {published data only}
Borgharkar S, Sun Pharmaceutical Industries Ltd.
Evaluation of efficacy and safety of agomelatine versus
venlafaxine ER in the treatment of major depressive
disorder. Clinical Trials Registry - India [http://ctri.nic.in]
2011.
Karaiskos 2013 {published data only}
Karaiskos D, Tzavellas E, Ilias I, Liappas I, Paparrigopoulos
T. Agomelatine and sertraline for the treatment of depression
in type 2 diabetes mellitus. International Journal of Clinical
Practice 2013;67(3):25760.
Montgomery 2004 {published data only}
Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux
M, Hindmarch I. Absence of discontinuation symptoms
with agomelatine and occurrence of discontinuation
symptoms with paroxetine: a randomized, double-blind,
placebo-controlled discontinuation. International Clinical
Vasile 2011 {published data only}
Vasile D, Vasiliu O, Vasile ML, Terpan M, Ojog DG.
Agomelatine versus selective serotoninergic reuptake
inhibitors in major depressive disorder and comorbid
diabetes mellitus [conference abstract]. European
Neuropsychopharmacology [abstracts from the 24th Congress
of the European College of Neuropsychopharmacology, ECNP
2011 Paris France, 3-7 Sept] 2011;21(Suppl 3):S3834.
References to ongoing studies

Servier Laboratories. Effects of agomelatine versus
escitalopram on emotional experiences in outpatients
suffering from major depressive disorder. An exploratory,
randomised, double-blind, international, multicentre study

37
with parallel groups: agomelatine (25 to 50 mg/day)

versus escitalopram (10 to 20 mg/day) over a 6-month
period [EUCTR2011-005320-17-GB; CL3-20098-060].
EU Clinical Trials Register [www.clinicaltrialsregister.eu]
[Accessed 20 September 2013] 2012.
Shah A, Rajarshi M. Efficacy and safety of agomelatine
with flexible dose (25 mg/day with blinded adjustment
at 50 mg) given orally for 8 weeks in Indian outpatients
with major depressive disorder. A randomised double-blind
national multicentric study with parallel groups, versus
sertraline (50 mg/day with blinded potential adjustment
at 100 mg) [CTRI/2010/091/006081; CL3-20098-074].
Clinical Trials Registry - India [http://ctri.nic.in] [Accessed
20 September 2013] 2012.
Udristoiu T, Servier Laboratories. Early effect of
agomelatine on general interest in outpatients suffering
major depressive disorder: a parallel group, randomised,
double-blind, multicentre study [ISRCTN28327843; CL320098-083]. Controlled-Trials.com [www.controlledtrials.com] [Accessed 20 September 2013] 2011.
GENRAS {published data only}
Medizinische Universitt Wien Univ Klinik f
Psychiatrie und Psychotherapie. GENRAS (GENetics
of Response to Agomelatine vs. EScitalopram)
[EUCTR2010-019423-61-AT]. EU Clinical Trials Register
[www.clinicaltrialsregister.eu] [Accessed 20 September
2013] 2010.
Lundbeck 2011 {published data only}
H Lundbeck A/S. A randomised, double-blind,
parallel-group, active-controlled, flexible dose study
evaluating the effects of Lu AA21004 versus agomelatine
in adult patients suffering from major depressive
disorder with inadequate response to antidepressant
treatment [NCT01488071; EUCTR2011-002362-21].
ClinicalTrials.gov [www.clinicaltrials.gov] [Accessed 20
September 2013] 2011.
NCT01483053 {published data only}
Baker IDI Heart and Diabetes Institute. A randomised
trial investigating the cardiovascular effects of
agomelatine and escitalopram in patients with major
depressive disorder [NCT01483053]. ClinicalTrials.gov
[www.clinicaltrials.gov] [Accessed 20 September 2013]
2011.
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Indicates the major publication for the study

40
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

CAGO2303
Methods
Multicentre (51 centres), double-blind controlled trial, randomised, parallel group design
Study conducted from 28 March 2007-20 June 2008
Duration: 8 weeks
Participants were randomised to 25 mg/day of agomelatine, 20 mg/day of paroxetine
and placebo, in a 1:1:1 ratio
Participants
Men and women aged 18-70 (inclusive) with MDD according to DSM-IV criteria
Eligibility criteria: HAMD-17 score of 22 and over
Age: 18-70 years
Sample size: agomelatine = 169; paroxetine = 168; placebo = 166
Setting: unclear
Country: USA
Interventions
Agomelatine (25 mg/day)

Paroxetine (20 mg/day)
Placebo (identically coated tablets)
Participants who had not improved by Week 4 received an increase to dose level 2
(agomelatine 50 mg/day or paroxetine 40 mg/day or matching placebo)
The core study comprised a pre-randomisation phase and a 8-week double-blind phase,
followed by a 1-week double-blind taper phase. Participants who did not enrol into the
open-label extension phase and participants who prematurely discontinued were required
to attend a follow-up interview
Outcomes
Primary efficacy variables:

- Change from baseline to Week 8 on HAMD-17 total score
Secondary efficacy variables:
- Change from baseline to Week 8 (LOCF) on the total score of the Arizona Sexual
Experience Scale
- Proportion of participants with clinical improvement as defined by a score of 1 or 2 in
CGI at Week 8 (LOCF)
- Proportion of participants who achieved clinical remission as defined by a total score
of 7 on HAMD-17 (LOCF)
- Symptoms of anxiety and depression as measured by the change from baseline to Week
8 (LOCF) on the total score of the HADS
Safety variables:
- Frequency of adverse events and serious adverse events during the 8-week treatment
period
- Changes in laboratory values during the 8-week treatment period
- Changes in ECGs during the 8-week treatment period
- Changes in vitals signs during the 8-week treatment period
Notes
Unpublished study. No details on study authors.
Risk of bias
41
CAGO2303
(Continued)
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Unclear risk

bias)
Comment: no information provided
Allocation concealment (selection bias)
Unclear risk
Blinding of participants and personnel Low risk

(performance bias)
All outcomes
Quote: . . . Matching placebo film-coated

oral tablets and paroxetine 20 mg, . . .
double-blind trial
Comment: probably done
Blinding of outcome assessment (detection Low risk

bias)
All outcomes
Quote: . . . double blind

Incomplete outcome data (attrition bias)

All outcomes
Unclear risk
Quote: . . . the primary efficacy analysis

was performed on the ITT population
Attrition was balanced between groups
Selective reporting (reporting bias)
Low risk
The trial was registered, all mentioned outcomes listed in the report. However, no
protocol was available. Adverse effects were
reported only if the incidence was at least
2% per group, but serious adverse effects
were reported
Other bias
High risk
Study funded by Servier, the drug company

manufacturing agomelatine
CL3-022
Methods
Multicenter (74 centres), randomised, parallel group, double-blind controlled trial

Study conducted from September 1999-August 2001
Duration: 6 weeks
The randomisation of treatments (agomelatine, placebo, fluoxetine) was non-adaptive,
non-centralised, and balanced with a 1:1:1 ratio. There was no stratification and permutation blocks were of fixed size = 6
Participants
Men or women suffering from a single or recurrent episode of MDD according to DSMIV criteria, with or without melancholic features, without atypical features, and without
psychotic features
Eligibility criteria: HAM-D total score of 22 or over. The decrease in HAM-D total score
should not be more than 20% between start of run-in and inclusion visits, and a severity
of illness 4 on the CGI
Age: 18-59 years (inclusive)
Sample size: agomelatine = 133; fluoxetine = 137; placebo = 149
Setting: inpatients and outpatients

42
CL3-022
(Continued)
Country: France
Interventions

Fluoxetine (25 mg/day)
Placebo
The study comprised a single-blind run-in placebo period with a duration ranging from
7-14 days, an active double-blind placebo-controlled treatment period of 6 weeks (W0W6), an optional double-blind placebo-controlled extension treatment period of 18
weeks (W6-W24), and a follow-up period of 1 week without treatment (W7 or W25)
Outcomes
Primary efficacy variable:

- last post-baseline value of HAM-D total score assessed by the investigator
- CGI
- MADRS
- HAM-A
- LSEQ
All but the LSEQ were assessed by the investigator
Notes
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Low risk

bias)
Quote: . . . The randomisation of treatments [ . . . ] was non-adaptive, non-centralised, and balanced with a 1:1:1 ratio.
There was no stratification and permutation blocks were of fixed size = 6
Quote: . . . non centralised

Comment: not enough information provided
Unclear risk

(performance bias)
All outcomes
Quote: . . . agomelatine, placebo and fluoxetine [ . . . ] were disguised in tablets or

capsules (or tablets) of identical appearance
and taste

bias)
All outcomes


All outcomes
The attrition was balanced between groups.

However, no more information was provided
Unclear risk

43
CL3-022
(Continued)
High risk
The study was a trial of a study conducted

by the pharmaceutical company (Servier)
to obtain approval of agomelatine in Europe, from EMA. Data are from EMA report only, and no protocol is available
Other bias
High risk
Trial sponsored by drug manufacturer

The pharmaceutical company (Servier) was
contacted, but they were not able to provide
us with any additional data
CL3-023
Methods
Multicentre, randomised, double-blind, parallel group, controlled trial

Study conducted from December 1999-September 2001
Duration: 6 weeks
The randomisation of treatments (agomelatine, placebo, paroxetine) was non-adaptive,
Participants
Men and women suffering from a single or recurrent episode of MDD according to
DSM-IV criteria, with or without melancholic features, without atypical features, and
without psychotic features
Eligibility criteria: HAM-D Total score of 22
Sample size: agomelatine = 142; paroxetine = 138; placebo = 137
Country: international (countries not stated)
Interventions

Placebo
The study comprised a single blind run-in placebo period with duration ranging from
Outcomes

- Last post-baseline value of HAM-D total score assessed by the investigator
- CGI
- MADRS
- HAM-A
- LSEQ
Notes

44
CL3-023
(Continued)
Risk of bias
Bias
Authors judgement

bias)
Quote: . . . The randomisation of treatments [. . . ] was non-adaptive, non-centralised, and balanced with a 1:1:1 ratio.

Unclear risk

(performance bias)
All outcomes
Quote: . . . Agomelatine, placebo and [.

. . ] paroxetine were disguised in tablets or
and taste

bias)
All outcomes
Quote: . . . double blind.


All outcomes
Unclear risk
Attrition was balanced between groups,

however, no further information was provided
High risk

by the pharmaceutical company (Servier)
to obtain approval for agomelatine in Europe, from EMA. Data are from EMA report only, and no protocol is available
Other bias
High risk


45
CL3-024
Methods
Multicentre, randomised, parallel group, double-blind controlled trial

Study conducted from June 2000-May 2002
Duration: 6 weeks
The randomisation of treatments (agomelatine, placebo, fluoxetine) was non-adaptive,
Participants
Men or women suffering from a single or recurrent episode of MDD according to DSMIV criteria, with or without melancholic features, without atypical features, and without
psychotic features
Eligibility criteria: HAM-D Total score of 22
Sample size: agomelatine 25 mg/d = 150; agomelatine 50 mg/d = 151; fluoxetine = 148;
placebo = 158
Country: multinational (countries not stated)
Interventions

Fluoxetine (20 mg/day)
Placebo
The study comprised a single blind run-in placebo period with a duration ranging from
Outcomes

- Last post-baseline value of HAM-D total score assessed by the investigator
- CGI
- MADRS
- HAM-A
- LSEQ
Notes
Risk of bias
Bias
Authors judgement

bias)


Quote: . . . The randomisation of treatments [. . . ] was non-adaptive, non-centralised, and balanced with a 1:1:1 ratio.
46
CL3-024
(Continued)
Unclear risk


(performance bias)
All outcomes
Quote: . . . agomelatine, placebo and [.

. .] paroxetine were disguised in tablets or
and taste

bias)
All outcomes


All outcomes
Unclear risk
Attrition was balanced between groups.

High risk

by the pharmaceutical company Servier to
obtain approval of agomelatine in Europe,
from EMA. Data are from EMA report
only, and no protocol is available
Other bias
High risk

Corruble 2013
Methods
Multicentre (51 centres), randomised, parallel group, double-blind controlled trial

Duration: 12 weeks (with 12-week extension)
Participants
Men or women suffering from a moderate to severe MDD according to DSM-IVTR criteria, single or recurrent episode (at least 4 weeks), with or without melancholic
features, without seasonal pattern, without psychotic features and without catatonic
features
Eligibility criteria: HAM-D 17 total score of 22; CGI-S score of 4; HADS score of
11. HAM-D 17 total score had to be stable between election and inclusion (decrease
< 20%)
Sample size: agomelatine = 164; escitalopram = 160
Setting: outpatients
Country: multinational (Australia, Brasil, Canada, France, Russia, South Africa, UK)
Interventions
Agomelatine (25-50 mg/day)

Escitalopram (10-20 mg/day)
A double-blind treatment period of 24 weeks (a 12-week mandatory double-blind treat-

47
Corruble 2013
(Continued)
ment period followed by a 12-week extension period (for participants having a CGI-I
score 42 at week 12)) preceded by a 3-7-day run-in selection period between selection
and inclusion visits (week 0). At week 0, participants were randomised to 1 of 2 treatment groups: agomelatine or escitalopram. From week 0, participants received 25 mg/d
agomelatine or 10 mg/d escitalopram. In case of insufficient improvement (criteria blind
for the investigator and participant), the dosage of agomelatine was increased to 50 mg/
d and that of escitalopram to 20 mg/d from 2 weeks onwards
Outcomes

- HAMD-17
- CGI
- Sleep satisfaction Visual Analogue Scale
- Global Assessment of Functioning
- Oxford Questionnaire on Emotional Side-Effects of Antidepressants (OQUESA)
Safety variables:
- spontaneous report of adverse events by participants at each visit
- 12-lead ECG abnormalities at week 0, 12 and 24 or at time of withdrawal
- biological samplings at week 0, 12 and 24 or at time of withdrawal
- physical examination at selection, inclusion and 24 weeks
Notes
12 weeks of mandatory treatment, 12 week extension period for participants with CGII 2 (after the first 12 weeks of mandatory treatment)
Data were extracted for the first 12 week of mandatory treatment only
Risk of bias
Bias
Authors judgement

bias)
Quote: Eligible patients were assigned to

agomelatine or escitalopram treatment according to a balanced (nonadaptive) randomization with stratification on the clinical centre [ . . . ] in a blinded condition
manner for patients and investigators
Low risk
Quote: . . . The treatment allocation and

the dose increase were done centrally using
an Interactive Response System . . .

(performance bias)
All outcomes
Quote: Treatments were identically labelled


bias)
All outcomes


48
Corruble 2013
(Continued)

All outcomes
Unclear risk

High risk
The FAS analysis is not fully reported, so it

is unclear if all patients were included. Also,
safety data were reported at 24 weeks only,
in spite of the fact that they were collected
at week 12
Other bias
High risk
Trial sponsored by drug manufacturer
Hale 2010
Methods
Multicentre (41 centres), double-blind, randomised, parallel-group comparative study

Study conducted from 2005-2008
Duration: 8 weeks
Participants
Men and women (outpatients), with a diagnosis of MDD of severe intensity according
to DSM-IV-TR, confirmed by the MINI
Elgibility criteria: HAMD-17 25, CGI 4, at least 7 symptoms among symptoms
A1-A9 of the diagnostic criteria for major depressive episode (marked interference with
occupational functioning, usual social activities, or relationships with others) with a
single or recurrent episode that had already lasted at least 4 weeks. The HAMD-17 total
score did not decrease between selection and inclusion by more than 20%. At inclusion,
the sum of items 1 (depressed mood), 2 (feelings of guilt), 5 (insomnia, middle of the
night), 6 (insomnia, early hours of the morning), 7 (work and activities), 8 (retardation)
, 10 (psychic anxiety), and 13 (general somatic symptoms) were at least 55% of the
HAMD-17 total score, to ensure the expected weight of the depression symptoms the
HAMD-17 total score was still at least 25, and the CGI-S score was still at least 4
Exclusion criteria: criteria related to the depressive episode included seasonal pattern,
psychotic features, and postpartum onset. Other exclusion criteria included: marked
suicidal intent and/or known suicidal tendencies for the current episode (score of 4 on
HAMD-17 item 3 or the investigators opinion); bipolar disorder; anxiety symptoms
such as panic attacks; obsessive compulsive disorder; post-traumatic stress disorder; drug
abuse or dependency; resistance to fluoxetine for current episode; treatment with ECT
or formal psychotherapy within the last 3 months, or light-therapy started within the
last 2 weeks; previous failure to respond to the administration of an appropriate dose of
2 different antidepressant treatments (including fluoxetine) for at least 4 weeks each, for
the current and previous episodes; neurologic disorders (dementia, seizure, and stroke);
and severe or uncontrolled organic disorders (neoplastic, cardiovascular, pulmonary, or
digestive disorders, unstabilised type 1 or 2 diabetes)
Age: 18-65 years
Sample size: agomelatine = 252; fluoxetine = 263
Countries: international (Argentina, Brazil, Italy, Spain, UK)

49
Hale 2010
(Continued)
Interventions

Fluoxetine (20-40 mg/day)
After a 3-7-day drug-free period (according to the half-life of any earlier treatment),
participants were randomly assigned to a treatment group, with visits every 2 weeks.
When there was insufficient improvement according to predefined criteria, the dose of
agomelatine was increased to 50 mg/day after 2 weeks, and fluoxetine to 40 mg/day after
4 weeks, in line with current prescribing guidelines for the 2 agents
Other antidepressants, hypnotics, anxiolytics, and neuroleptic agents were prohibited
during the study and for a variable period before inclusion, depending on the half-life.
Notably, treatment with hypnotics or anxiolytics had to be stopped at selection visit
at the latest, though zolpidem was allowed until week 2 (maximal dose 10 mg/day), if
required by the patients condition
Outcomes

- HAMD-17
- CGI-S
- CGI-I
- sleep (using HAM-D sleep items)
- anxiety (using HAM-A total score and psychic and somatic scores)
- responders (defined by a decrease of at least 50% in total score of HAMD-17 from
baseline or a CGI-I score of 1 or 2)
- remitters (participants with HAM-D17 total score of 6 or less or a CGI-I score of 1)
- HAM-A scale
Safety variables:
- adverse events reported by the participants
- somatic complaints expressed spontaneously or upon enquiry
- body mass index (weeks 0 and 8)
- sitting blood pressure (weeks 0 and 8)
- heart rate (weeks 0 and 8)
- ECG (weeks 0 and 8)
- biochemistry and hematology (weeks 0 and 8)
Compliance assessed by counting returned capsules at each visit from week 2 onwards
Notes
Study funded by Servier, the drug company manufacturing agomelatine. The authors
have received honoraria, research grants, or both, from Servier
Risk of bias
Bias
Authors judgement

bias)
Quote: . . . patients were randomly assigned to receive agomelatine (25 mg/day)

or fluoxetine (20 mg/day)
Unclear risk

50
Hale 2010
(Continued)

(performance bias)
All outcomes
Quote: . . . During the entire duration

of the study, all patients took two capsules
orally in the morning and one capsule in the
evening, irrespective [of ] the treatment and
daily dosage allocated. Agomelatine was administered in the evening, whereas fluoxetine was administered in the morning according to current recommendations. The
appearance and taste of the study treatment
were the same from inclusion to the end
of the study for all patients. The packaging
and labelling were identical

bias)
All outcomes
Quote: . . . Both investigators and patients

were blind to the criteria determining insufficient improvement, as well as the decision to up-titrate, which were applied centrally using an interactive voice-response
system
Quote: . . . double-blind

All outcomes
Low risk
Balanced attrition between groups (30/252

for agomelatine and 49/263 for fluoxetine)
Quote: . . . The full analysis set (FAS)
(intention to treat principle) consisted of
patients in the randomised set who took
at least one dose of the study treatment
and with a baseline (week 0) evaluation and
with at least one post-baseline evaluation of
the primary criterion over the period from
week 0 to week 8. The safety set was defined as all included patients who took at
least one dose of study treatment
Low risk
All outcomes and safety variables stated

were reported
Other bias
High risk
Study was funded by Servier, the pharmaceutical company that manufactures

agomelatine

51
Kasper 2010
Methods
Multicentre (37 centres), double-blind, randomised exploratory study with parallelgroup design
Study conducted from 2005-2006
Duration: 6 weeks
Participants
Outpatients, men and women with a primary diagnosis of MDD, single or recurrent, of
moderate or severe intensity according to DSM-IV-TR criteria, confirmed by the MINI
Eligibility criteria: an HDRS score 22, and a sum of 3 on HAM-D items 5 (insomnia:
middle of the night) and 6 (insomnia: early hours of the morning)
Exclusion criteria: seasonal pattern; psychotic features, or catatonic symptoms; postpartum depression; current episode had already lasted at least 4 weeks; high risk of suicide or
a previous suicide attempt within 6 months (score 2 on HDRS item 3); bipolar disorder;
anxiety symptoms such as current panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, or acute stress disorder; drug abuse or dependency within the
past 12 months; previous depression resistance to antidepressants; treatment with ECT
or formal psychotherapy within 3 months, or light-therapy started within last 2 weeks;
screening positive on clinical screening evaluation for sleep disorders, including obstructive sleep apnoea and restless legs syndrome; neurologic disorders (dementia, seizure,
and stroke); obesity with functional impairment; serious or not stabilised organic disease (neoplasia, cardiovascular or pulmonary disease, or uncontrolled type 1 or type 2
diabetes)
Other antidepressants, hypnotics, anxiolytics, and neuroleptic agents were prohibited
during the study and for a variable period before inclusion, depending on half-life. When
the washout period of hypnotics or anxiolytics was applicable for the study, the treatment
had to be stopped at selection visit at the latest appointment
Age: 18 to 60 years
Sample size: agomelatine = 154; sertaline = 159
Countries: multinational (France, Germany, Austria, Spain, Italy, and Poland)
Interventions

Sertraline (50-100 mg/day)
After a washout period according to previous drugs half-lives of at least 1 week, increasing
to 2 weeks if the participant had previously received monoamine oxidase inhibitors, and
to a maximum of 5 weeks if the participant had previously been treated with fluoxetine
or trazodone, eligible participants were randomly assigned to a treatment group. 4 visits
were scheduled: at week 0 (baseline) and then every 2 weeks at weeks 2, 4, and 6
After 2 weeks, a dose increase to agomelatine 50 mg/d or sertraline 100 mg/d was possible
if there was insufficient improvement according to predefined criteria
Outcomes
Efficacy variables:
- actigraphy
- Non-Parametric Circadian Rhythms Analysis (NPCRA)
- LSEQ
- HAMD-17
- HAM-A
- CGI-S
- CGI-I
Safety variables:
- adverse events reported by the participants

52
Kasper 2010
(Continued)
- somatic complaints expressed spontaneously or upon enquiry

- body mass index (weeks 0 and 6)
- blood pressure (weeks 0 and 6)
- heart rate (weeks 0 and 6)
- ECG (week 0 and in case of withdrawal from the study)
- biochemistry and haematology (weeks 0 and 6)
Compliance was assessed by counting returned capsules at each visit from week 2
Notes
Study sponsored by Servier, the pharmaceutical company that manufactures agomelatine

Conflicts of interest declaration:
Dr Kasper has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers
Squibb, GlaxoSmithKline, Organon, Sepracor, and Servier; has served as a consultant or
on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly,
Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen, and Novartis; and has
served on speakers bureaus for AstraZeneca, Eli Lilly, Lundbeck, Schwabe, Sepracor,
Servier, Pierre Fabre, and Janssen.
Dr Hajak has served on the speakers boards of AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, Cephalon, EuMeCom, GlaxoSmithKline, JanssenCilag, Eli Lilly, Lundbeck, Merz, Neurim, Novartis, Organon, Pfizer, Sanofi-Aventis,
Servier, Takeda, and Wyeth; has been a consultant or member of advisory board of
Actelion, AstraZeneca, Bristol-Myers Squibb, Euro RSCG Life Worldwide, Gerson Lerman Group, Janssen-Cilag, Eli Lilly, Lundbeck, McKinsey, Merck, Network of Advisors,
Neurim, Neurocrine, Novartis, Organon, Pfizer, Proctor & Gamble, Purdue, SanofiAventis, Schering Plough, Sepracor, Servier, Takeda, and Wyeth; and has received research funding from Actelion, AstraZeneca, Boehringer Ingelheim, BrainLab, GlaxoSmithKline, Lundbeck, Neurim, Novartis, Organon, Orphan, Sanofi-Aventis, Sepracor,
Servier, and Takeda
Dr Wulff has received honoraria for data analysis and consulting from Servier
Dr Hoogendijk has lectured and been a member of advisory boards for Lundbeck,
Servier, Eli Lilly, and Organon/Schering Plough, for which the Foundation for Depression Research GGZBA has received grants and salary.
Dr Montejo has received honoraria from Servier, Eli Lilly, Bristol- Myers Squibb, GlaxoSmithKline, Sanofi, AstraZeneca, Boehringer, and Wyeth and has served on advisory
boards for Eli Lilly, Boehringer, GlaxoSmithKline, Servier, and AstraZeneca
Dr Smeraldi has served as consultant or speaker for Janssen-Cilag, Innova-Pharma, and
Wyeth
Dr Rybakowski has served as consultant or speaker for Adamed-Poland, AstraZeneca,
Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Lundbeck, Organon, Pfizer, Sanofi-Aventis, and Servier
Dr Quera-Salva has served as a consultant or advisory board member for Servier
Dr Wirz-Justice has been a consultant and speaker for Servier.
Dr Picarel-Blanchot is an employee of Servier.
Dr Bayl has received honoraria from Bristol-Myers Squibb, Janssen-Cilag, Servier,
Sanofi-Aventis, UCB Pharma Research Support Bioprojet, Eli Lilly, Janssen-Cilag, and
Servier.
Risk of bias
Bias
Authors judgement


53
Kasper 2010
(Continued)

bias)
Quote: . . . Eligible patients were randomly assigned

Unclear risk

(performance bias)
All outcomes
Quote: . . . During the entire duration of

the study, all patients took orally 2 tablets
once a day in the evening, irrespective of the
treatment and daily dosage allocated. The
appearance and the taste of the study treatment were the same from inclusion to the
end of the treatment period for all patients.
The packaging and the labelling were identical

bias)
All outcomes
Quote: . . . the dose increase were applied centrally using an Interactive Voice
Response System, and the investigator and
the patient were blind to them

All outcomes
Low risk
Balanced attrition between groups (21/154

for agomelatine and 30/159 for sertraline)
No missing outcome data
Low risk
All outcomes and safety variables stated are

reported
Other bias
High risk
Study was funded by Servier, the pharmaceutical company manufacturing agomelatine

54
Kennedy 2008
Methods
Multicentre (43 centres), double-blind double-dummy, randomised, parallel- group,

placebo-controlled study
Study conducted from October 2002-May 2004
Duration: 12 weeks
Participants in the agomelatine group received 2 placebo capsules in the morning and 2
agomelatine 25 mg capsules in the evening. Participants in the venlafaxine group were
prescribed 2 placebo capsules in the evening throughout the study and 2 venlafaxine 37.
5 mg capsules in the morning for the first 2 weeks, followed by 2 x 75 mg capsules in the
morning for the remaining 10 weeks. Outcome measures were administered at baseline
and after 2, 6, 10, and 12 weeks
Participants
Men and women with DSM-IV criteria for MDD

Eligibility criteria: before treatment required 1) to score 20 on MADRS and to be free
of antidepressant medication for a minimum of 7 days (3 weeks in the case of fluoxetine
or nonselective monoamine oxidase inhibitors); and 2) to have engaged in sexual activity
(intercourse and/or self-stimulation) in the past 2 weeks
Exclusion criteria: concurrent anxiety disorders; substance abuse or dependence disorders; bipolar disorder; MDD with psychotic or catatonic features; postpartum depression;
pregnancy, lactation, or inadequate contraception; evidence of active suicidal ideation or
suicide attempt in the past 6 months; previous failure to respond to either of the protocol
treatments; and neurological or unstable medical conditions
Age: 18 to 60 years
Sample size: agomelatine = 137; venlafaxine = 140
Countries: multinational (Canada, France, UK)
Interventions

Venlafaxine (75-150 mg/day)
Outcomes
Primary variables:
- Sex function scale
Secondary variables:
- MADRS
- CGI-S
- CGI-I
Safety variables:
- spontaneously reported adverse events
Notes
Primary outcome was the change on Sex FX and not efficacy

Study sponsored by Servier, the pharmaceutical company manufacturing agomelatine
Conflict of interest declaration:
Dr Kennedy has received research funding from Astra- Zeneca, Eli Lilly, GlaxoSmithKline, Janssen Ortho, Lundbeck, and Merck Frosst. At the time of the article publication
he was a consultant to ANS, Biovail, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Institut de Recherches Internationales Servier, Janssen-Ortho, Lundbeck, Organon,
Pfizer, and Wyeth
Dr Rasmussen is a consultant to Institut de Recherches Internationales Servier
Risk of bias
55
Kennedy 2008
(Continued)
Bias
Authors judgement

bias)
Quote: . . . 277 were randomised to receive either agomelatine (n = 137) or venlafaxine XR (n = 140)
Unclear risk

(performance bias)
All outcomes
Quote: . . . A double-dummy design was

applied

bias)
All outcomes

All outcomes
High risk
Quote: . . . Of 320 outpatients aged 18 to

60 years who were enrolled, 277 were randomised to receive either agomelatine (n =
137) or venlafaxine XR (n = 140). Nonrandomisation occurred mainly because of abnormal laboratory values or unacceptable
concomitant medications
Comment: no data on exclusion criteria divided by medication
Low risk

were reported
Other bias
High risk
Study was sponsored by the drug company

that manufactures agomelatine (Servier)
Lemoine 2007
Methods
Multicentre (56 centres), double-blind, randomised, parallel-group study

Study conducted from November 2002-June 2004
Duration: 6 weeks
Participants
Men and women with DSM-IV criteria for MDD

Eligibility criteria: HAM-D score of 20
Exclusion criteria: psychotic features or catatonic symptoms; postpartum depression;
high risk of suicide or previous suicide attempt within 6 months; bipolar disorder; anxiety
symptoms such as panic attacks; obsessive-compulsive disorders; post-traumatic stress
disorders; drug abuse or dependency; previous depression resistant to antidepressants;
treatment with ECT 3 months or formal psychotherapy within 1 month; screening
positive on clinical screening evaluation for sleep disorders, including obstructive sleep

56
Lemoine 2007
(Continued)
apnoea and restless legs syndrome; recent or planned transmeridian air travel (time change
of 3 hours) or phototherapy within 2 weeks; neurologic disorders (dementia, seizure,
stroke); obesity with functional impairment; serious or not stabilised organic disorders
(neoplasia, cardiovascular, pulmonary, uncontrolled type 1 or type 2 diabetes)
Age: 18-65 years
Countries: multinational (France and Spain)
Interventions

Venlafaxine (75-150 mg/day)
After a brief (< 7 days) washout period without study treatment, participants were
randomly assigned to receive agomelatine 25 mg/day or venlafaxine 75 mg/day for a 6week treatment period
Participants took 2 capsules daily, 1 in the morning and 1 in the evening. Agomelatinetreated participants took the placebo capsule in the morning and the agomelatine 25
mg capsule in the evening; venlafaxine-treated participants took a capsule of venlafaxine
37.5 mg in the morning and evening. In participants with insufficient response at week
2, based on a predetermined cut-off on the 17-item HAM-D and global improvement
score of the CGI the doses were increased to 1 capsule of agomelatine 50 mg in the
evening and 1 placebo capsule in the morning and to venlafaxine 150 mg (75 mg twice
daily)
Outcomes
Efficacy variables:
- LSEQ
- visual Analogue Scale for daytime sleepiness and feeling well
- sleep diary
- HAM-D
- CGI-I
Safety variables
- adverse events presented or reported by the participants
- any abnormal value judged to be clinically relevant by the investigator
Notes
Primary outcome was the getting to sleep score on LSEQ

Study sponsored by Servier, the pharmaceutical company that manufactures agomelatine
The authors received honoraria from Servier in conjunction with this study
Risk of bias
Bias
Authors judgement

bias)
Quote: . . . patients were randomly assigned..

Comment: no information provided.
Unclear risk

57
Lemoine 2007
(Continued)

(performance bias)
All outcomes
Quote: . . . All capsules were identical in

appearance

bias)
All outcomes
Quote: . . . double-blind.

All outcomes
Low risk
Slightly higher attrition rare with venlafaxine (15/165) than agomelatine(36/167)

but reasons reported
No missing outcome data
Low risk

were reported
Other bias
High risk
Study was sponsored by the drug company

that manufactures agomelatine (Servier)
Loo 2002a
Methods
Multicentre (102 centres), randomised, double-blind, placebo-controlled trial

Duration: 8 weeks
In order to exclude rapid placebo responders, participants received placebo for 1 week
before inclusion in the study; those with a reduction of 20% in the HAM-D total score
were not included
Participants
Men and women with a DSM-IV diagnosis of MDD and bipolar II depression
Eligibility criteria: HAM-D 17 score of 22
Exclusion criteria: severe unstable disease or disease that could interfere with study evaluations or circadian rhythms
Age: 18-65 years
Sample size: agomelatine 1 mg = 141; agomelatine 5 mg = 147; agomelatine 25 mg =
137; paroxetine = 147; placebo = 139
Countries: multinational (Belgium, France, UK)
Interventions
Agomelatine (1 mg, 5 mg and 25 mg/day)

Placebo
Concomitant treatment with psychotropic drugs was not allowed with the exception of
benzodiazepines at restricted doses. High potency benzodiazepines, such as alprazolam
and triazolam,were not permitted. Drugs that were thought to be able to influence study
evaluations by acting on participants mood or circadian rhythms, such as beta-blockers,
central alpha-blockers, nonsteroidal anti-inflammatory drugs and exogenous melatonin,
were not allowed. In participants receiving prior psychotropic medication, a washout
period of 1-4 weeks was required depending on the drugs half-life

58
Loo 2002a
(Continued)
Outcomes
Primary outcomes:
- HAM-D final score
- response (defined as 50% reduction of HAMD-17)
- remission (defined as HAMD-17 of < 7)
Secondary outcomes:
- MADRS
- HAM-A
- CGI
Safety variables:
- number of participants experiencing adverse events
- physical examination
- standard biological tests centrally assessed
- ECG
Notes
The primary goal of the study was to compare 3 different doses of agomelatine with both
placebo and the active comparator paroxetine
No information about conflict of interest reported
Risk of bias
Bias
Authors judgement

bias)
Unclear risk

(performance bias)
All outcomes
Quote: . . . patients were randomised in

double-blind conditions . . .

bias)
All outcomes


All outcomes
High risk

However, data are available only for included participants. No data on number of
people randomised
High risk

were reported. However, the trial was not
registered and there is no protocol available
Other bias
Unclear risk
It was not clear whether the study was sponsored or not. The authors did not report
any information on potential conflict of interest

59
Martinotti 2012
Methods
Multisite (2 sites), open-label, randomised, parallel group pilot study

Study conducted from January-November 2010
Duration: 8 weeks
Participants
Men and women with DSM-IV-TR diagnosis of MDD

Exclusion criteria: presence of a medical condition that could either interfere with the
assessment of the drug treatment or be unsafe for the participant (i.e. cirrhosis, renal impairment, unstable hypertension, hypotension, diabetes mellitus, convulsions); history
of bipolar disorder; schizophrenia; schizoaffective disorder; eating disorder; obsessivecompulsive disorder; substance dependence; concomitant use of other antidepressant
drugs (in this case, a washout period of 7 days was required); and pregnancy and breastfeeding or non-effective contraception
Age: 18-60 years
Setting:outpatients
Countries: Italy
Interventions

Venlafaxine (75 mg/day)
After screening to assess eligibility, participants were randomly started on agomelatine
at a dose of 25 mg/d (n = 30) or on venlafaxine 75 mg/d (n = 30). A single dose of 25
mg/d agomelatine was administered at 8:00 pm. If after 2 weeks there was no clinical
response, in the clinicians judgment, the dosage could be increased to a single dose of
50 mg/d. Venlafaxine was administered as a single dose of 75 mg/d, at 8:00 am. If after
2 weeks there was no clinical response, in the clinicians judgment, the dosage could be
increased to a single dose of 150 mg/d
Outcomes
Primary outcomes:
- SHAPS (anhedonia)
Secondary outcomes:
- HAM-D
- HAM-A
- CGI
Safety parameters:
- ECG at the start and end of the study
- urinalysis at the start and end of the study
- haematological and clinical chemical analyses of blood samples (including liver enzymes) at the start and end of the study
- self-reported adverse events
Notes
Primary aim of the study was the comparison of the effects of agomelatine and venlafaxine
on anhedonia in people with major depression
The authors declared no conflicts of interest. Study was not sponsored by any pharmaceutical organisation
Risk of bias
Bias
Authors judgement

60
Martinotti 2012
(Continued)

bias)
Quote: randomised. Randomization

was nonadaptive, balanced, and stratified
on the center. After recruitment of a patient, an interactive computer-based system
allocated a therapeutic unit number . . .
Quote: . . . randomisation was nonadaptive, balanced, and stratified on the center. After recruitment of a patient, an interactive computer-based system allocated
a therapeutic unit number
Low risk
Blinding of participants and personnel High risk

(performance bias)
All outcomes
Quote: open-label
Comment: study was open-label
Blinding of outcome assessment (detection High risk

bias)
All outcomes
Quote: open-label
Comment: study was open-label

All outcomes
High risk
Quote: . . . A total of 92 patients were

screened, of whom 32 were excluded from
the study
Comment: no data on the reasons for exclusion
High risk
No information provided about type(s) of

adverse event
Other bias
Unclear risk
No information available
Quera-Salva 2011
Methods
Multicentre (24 centres), randomised, parallel-group, double-blind controlled trial

Study conducted from May 2007-October 2008
Duration: 6 weeks
Participants
Men and women with DSM-IV-TR diagnosis of MDD, confirmed by the MINI
Eligibility criteria: MDD (single or recurrent episode) of moderate or severe intensity,
HAM-D total score of at least 22
Exclusion criteria: seasonal pattern; postpartum onset; psychotic; or catatonic features;
marked suicidal risk (HAM-D item 3 score > 2); resistant depression (i.e. people who
have not responded previously to 2 different antidepressant treatments of at least 4 weeks
at an appropriate dose); ECT for the current episode; sleep deprivation or light therapy
during the 2 weeks before selection; bipolar disorder and drug abuse or dependency;
shift workers or people with recent transmeridian travel; uncontrolled organic disease;

61
Quera-Salva 2011
(Continued)
women without effective contraception; and after the first Polysomnographic recording
(PSG), people with > 10 apnoeas- hypopnoeas per hour of sleep or > 10 periodic leg
movements per hour of sleep with arousal
Age: 18-60 years
Sample size: agomelatine = 71; escitalopram = 67
Countries: international (Australia, Austria, Brazil, Finland, France, Germany, Spain,
Taiwan)
Interventions

Escitalopram (10-20 mg/day)
After a maximum run-in period of 10 days without treatment, participants were randomly assigned to receive agomelatine 25 mg/day or escitalopram 10 mg/day for 2
weeks, after which the dose could be increased either to agomelatine 50 mg/day or to
escitalopram 20 mg/day if there was insufficient improvement of depressive symptoms.
Participants scoring > 4 on the CGI-I after 6 weeks of treatment were not allowed to
continue in the extension period
Outcomes
Efficacy variables:
- PSG recordings
- HAM-D
- CGI-S
- CGI-I
Safety variables:
- adverse events reported by the participant or upon enquiry, assessed and recorded at
each visit (the investigator had to evaluate the event in terms of severity, relationship to
study medication, and seriousness)
- heart rate at selection and at weeks 6 and 24
- blood pressure at selection and at weeks 6 and 24
- body mass index at selection and at weeks 6 and 24
- biochemistry and haematology at selection, week 6, and week 24
- ECG at selection and at the last visit
Notes
The main aim of the study was to characterise the effects of agomelatine on sleep and
wake parameters by comparing its effect with that of the SSRI escitalopram
The authors have received honoraria, research grants, or both, from Servier. The authors declared they have no other relevant affiliations or financial involvement with any
organisation or entity in conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed below
Conflict of interest from other pharmaceutical companies:
Dr MA Quera Salva: advisory board member of Ferrer international (Barcelona, Spain)
Professor Goeran Hajak: speakers board, consultant, advisory board member author
fees or research funding by Actelion, Affectis, Astra-Zeneca, Bayerische Motorenwerke,
Bayer Vital, Brain Lab, Bristol-Myers, Cephalon, Daimler Benz, Elsevier, EuMeCom, Essex, Georg Thieme, Gerson Lerman Group Council Healthcare Advisors, GlaxoSmithKline, Janssen-Cilag, Lilly, Lundbeck, McKinsey, Merck, Merz, Network of Cilag, Lilly,
Lundbeck, Mc Kinsey, Merck, Merz, Network of Advisors, Neurim, Neurocrine, Novartis, Organon, Orphan, Pfizern Pharmacia, Proctor and Gamble, Purdue, Sanofi-Aventis,
Schering-Ploungh, Sepracor, Springer, Takeda, Transcept, Urban Fischer, Volkswagen,

62
Quera-Salva 2011
(Continued)
and Wyeth
Risk of bias
Bias
Authors judgement

bias)
Quote: . . . patients were randomly assigned

Low risk
Quote: . . . The centralized, balanced randomisation was stratified by center and age
( 40 vs >40 years) using an interactive
voice response system

(performance bias)
All outcomes
Quote: . . . The patients and the investigators were blinded to the dose increase,
which was determined centrally by interactive voice response system according to the
predefined criteria, The appearance and
taste of the study treatments were the same
from inclusion to the end of the treatment
period for all patients. The packaging and
the labeling were identical

bias)
All outcomes
Quote: double-blind

All outcomes
Low risk
Attrition rate was balanced between groups
Low risk

were reported
Other bias
High risk
The authors have received honoraria, research grants, or both, from Servier
Shu 2013
Methods
Multicentre (39 centres), randomised, parallel-group, double-blind controlled trial

Duration: 8 weeks
Participants
Men and women with DSM-IV-TR diagnosis of MDD

Eligibility criteria: MDD (single or recurrent episode that had already lasted at least 4
weeks) of moderate or severe intensity; HAM-D total score of at least 22 and CGI-S score

63
Shu 2013
(Continued)
of at least 4; with or without melancholic features; without seasonal pattern; without

psychotic features and without postpartum onset for the current episode
Exclusion criteria: all other psychiatric disorders comorbid with MDD; physical problems (including GT or transaminases values > 3 times the upper normal limit (> 2
times the upper normal limit in mainland China) or/and creatinemia >150 mol/l (1.
7 mg/dL), and/or alpha-fetoprotein abnormal value (in mainland China); any of the
following disorders from DSM IV-TR, identified with the MINI: 1) chronic depression
(> 2 years of a depressive episode); bipolar disorder I and II; MDD superimposed on
dysthymic disorder according to DSM IV-TR (double depression); current panic disorder; obsessive compulsive disorder; post-traumatic stress disorder; acute stress disorder;
schizoaffective disorder of depressive type; or any other psychotic disorder, including
major depression with psychotic features; 2) alcohol or drug abuse or dependence within
the past 12 months; any personality disorder that might compromise the study. Patients
were also excluded if they were at risk of suicide (according to the investigator) or had
a rating of 4 points on item 3 of HAMD-17; had not responded to previous administration of 2 different antidepressant treatments at an appropriate dose of for at least 4
weeks (including fluoxetine) for the current episode; had neurologic disorders (dementia,
seizure, and stroke); severe or uncontrolled organic disorders (neoplastic, cardiovascular,
pulmonary, or digestive disorders, unstabilised type 1 or 2 diabetes). People were also
excluded if they had received any of the following recent/concomitant therapies: insightoriented and structured psychotherapy (interpersonal therapy, psychoanalysis, cognitive
behavioural therapy) started within 3 months of inclusion; light therapy started within
2 weeks; oral antipsychotic drugs within 4 weeks; depot neuroleptics within 6 months;
ECT within the last 3 months
Age: 18-65 years
Sample size: agomelatine = 314; fluoxetine = 314
Countries: international Asia (Hong Kong, China, Singapore, Malaysia, Taiwan, South
Korea)
Interventions

Fluoxetine (20-40 mg/day)
Washout time required for antidepressants was usually 1 week (2 weeks for non selective
MAOIs and tricyclics). Hypnotics, anxiolytics, and neuroleptic agents were prohibited
during the study and for a variable period before inclusion, depending on the half-life.
Notably, treatment with hypnotics or anxiolytics had to be stopped at selection visit
at the latest, though zolpidem was allowed until week 2 (maximal dose 10 mg/day), if
required by the patients condition
A double-blind treatment period of 8 weeks (from W0-W8) was preceded by a selection
period of 4-10 days before inclusion (W0) visit and followed by a 1 week untreated
period until last study visit (follow-up visit). At W0, participants were randomised to
1 of 2 treatment groups: agomelatine or fluoxetine. From W0, participants received
agomelatine 25 mg/day or fluoxetine 20 mg/day. If there was insufficient improvement determined using blinded criteria defined by the sponsor prior to the study start - dosage
of agomelatine was increased to 50 mg/day after 2 weeks, and dosage of fluoxetine to 40
mg/day after 4 weeks
Outcomes
Primary outcomes:
- HAM-D final score

64
Shu 2013
(Continued)
Secondary outcomes:
- Response (defined as 50% reduction of HAMD-17)
- HAM-A
- CGI-S
- CGI-I
- LSEQ
- TESS
Safety variables:
- emergent adverse events spontaneously reported by the participant at each visit
- physical examination
- vital signs (SBP and DBP, heart rate, and weight) at selection and week 8
- standard biological tests
- liver B ultrasound (for China only)
- ECG
Notes
Completed trial still in press; unregistered trial, no further data available
Risk of bias
Bias
Authors judgement

bias)
Quote: . . . patients were randomised in

one of the two treatment groups
Low risk
Quote: Eligible patients were assigned to

agomelatine or fluoxetine treatment according to a balanced (non-adaptive) randomisation with stratification on the clinical centre. The computer-generated randomisation list was drawn up in blind by I.
R.I.S. Biometry Department.

(performance bias)
All outcomes
Quote: The dosage schedule (three capsules once a day), the study treatment appearance (2 red capsules in the morning and
1 yellow capsule in the evening) and the
taste were the same from inclusion to the
end of the treatment period for all patients.
Capsules were packaged in identical blisters with identical labelling., All study
personnel and participants were blinded to
treatment assignment and dose for the duration of the study.

65
Shu 2013
(Continued)

bias)
All outcomes
Quote: double-blind, All study personnel and participants were blinded to treatment assignment and dose for the duration
of the study.

All outcomes
Unclear risk
Attrition rate was balanced between groups
Unclear risk
Some outcomes and safety variables stated

were reported. More safety data and different exclusion criteria were reported for data
from China, but these were not reported in
the paper
Other bias
High risk
It was not clear whether the study was sponsored by a drug company or not. Trial number not reported
Abbreviations
> = greater/more than
< = less than
= greater than or equal to
= less than or equal to
CGI = Clinical Global Impression
CGI-I = Clinical Global Impression - Improvement
CGI-S = Clinical Global Impression - Severity
DBP = diastolic blood pressure
DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition
DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
ECG = electrocardiogram
ECT = electroconvulsive therapy
FAS = full analysis set
EMA = European Medicines Agency
HADS = Hospital Anxiety and Depression Scale
HAM-A = Hamilton Anxiety rating scale
HAM-D = Hamilton Rating Scale for Depression
HAMD-17 = original 17-point version of HAM-D/HDRS
HDRS = Hamilton Rating Scale for Depression
LOCF = last observation carried forward
LSEQ = Leeds Sleep Evaluation Questionnaire
MADRS = Montgomery and Asberg Depression Rating Scale
MDD = Major Depressive Disorder
MINI = Mini-International Neuropsychiatric Interview
OQUESA = Oxford Questionnaire on Emotional Side effect of Antidepressants
SBP = systolic blood pressure
SHAPS = Snaith Hamilton Rating Scale
SexFX = the sex effects scale
66
TESS = Traumatic Exposure Severity Scale
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
CAGO2301
Wrong comparison (no active control group)
CAGO2302
CAGO2304
CL2-009
CL3-021
CL3-025
CL3-026
Corral 2009
Goodwin 2009
Heun 2013
Kennedy 2006
Loo 2002b
Wrong comparison (comparisons of 2 agomelatine doses)
Olie 2007
Rouillon 2008
Saletu 2011
Save 2011
Serfaty 2010
Stahl 2010
Tseng 2007
Withdrawn prior to enrolment
Zajecka 2010

67
Characteristics of studies awaiting assessment [ordered by study ID]

CL3-027
Methods
Unclear
Participants
. . . largely resistant hospitalised depressed patients
Interventions
Unclear, probably only placebo controlled
Outcomes
Unclear
Notes
This unpublished study is mentioned in the EMA report, no further information available
CL3-048
Methods
12-week multicentre, randomised, double-blind controlled trial
Participants
Older, depressed outpatients with major depression according to DSM-IV
Interventions
Agomelatine (25-50 mg/day), paroxetine (20-30 mg/d)
Outcomes
LSEQ, HAM-D, CGI, MADRS, HAM-A
Notes
Completed but unpublished trial, some data were reported in Kasper 2013, but were insufficient for inclusion
CL3-062
Methods
6-month randomised double-blind, parallel group international multicentre trial
Participants
Outpatients with major depression according to DSM-IV
Interventions
Agomelatine (25-50 mg/day) vs SNRI
Outcomes
HAM-D, CGI, Pittsburgh Sleep Quality Index, LESQ, SDS
Notes
Completed but unpublished trial, no further data available
CL3-073
Methods
3-week, randomised, double then single-blind, controlled, parallel groups, international, multicentre safety trial with
a 5-week open extension period
Participants
Interventions
Agomelatine (25 mg/day), paroxetine, venlafaxine
Outcomes
Number of discontinuation emergent symptoms according to the DESS check-list

68
CL3-073
(Continued)
Notes
Completed but unpublished trial. Primary objective: Compare three different ways to initiate agomelatine after
antidepressant treatment by SSRI or SNRI
CRSC11003
Methods
6-week multicentre, randomised, double-blind controlled trial
Participants
Older depressed outpatients with major depression according to DSM-IV
Interventions
Agomelatine (25-50 mg/day), paroxetine (20-30 mg)
Outcomes
HAM-D, CGI
Notes
CTRI/2011/04/001659
Methods
Randomised, open-label multicentre trial
Participants
People with major depression according to DSM-IV
Interventions
Agomelatine (25-50 mg/day), venlafaxine (37.5-150 mg/day)
Outcomes
HAM-D, CGI
Notes
Karaiskos 2013
Methods
4-month, observational, open-label study
Participants
People with major depression according to DSM-IV-TR and comorbid non-optimally controlled type 2 diabetes
mellitus
Interventions
Agomelatine (25-50 mg/day), sertraline (50-100 mg/day)
Outcomes
HAM-D, HAM-A
Notes
Unclear randomisation

69
Montgomery 2004
Methods
14-week multicentre, randomised, double-blind controlled trial, (2 weeks placebo controlled discontinuation phase)
Participants
People with major depression according to DSM-IV, sustained remitters (MADRS 12 at week 8,10,12) in the
placebo trial
Interventions
Agomelatine (25 mg/day), paroxetine (20 mg/day), placebo
Outcomes
DESS symptoms during first week of withdrawal, MADRS, HAM-A, CGI, partial relapse
Notes
Data for the first trial period (agomelatine vs paroxetine for 12 weeks) were not reported
Vasile 2011
Methods
6 month single-blind trial
Participants
People with MDD and diabetes mellitus
Interventions
Agomelatine, fluoxetine, sertraline
Outcomes
HAM-D, CGI, GAF
Notes
Conference abstract, no further information available, randomisation unclear
Abbreviations
= less than or equal to
DESS = Discontinuation Emergent Signs and Symptoms
DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
EMA = European Medicines Agency
GAF = Global Assessment of Functioning
HAM-A = Hamilton Anxiety rating scale
SDS = Sheehan Disability Scale

70
Characteristics of ongoing studies [ordered by study ID]

CL3-060
Trial name or title
CL3-20098-060
Methods
6-month randomised, double-blind, parallel-group multicentre trial
Participants
Adult outpatients with major depression according to DSM-IV
Interventions
Agomelatine (25-50 mg/day) versus escitalopram (10-20 mg/day)
Outcomes
emotional experiences, antidepressant efficacy
Starting date
June 2012
Contact information
Institut de Recherches Internationales Servier; clinicaltrials@servier.com
Notes
CL3-074
Trial name or title
CL3-20098-074
Methods
8-week randomised, double-blind, parallel-group, multicentre trial
Participants
Adult Indian outpatients with MDD according to DSM-IV
Interventions
Agomelatine (25-50 mg/day), sertraline (50-100 mg/day)
Outcomes
HAM-D, CGI, HADS, SDS, LESQ
Starting date
January 2011
Contact information
Dr Vihang Vahia (vvahia@hotmail.com); Dr Ashutosh Shah (ashutosh.shah@in.netgrs.com)
Notes
CL3-083
Trial name or title
CL3-20098-083
Methods
12-week, randomised, double-blind, parallel-group, multicentre trial
Participants
Interventions
Therapeutic oral doses of agomelatine and therapeutic oral doses of selective serotonin reuptake inhibitors
Outcomes
Unclear: early effect of agomelatine

71
CL3-083
(Continued)
Starting date
May 2011
Contact information
Prof Tudor Udristoiu, Spitalul Clinic de Neuropsihiatrie Craiova, Clinica 1 Psihiatrie, Aleea Potelu No 24,
Craiova, 200317, Romania
Notes
GENRAS
Trial name or title
GENRAS
Methods
Randomised, single-blind trial
Participants
In- and outpatients with major depression according to DSM-IV
Interventions
Agomelatine (25-50 mg/day), escitalopram (20 mg/day)
Outcomes
The genetics of antidepressant response to agomelatine and escitalopram
Starting date
October 2010
Contact information
Medizinische Universitt Wien,Univ Klinik f Psychiatrie und Psychotherapie
Notes
Lundbeck 2011
Trial name or title
Methods
12 week, randomised, double-blind, parallel-group, multicentre trial
Participants
Adult outpatients treated with inadequate response to an SRI antidepressant (monotherapy) prescribed to
treat major depression according to DSM-IV
Interventions
Lu AA21004 (vortioxetine, 10-20 mg/day) versus agomelatine (25-50 mg/day)
Outcomes
MADRS
Starting date
January 2012
Contact information
H Lundbeck A/S; LundbeckClinicalTrials@lundbeck.com
Notes

72
NCT01483053
Trial name or title
NCT01483053 Cardiovascular effects of agomelatine and escitalopram in patients with major depressive
disorder
Methods
Randomised, open label parallel-group, multicentre trial
Participants
People with MDD or MDD with melancholia according to DSM-IV
Interventions
Agomelatine (25-50 mg/day), escitalopram (10-20 mg/day)
Outcomes
Sympathetic nervous activity, blood pressure regulation
Starting date
Not yet open for participant recruitment (August 2012)
Contact information
Markus Schlaich, Baker IDI Heart and Diabetes Institute
Notes
Abbreviations
SDS = Sheehan Disability Scale
SRI = serotonin reuptake inhibitor

73
DATA AND ANALYSES
Comparison 1. Agomelatine vs SSRI
Outcome or subgroup title

1 Response rates
1.1 Agomelatine vs paroxetine
1.2 Agomelatine vs fluoxetine
1.3 Agomelatine vs sertraline
1.4 Agomelatine vs
escitalopram
2 Remission rates
2.4 Agomelatine vs
escitalopram
3 Total drop outs
3.4 Agomelatine vs
escitalopram
4 Drop out due to inefficacy
4.4 Agomelatine vs
escitalopram
5 Drop outs due to side effects
5.4 Agomelatine vs
escitalopram
6 Total number of patients with
side effects
6.4 Agomelatine vs
escitalopram
7 Sleepiness or drowsiness
7.4 Agomelatine vs
escitalopram
No. of
studies
No. of
participants
10
3
4
1
2
3826
1189
1862
313
462
Risk Ratio (M-H, Random, 95% CI)

1.01 [0.95, 1.08]

0.92 [0.77, 1.09]
1.01 [0.92, 1.11]
1.11 [0.94, 1.30]
1.05 [0.95, 1.16]
10
3
4
1
2
3826
1189
1862
313
462

0.83 [0.68, 1.01]

0.61 [0.32, 1.18]
0.76 [0.55, 1.05]
1.12 [0.80, 1.58]
1.13 [0.94, 1.35]
10
3
4
1
2
3826
1189
1862
313
462

0.95 [0.83, 1.09]

1.01 [0.80, 1.28]
0.96 [0.74, 1.26]
0.72 [0.43, 1.21]
0.81 [0.50, 1.32]
9
3
3
1
2
3377
1189
1413
313
462

0.99 [0.71, 1.37]

1.07 [0.64, 1.80]
0.97 [0.57, 1.65]
0.52 [0.16, 1.68]
1.34 [0.43, 4.21]
9
3
3
1
2
3377
1189
1413
313
462

0.68 [0.51, 0.91]

0.83 [0.49, 1.41]
0.74 [0.50, 1.09]
0.37 [0.14, 1.00]
0.40 [0.15, 1.06]
2490
0.91 [0.84, 0.98]
2
2
1
1
905
1141
307
137

0.86 [0.78, 0.94]

1.00 [0.89, 1.11]
0.98 [0.78, 1.23]
0.81 [0.66, 0.99]
5
2
1
1
1
1868
905
513
313
137

0.96 [0.43, 2.15]

0.63 [0.32, 1.21]
1.75 [0.78, 3.93]
4.65 [1.02, 21.16]
0.19 [0.02, 1.55]
Statistical method

Effect size
74
8 Insomnia
9 Dry mouth
10 Constipation
10.1 Agomelatine vs
fluoxetine
11 Dizziness
11.1 Agomelatine vs
paroxetine
11.2 Agomelatine vs
fluoxetine
11.3 Agomelatine vs
escitalopram
12 Agitation or anxiety
12.1 Agomelatine vs
paroxetine
12.2 Agomelatine vs
fluoxetine
13 Suicide wishes, gestures or
attempts
13.1 Agomelatine vs
paroxetine
14 Completed suicide
14.1 Agomelatine vs
paroxetine
15 Vomiting or nausea
15.1 Agomelatine vs
paroxetine
15.2 Agomelatine vs
fluoxetine
15.3 Agomelatine vs
escitalopram
16 Diarrhoea
16.1 Agomelatine vs
paroxetine
16.2 Agomelatine vs
fluoxetine
16.4 Agomelatine vs
escitalopram
17 Sexual dysfunction
17.1 Agomelatine vs
paroxetine
18 Abnormal liver function tests
18.1 Agomelatine vs
paroxetine
2
1
1
5
2
2
1
1
1
1192
572
620
2349
905
1133
311
513
513

0.78 [0.38, 1.59]

0.54 [0.21, 1.38]
1.13 [0.44, 2.88]
0.94 [0.64, 1.40]
0.90 [0.51, 1.57]
0.96 [0.49, 1.89]
1.05 [0.40, 2.72]
2.81 [0.75, 10.46]
2.81 [0.75, 10.46]
4
1
1603
333

1.00 [0.64, 1.55]

0.80 [0.32, 1.96]
1133
1.17 [0.71, 1.94]
137
0.23 [0.03, 2.03]
2
1
1192
572

1.02 [0.46, 2.27]

1.21 [0.40, 3.62]
620
0.83 [0.26, 2.70]
572
0.86 [0.17, 4.41]
572
0.86 [0.17, 4.41]
1
1
572
572

0.35 [0.02, 5.49]

0.35 [0.02, 5.49]
5
2
2175
905

0.70 [0.33, 1.45]

0.34 [0.23, 0.52]
1133
1.54 [0.30, 7.90]
137
0.65 [0.26, 1.61]
4
1
1533
572

0.80 [0.46, 1.40]

0.52 [0.19, 1.43]
513
1.05 [0.37, 2.96]
1
1
311
137

0.70 [0.25, 1.91]

1.86 [0.35, 9.82]
1
1
333
333

0.14 [0.04, 0.47]

0.14 [0.04, 0.47]
4
1
1755
318

3.04 [0.90, 10.22]

3.04 [0.32, 28.89]

75
18.2 Agomelatine vs
fluoxetine
19 Depression scales endpoint
score
19.1 Agomelatine vs
paroxetine
19.2 Agomelatine vs
fluoxetine
19.4 Agomelatine vs
escitalopram
20 Subgroup analysis: dosing response rates
20.1 Flexible dosing
20.2 Fixed dosing
21 Sensitivity analysis: excluding
trials with > 20% drop outs response rates
21.1 Agomelatine vs
paroxetine
21.2 Agomelatine vs
fluoxetine
21.4 Agomelatine vs
escitalopram
imputed response rates
22.1 Agomelatine vs
paroxetine
22.2 Agomelatine vs
fluoxetine
22.4 Agomelatine vs
escitalopram
imputed remission rates
23.1 Agomelatine vs
paroxetine
23.2 Agomelatine vs
fluoxetine
23.4 Agomelatine vs
escitalopram
trials with imputed SDs
24.1 Agomelatine vs
paroxetine
24.2 Agomelatine vs
fluoxetine
1124
3.02 [0.60, 15.17]
1
10
313
3457

Std. Mean Difference (IV, Random, 95% CI)
3.10 [0.13, 75.44]

0.00 [-0.11, 0.12]
882
0.16 [-0.11, 0.43]
1816
-0.01 [-0.15, 0.13]
1
2
306
453

-0.23 [-0.46, -0.01]

-0.08 [-0.26, 0.11]
10
3826
1.01 [0.95, 1.08]
6
4
5
2255
1571
1516

1.03 [0.94, 1.12]

0.97 [0.88, 1.07]
1.06 [0.97, 1.16]
280
0.93 [0.74, 1.17]
785
1.03 [0.84, 1.27]
1
1
313
138

1.11 [0.94, 1.30]

1.15 [0.87, 1.54]
3097
1.02 [0.95, 1.10]
909
0.90 [0.67, 1.21]
1413
1.02 [0.91, 1.15]
1
2
313
462

1.11 [0.94, 1.30]

1.05 [0.95, 1.16]
2331
0.97 [0.83, 1.14]
909
0.81 [0.67, 0.97]
785
0.98 [0.67, 1.45]
1
1
313
324

1.12 [0.80, 1.58]

1.12 [0.93, 1.35]
2524
0.01 [-0.15, 0.16]
882
0.16 [-0.11, 0.43]
1207
-0.02 [-0.23, 0.18]
306
-0.23 [-0.46, -0.01]

76
24.4 Agomelatine vs
escitalopram
25 Sensitivity analysis: response
rates - best case
25.1 Agomelatine vs
paroxetine
25.2 Agomelatine vs
fluoxetine
25.4 Agomelatine vs
escitalopram
rates - worst case
26.1 Agomelatine vs
paroxetine
26.2 Agomelatine vs
fluoxetine
26.4 Agomelatine vs
escitalopram
27 Sensitivity analysis: remission
rates - best case
27.1 Agomelatine vs
paroxetine
27.2 Agomelatine vs
fluoxetine
27.4 Agomelatine vs
escitalopram
28 Sensitivity analysis:remission
rates - worst case
28.1 Agomelatine vs
paroxetine
28.2 Agomelatine vs
fluoxetine
28.4 Agomelatine vs
escitalopram
29 Sensitivity anal: excluding
studies with bipolar
participants - response rates
29.1 Agomelatine vs
paroxetine
30 Additional subgroup analysis:
unpublished vs published trials
- response rates
30.1 Unpublished
30.2 Published
129
-0.21 [-0.55, 0.14]
10
3826
1.05 [0.99, 1.11]
1189
0.96 [0.83, 1.11]
1862
1.06 [0.99, 1.14]
1
2
313
462

1.15 [0.98, 1.35]

1.08 [0.93, 1.26]
10
3826
0.98 [0.92, 1.04]
1189
0.88 [0.73, 1.07]
1862
0.98 [0.90, 1.07]
1
2
313
462

1.08 [0.92, 1.27]

1.03 [0.94, 1.13]
3502
0.91 [0.72, 1.15]
1189
0.75 [0.48, 1.17]
1862
0.89 [0.61, 1.30]
1
1
313
138

1.22 [0.87, 1.69]

1.42 [0.74, 2.71]
3502
0.73 [0.57, 0.94]
1189
0.57 [0.29, 1.12]
1862
0.74 [0.52, 1.05]
1
1
313
138

1.08 [0.77, 1.50]

0.79 [0.43, 1.43]
617
0.84 [0.70, 1.03]
617
0.84 [0.70, 1.03]
10
3826
1.01 [0.95, 1.08]
4
6
1336
2490

0.90 [0.81, 1.00]

1.05 [1.00, 1.11]

77
Comparison 2. Agomelatine vs SNRI
Outcome or subgroup title

1 Response rates
1.1 Agomelatine vs venlafaxine
2 Remission rates
3 Total drop outs
4 Drop out due to inefficacy
5 Drop outs due to side effects
6 Total number of patients with
side effects
7 Sleepiness or drowsiness
8 Insomnia
9 Dry mouth
10 Constipation
10.1 Agomelatine vs
venlafaxine
11 Dizziness
11.1 Agomelatine vs
venlafaxine
12 Vomiting or nausea
12.1 Agomelatine vs
venlafaxine
13 Diarrhoea
13.1 Agomelatine vs
venlafaxine
14 Depression scales endpoint
score
14.1 Agomelatine vs
venlafaxine
15 Subgroup analysis: dosing response rates
15.1 Flexible dosing
15.2 Fixed dosing
16 Subgroup analysis: severity response rates
16.1 Agomelatine vs
venlafaxine (moderate
depression)
16.2 Agomelatine vs
venlafaxine (severe depression)
No. of
studies
No. of
participants
3
3
3
3
2
2
1
1
2
2
2
669
669
669
669
392
392
332
332
608
608
611

1.06 [0.98, 1.16]

1.06 [0.98, 1.16]
1.08 [0.94, 1.24]
1.08 [0.94, 1.24]
0.40 [0.24, 0.67]
0.40 [0.24, 0.67]
1.01 [0.21, 4.94]
1.01 [0.21, 4.94]
0.30 [0.15, 0.59]
0.30 [0.15, 0.59]
0.72 [0.44, 1.18]
2
1
1
1
1
1
1
1
1
611
334
334
332
332
332
332
332
332

0.72 [0.44, 1.18]

0.76 [0.27, 2.14]
0.76 [0.27, 2.14]
0.25 [0.03, 2.24]
0.25 [0.03, 2.24]
0.51 [0.13, 1.99]
0.51 [0.13, 1.99]
0.87 [0.30, 2.53]
0.87 [0.30, 2.53]
1
1
332
332

0.19 [0.06, 0.64]

0.19 [0.06, 0.64]
2
2
609
609

0.42 [0.17, 1.08]

0.42 [0.17, 1.08]
1
1
332
332

2.70 [0.73, 10.00]

2.70 [0.73, 10.00]
668
-0.07 [-0.22, 0.08]
668
-0.07 [-0.22, 0.08]
669
1.06 [0.98, 1.16]
1
2
3
332
337
669

1.08 [0.95, 1.23]

1.05 [0.94, 1.17]
1.06 [0.98, 1.16]
277
1.04 [0.93, 1.17]
392
1.09 [0.96, 1.23]
Statistical method

Effect size
78

trials with > 20% drop outs
17.1 Agomelatine vs
venlafaxine
imputed remission rates
18.1 Agomelatine vs
venlafaxine
rates - best case
19.1 Agomelatine vs
venlafaxine
rates - worst case
20.1 Agomelatine vs
venlafaxine
rates - best case
21.1 Agomelatine vs
venlafaxine
rates - worst case
22.1 Agomelatine vs
venlafaxine
392
1.09 [0.96, 1.23]
392
1.09 [0.96, 1.23]
337
1.09 [0.93, 1.26]
337
1.09 [0.93, 1.26]
669
1.06 [0.98, 1.16]
669
1.06 [0.98, 1.16]
669
1.06 [0.97, 1.15]
669
1.06 [0.97, 1.15]
669
1.09 [0.95, 1.25]
669
1.09 [0.95, 1.25]
669
1.08 [0.94, 1.24]
669
1.08 [0.94, 1.24]

79
Analysis 1.1. Comparison 1 Agomelatine vs SSRI, Outcome 1 Response rates.

Review:
Agomelatine versus other antidepressive agents for major depression
Comparison: 1 Agomelatine vs SSRI

Outcome: 1 Response rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
70/169
91/168
6.2 %
0.76 [ 0.61, 0.96 ]
CL3-023
71/142
74/138
6.3 %
0.93 [ 0.74, 1.17 ]
243/425
81/147
9.9 %
1.04 [ 0.88, 1.23 ]
736
453
22.4 %
0.92 [ 0.77, 1.09 ]
1 Agomelatine vs paroxetine
Loo 2002a
Subtotal (95% CI)
Total events: 384 (Agomelatine), 246 (SSRI)

Heterogeneity: Tau2 = 0.01; Chi2 = 4.52, df = 2 (P = 0.10); I2 =56%
Test for overall effect: Z = 0.97 (P = 0.33)
2 Agomelatine vs fluoxetine
CL3-022
68/133
77/137
6.4 %
0.91 [ 0.73, 1.14 ]
CL3-024
155/301
79/148
8.5 %
0.96 [ 0.80, 1.16 ]
Hale 2010
177/252
164/263
14.6 %
1.13 [ 1.00, 1.27 ]
Shu 2013
205/314
209/314
16.2 %
0.98 [ 0.88, 1.10 ]
1000
862
45.7 %
1.01 [ 0.92, 1.11 ]
Subtotal (95% CI)

3 Agomelatine vs sertraline
105/154
98/159
10.3 %
1.11 [ 0.94, 1.30 ]
154
159
10.3 %
1.11 [ 0.94, 1.30 ]
136/164
128/160
17.5 %
1.04 [ 0.93, 1.15 ]
Quera-Salva 2011
44/71
36/67
4.2 %
1.15 [ 0.87, 1.54 ]
Subtotal (95% CI)
235
227
21.7 %
1.05 [ 0.95, 1.16 ]
100.0 %
1.01 [ 0.95, 1.08 ]
Kasper 2010
Subtotal (95% CI)

Heterogeneity: not applicable
4 Agomelatine vs escitalopram
Corruble 2013

Heterogeneity: Tau2 = 0.0; Chi2 = 0.53, df = 1 (P = 0.47); I2 =0.0%
Total (95% CI)
2125
1701
0.5
0.7
Favours SSRI
1.5
Favours agomelatine
(Continued . . . )

80
(. . .
Study or subgroup
Agomelatine
SSRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Continued)
Risk Ratio
MH,Random,95%
CI
Weight

Test for subgroup differences: Chi2 = 2.68, df = 3 (P = 0.44), I2 =0.0%
0.5
0.7
Favours SSRI
1.5
Favours agomelatine
Analysis 1.2. Comparison 1 Agomelatine vs SSRI, Outcome 2 Remission rates.

Review:

Outcome: 2 Remission rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
9/169
37/168
5.4 %
0.24 [ 0.12, 0.49 ]
CL3-023
32/142
36/138
9.2 %
0.86 [ 0.57, 1.31 ]
Loo 2002a
96/425
37/147
10.8 %
0.90 [ 0.65, 1.25 ]
736
453
25.3 %
0.61 [ 0.32, 1.18 ]
CAGO2303
Subtotal (95% CI)

CL3-022
18/133
25/137
7.0 %
0.74 [ 0.42, 1.29 ]
CL3-024
67/301
65/148
11.7 %
0.51 [ 0.38, 0.67 ]
Hale 2010
173/252
190/263
14.5 %
0.95 [ 0.85, 1.06 ]
Shu 2013
75/314
84/314
11.9 %
0.89 [ 0.68, 1.17 ]
1000
862
45.2 %
0.76 [ 0.55, 1.05 ]
Subtotal (95% CI)
0.5
0.7
Favours SSRI
1.5
Favours agomelatine
(Continued . . . )

81
(. . .
Study or subgroup
Agomelatine
SSRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI

49/154
45/159
10.6 %
1.12 [ 0.80, 1.58 ]
154
159
10.6 %
1.12 [ 0.80, 1.58 ]
100/164
87/160
13.4 %
1.12 [ 0.93, 1.35 ]
Quera-Salva 2011
15/71
12/67
5.5 %
1.18 [ 0.60, 2.33 ]
Subtotal (95% CI)
235
227
18.9 %
1.13 [ 0.94, 1.35 ]
100.0 %
0.83 [ 0.68, 1.01 ]
Kasper 2010
Subtotal (95% CI)

Corruble 2013

Total (95% CI)
2125
1701

Heterogeneity: Tau2 = 0.07; Chi2 = 40.49, df = 9 (P<0.00001); I2 =78%
Test for subgroup differences: Chi2 = 6.95, df = 3 (P = 0.07), I2 =57%
0.5
0.7
Favours SSRI
1.5
Favours agomelatine

82
Analysis 1.3. Comparison 1 Agomelatine vs SSRI, Outcome 3 Total drop outs.

Review:

Outcome: 3 Total drop outs
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
36/169
38/168
11.5 %
0.94 [ 0.63, 1.41 ]
CL3-023
23/142
22/138
6.5 %
1.02 [ 0.59, 1.74 ]
104/425
34/147
16.3 %
1.06 [ 0.75, 1.48 ]
736
453
34.3 %
1.01 [ 0.80, 1.28 ]
Loo 2002a
Subtotal (95% CI)


CL3-022
22/133
19/137
5.8 %
1.19 [ 0.68, 2.10 ]
CL3-024
69/301
29/148
12.5 %
1.17 [ 0.79, 1.72 ]
Hale 2010
30/252
49/263
10.6 %
0.64 [ 0.42, 0.97 ]
Shu 2013
70/314
70/314
21.9 %
1.00 [ 0.75, 1.34 ]
1000
862
50.8 %
0.96 [ 0.74, 1.26 ]
Subtotal (95% CI)

21/154
30/159
7.1 %
0.72 [ 0.43, 1.21 ]
154
159
7.1 %
0.72 [ 0.43, 1.21 ]
20/164
23/160
6.0 %
0.85 [ 0.49, 1.48 ]
Quera-Salva 2011
6/71
8/67
1.8 %
0.71 [ 0.26, 1.93 ]
Subtotal (95% CI)
235
227
7.8 %
0.81 [ 0.50, 1.32 ]
100.0 %
0.95 [ 0.83, 1.09 ]
Kasper 2010
Subtotal (95% CI)

Corruble 2013

Total (95% CI)
2125
1701
0.1 0.2
0.5
Favours agomelatine
10
Favours SSRI
(Continued . . . )

83
(. . .
Study or subgroup
Agomelatine
SSRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Continued)
Risk Ratio
MH,Random,95%
CI
Weight

0.1 0.2
0.5
Favours agomelatine
10
Favours SSRI
Analysis 1.4. Comparison 1 Agomelatine vs SSRI, Outcome 4 Drop out due to inefficacy.
Review:

Outcome: 4 Drop out due to inefficacy
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
1/169
2/168
1.9 %
0.50 [ 0.05, 5.43 ]
CL3-023
9/142
10/138
14.0 %
0.87 [ 0.37, 2.09 ]
37/425
10/147
23.4 %
1.28 [ 0.65, 2.51 ]
736
453
39.3 %
1.07 [ 0.64, 1.80 ]
Loo 2002a
Subtotal (95% CI)


CL3-022
14/133
10/137
17.6 %
1.44 [ 0.66, 3.13 ]
Hale 2010
7/252
13/263
13.0 %
0.56 [ 0.23, 1.39 ]
Shu 2013
10/314
10/314
14.3 %
1.00 [ 0.42, 2.37 ]
699
714
44.9 %
0.97 [ 0.57, 1.65 ]
Subtotal (95% CI)

0.01
0.1
Favours agomelatine
10
100
Favours SSRI
(Continued . . . )

84
(. . .
Study or subgroup
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
Agomelatine
SSRI
n/N
n/N
4/154
8/159
7.6 %
0.52 [ 0.16, 1.68 ]
154
159
7.6 %
0.52 [ 0.16, 1.68 ]
5/164
3/160
5.3 %
1.63 [ 0.40, 6.69 ]
Quera-Salva 2011
2/71
2/67
2.8 %
0.94 [ 0.14, 6.51 ]
Subtotal (95% CI)
235
227
8.1 %
1.34 [ 0.43, 4.21 ]
100.0 %
0.99 [ 0.71, 1.37 ]

Kasper 2010
Subtotal (95% CI)

Corruble 2013

Total (95% CI)
1824
1553

0.01
0.1
Favours agomelatine
10
100
Favours SSRI

85
Analysis 1.5. Comparison 1 Agomelatine vs SSRI, Outcome 5 Drop outs due to side effects.
Review:

Outcome: 5 Drop outs due to side effects
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
4/169
8/168
5.9 %
0.50 [ 0.15, 1.62 ]
CL3-023
6/142
6/138
6.7 %
0.97 [ 0.32, 2.94 ]
27/425
10/147
16.7 %
0.93 [ 0.46, 1.88 ]
736
453
29.3 %
0.83 [ 0.49, 1.41 ]
Loo 2002a
Subtotal (95% CI)


CL3-022
3/133
3/137
3.3 %
1.03 [ 0.21, 5.01 ]
Hale 2010
10/252
17/263
14.1 %
0.61 [ 0.29, 1.32 ]
Shu 2013
27/314
35/314
36.1 %
0.77 [ 0.48, 1.24 ]
699
714
53.5 %
0.74 [ 0.50, 1.09 ]
Subtotal (95% CI)


Kasper 2010
5/154
14/159
8.3 %
0.37 [ 0.14, 1.00 ]
154
159
8.3 %
0.37 [ 0.14, 1.00 ]
4/164
13/160
6.8 %
0.30 [ 0.10, 0.90 ]
Quera-Salva 2011
2/71
2/67
2.2 %
0.94 [ 0.14, 6.51 ]
Subtotal (95% CI)
235
227
9.0 %
0.40 [ 0.15, 1.06 ]
100.0 %
0.68 [ 0.51, 0.91 ]
Subtotal (95% CI)

Corruble 2013

Total (95% CI)
1824
1553

0.01
0.1
Favours agomelatine
10
100
Favours SSRI

86
Analysis 1.6. Comparison 1 Agomelatine vs SSRI, Outcome 6 Total number of patients with side effects.
Review:

Outcome: 6 Total number of patients with side effects
Study or subgroup
Agomelatine
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
120/167
135/166
24.7 %
0.88 [ 0.78, 1.00 ]
Loo 2002a
229/425
97/147
19.3 %
0.82 [ 0.71, 0.94 ]
592
313
44.0 %
0.86 [ 0.78, 0.94 ]
Subtotal (95% CI)
Total events: 349 (Agomelatine), 232 (Control)

Hale 2010
143/250
148/263
18.3 %
1.02 [ 0.87, 1.18 ]
Shu 2013
145/314
149/314
15.9 %
0.97 [ 0.82, 1.15 ]
564
577
34.3 %
1.00 [ 0.89, 1.11 ]
Subtotal (95% CI)

Kasper 2010
73/150
78/157
9.8 %
0.98 [ 0.78, 1.23 ]
150
157
9.8 %
0.98 [ 0.78, 1.23 ]
47/71
54/66
11.9 %
0.81 [ 0.66, 0.99 ]
71
66
11.9 %
0.81 [ 0.66, 0.99 ]
1377
1113
100.0 %
0.91 [ 0.84, 0.98 ]
Subtotal (95% CI)

Quera-Salva 2011
Subtotal (95% CI)

Total (95% CI)

0.1 0.2
0.5
Favours agomelatine
10
Favours SSRI

87
Analysis 1.7. Comparison 1 Agomelatine vs SSRI, Outcome 7 Sleepiness or drowsiness.

Review:

Outcome: 7 Sleepiness or drowsiness
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
13/167
15/166
25.7 %
0.86 [ 0.42, 1.75 ]
Loo 2002a
14/425
11/147
24.9 %
0.44 [ 0.20, 0.95 ]
592
313
50.6 %
0.63 [ 0.32, 1.21 ]
Subtotal (95% CI)


Hale 2010
15/250
9/263
24.3 %
1.75 [ 0.78, 3.93 ]
250
263
24.3 %
1.75 [ 0.78, 3.93 ]
9/154
2/159
15.1 %
4.65 [ 1.02, 21.16 ]
154
159
15.1 %
4.65 [ 1.02, 21.16 ]
Subtotal (95% CI)

Kasper 2010
Subtotal (95% CI)


Quera-Salva 2011
1/71
5/66
10.0 %
0.19 [ 0.02, 1.55 ]
Subtotal (95% CI)
71
66
10.0 %
0.19 [ 0.02, 1.55 ]
1067
801
100.0 %
0.96 [ 0.43, 2.15 ]

Total (95% CI)

0.001 0.01 0.1

Favours agomelatine
10 100 1000
Favours SSRI
(Continued . . . )

88
(. . .
Study or subgroup
Agomelatine
SSRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI

0.001 0.01 0.1
Favours agomelatine
10 100 1000
Favours SSRI
Analysis 1.8. Comparison 1 Agomelatine vs SSRI, Outcome 8 Insomnia.

Review:

Outcome: 8 Insomnia
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
11/425
7/147
50.5 %
0.54 [ 0.21, 1.38 ]
425
147
50.5 %
0.54 [ 0.21, 1.38 ]
9/310
8/310
49.5 %
1.13 [ 0.44, 2.88 ]
310
310
49.5 %
1.13 [ 0.44, 2.88 ]
735
457
100.0 %
0.78 [ 0.38, 1.59 ]
Loo 2002a
Subtotal (95% CI)

Shu 2013
Subtotal (95% CI)

Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

89
Analysis 1.9. Comparison 1 Agomelatine vs SSRI, Outcome 9 Dry mouth.

Review:

Outcome: 9 Dry mouth
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
16/167
16/166
35.4 %
0.99 [ 0.51, 1.92 ]
Loo 2002a
10/425
5/147
13.8 %
0.69 [ 0.24, 1.99 ]
592
313
49.2 %
0.90 [ 0.51, 1.57 ]
Subtotal (95% CI)


Hale 2010
8/250
8/263
16.5 %
1.05 [ 0.40, 2.76 ]
Shu 2013
8/310
9/310
17.4 %
0.89 [ 0.35, 2.27 ]
560
573
33.9 %
0.96 [ 0.49, 1.89 ]
Subtotal (95% CI)


Kasper 2010
8/152
8/159
16.9 %
1.05 [ 0.40, 2.72 ]
152
159
16.9 %
1.05 [ 0.40, 2.72 ]
1304
1045
100.0 %
0.94 [ 0.64, 1.40 ]
Subtotal (95% CI)

Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

90
Analysis 1.10. Comparison 1 Agomelatine vs SSRI, Outcome 10 Constipation.

Review:

Outcome: 10 Constipation
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
8/250
3/263
100.0 %
2.81 [ 0.75, 10.46 ]
250
263
100.0 %
2.81 [ 0.75, 10.46 ]
Hale 2010
Total (95% CI)


Test for subgroup differences: Not applicable
0.01
0.1
Favours agomelatine
10
100
Favours SSRI

91
Analysis 1.11. Comparison 1 Agomelatine vs SSRI, Outcome 11 Dizziness.

Review:

Outcome: 11 Dizziness
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
8/167
10/166
23.2 %
0.80 [ 0.32, 1.96 ]
167
166
23.2 %
0.80 [ 0.32, 1.96 ]
Hale 2010
7/250
9/263
20.2 %
0.82 [ 0.31, 2.16 ]
Shu 2013
24/310
18/310
52.5 %
1.33 [ 0.74, 2.41 ]
560
573
72.6 %
1.17 [ 0.71, 1.94 ]
CAGO2303
Subtotal (95% CI)

Subtotal (95% CI)


Quera-Salva 2011
1/71
4/66
4.1 %
0.23 [ 0.03, 2.03 ]
Subtotal (95% CI)
71
66
4.1 %
0.23 [ 0.03, 2.03 ]
798
805
100.0 %
1.00 [ 0.64, 1.55 ]

Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

92
Analysis 1.12. Comparison 1 Agomelatine vs SSRI, Outcome 12 Agitation or anxiety.

Review:

Outcome: 12 Agitation or anxiety
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
14/425
4/147
53.6 %
1.21 [ 0.40, 3.62 ]
425
147
53.6 %
1.21 [ 0.40, 3.62 ]
5/310
6/310
46.4 %
0.83 [ 0.26, 2.70 ]
310
310
46.4 %
0.83 [ 0.26, 2.70 ]
735
457
100.0 %
1.02 [ 0.46, 2.27 ]
Loo 2002a
Subtotal (95% CI)

Shu 2013
Subtotal (95% CI)

Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

93
Analysis 1.13. Comparison 1 Agomelatine vs SSRI, Outcome 13 Suicide wishes, gestures or attempts.
Review:

Outcome: 13 Suicide wishes, gestures or attempts
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
5/425
2/147
100.0 %
0.86 [ 0.17, 4.41 ]
425
147
100.0 %
0.86 [ 0.17, 4.41 ]
Loo 2002a
Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI
Analysis 1.14. Comparison 1 Agomelatine vs SSRI, Outcome 14 Completed suicide.

Review:

Outcome: 14 Completed suicide
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
1/425
1/147
100.0 %
0.35 [ 0.02, 5.49 ]
425
147
100.0 %
0.35 [ 0.02, 5.49 ]
Loo 2002a
Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

94
Analysis 1.15. Comparison 1 Agomelatine vs SSRI, Outcome 15 Vomiting or nausea.

Review:

Outcome: 15 Vomiting or nausea
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
10/167
27/166
20.2 %
0.37 [ 0.18, 0.74 ]
Loo 2002a
24/425
25/147
21.9 %
0.33 [ 0.20, 0.56 ]
592
313
42.1 %
0.34 [ 0.23, 0.52 ]
Subtotal (95% CI)


Test for overall effect: Z = 4.97 (P < 0.00001)
Hale 2010
20/250
30/263
21.8 %
0.70 [ 0.41, 1.20 ]
Shu 2013
22/310
6/310
18.1 %
3.67 [ 1.51, 8.92 ]
560
573
39.9 %
1.54 [ 0.30, 7.90 ]
Subtotal (95% CI)


Quera-Salva 2011
7/71
10/66
18.0 %
0.65 [ 0.26, 1.61 ]
Subtotal (95% CI)
71
66
18.0 %
0.65 [ 0.26, 1.61 ]
1223
952
100.0 %
0.70 [ 0.33, 1.45 ]

Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

95
Analysis 1.16. Comparison 1 Agomelatine vs SSRI, Outcome 16 Diarrhoea.

Review:

Outcome: 16 Diarrhoea
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
9/425
6/147
29.8 %
0.52 [ 0.19, 1.43 ]
425
147
29.8 %
0.52 [ 0.19, 1.43 ]
7/250
7/263
28.8 %
1.05 [ 0.37, 2.96 ]
250
263
28.8 %
1.05 [ 0.37, 2.96 ]
6/152
9/159
30.2 %
0.70 [ 0.25, 1.91 ]
152
159
30.2 %
0.70 [ 0.25, 1.91 ]
Quera-Salva 2011
4/71
2/66
11.1 %
1.86 [ 0.35, 9.82 ]
Subtotal (95% CI)
71
66
11.1 %
1.86 [ 0.35, 9.82 ]
898
635
100.0 %
0.80 [ 0.46, 1.40 ]
Loo 2002a
Subtotal (95% CI)

Hale 2010
Subtotal (95% CI)

Kasper 2010
Subtotal (95% CI)


Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

96
Analysis 1.17. Comparison 1 Agomelatine vs SSRI, Outcome 17 Sexual dysfunction.

Review:

Outcome: 17 Sexual dysfunction
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
3/167
21/166
100.0 %
0.14 [ 0.04, 0.47 ]
167
166
100.0 %
0.14 [ 0.04, 0.47 ]
CAGO2303
Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

97
Analysis 1.18. Comparison 1 Agomelatine vs SSRI, Outcome 18 Abnormal liver function tests.
Review:

Outcome: 18 Abnormal liver function tests
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
3/158
1/160
29.0 %
3.04 [ 0.32, 28.89 ]
158
160
29.0 %
3.04 [ 0.32, 28.89 ]
Hale 2010
4/252
1/263
30.9 %
4.17 [ 0.47, 37.10 ]
Shu 2013
2/301
1/308
25.7 %
2.05 [ 0.19, 22.45 ]
553
571
56.5 %
3.02 [ 0.60, 15.17 ]
CAGO2303
Subtotal (95% CI)

Subtotal (95% CI)


Kasper 2010
Subtotal (95% CI)
1/154
0/159
14.4 %
3.10 [ 0.13, 75.44 ]
154
159
14.4 %
3.10 [ 0.13, 75.44 ]
865
890
100.0 %
3.04 [ 0.90, 10.22 ]

Total (95% CI)


0.01
0.1
Favours agomelatine
10
100
Favours SSRI

98
Analysis 1.19. Comparison 1 Agomelatine vs SSRI, Outcome 19 Depression scales endpoint score.
Review:

Outcome: 19 Depression scales endpoint score
Study or subgroup
Agomelatine
Std.
Mean
Difference
SSRI
Weight
IV,Random,95% CI
Std.
Mean
Difference
Mean(SD)
Mean(SD)
IV,Random,95% CI
CAGO2303
162
17.1 (7.38)
163
14 (7.53)
10.1 %
0.41 [ 0.20, 0.63 ]
CL3-023
141
13 (8)
137
12.2 (8.1)
9.6 %
0.10 [ -0.14, 0.33 ]
Loo 2002a
135
12.77 (8.23)
144
13.09 (8.37)
9.6 %
-0.04 [ -0.27, 0.20 ]
29.3 %
0.16 [ -0.11, 0.43 ]
Subtotal (95% CI)
438
444

CL3-022
129
14.5 (8.2)
133
13.3 (7.6)
9.4 %
0.15 [ -0.09, 0.39 ]
CL3-024
295
12.69 (8.21)
146
12.5 (7.4)
10.8 %
0.02 [ -0.17, 0.22 ]
Hale 2010
247
11.1 (7.3)
257
12.7 (8.5)
11.6 %
-0.20 [ -0.38, -0.03 ]
Shu 2013
301
12 (7.4)
308
11.8 (8)
12.1 %
0.03 [ -0.13, 0.18 ]
43.9 %
-0.01 [ -0.15, 0.13 ]
9.9 %
-0.23 [ -0.46, -0.01 ]
9.9 %
-0.23 [ -0.46, -0.01 ]
Subtotal (95% CI)
972
844

Kasper 2010
Subtotal (95% CI)
150
10.3 (7)
150
156
12.1 (8.3)
156

Corruble 2013
Quera-Salva 2011
Subtotal (95% CI)
164
8.1 (7.689)
160
8.3 (7.972)
10.2 %
-0.03 [ -0.24, 0.19 ]
68
11.4 (5.9)
61
12.7 (6.7)
6.7 %
-0.21 [ -0.55, 0.14 ]
16.8 %
-0.08 [ -0.26, 0.11 ]
100.0 %
0.00 [ -0.11, 0.12 ]
232
221

Total (95% CI)
1792
1665

-0.5
-0.25
Favours agomelatine

0.25
0.5
Favours SSRI
99
Analysis 1.20. Comparison 1 Agomelatine vs SSRI, Outcome 20 Subgroup analysis: dosing - response rates.
Review:

Outcome: 20 Subgroup analysis: dosing - response rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
70/169
91/168
6.2 %
0.76 [ 0.61, 0.96 ]
Corruble 2013
136/164
128/160
17.5 %
1.04 [ 0.93, 1.15 ]
Hale 2010
177/252
164/263
14.6 %
1.13 [ 1.00, 1.27 ]
Kasper 2010
105/154
98/159
10.3 %
1.11 [ 0.94, 1.30 ]
44/71
36/67
4.2 %
1.15 [ 0.87, 1.54 ]
205/314
209/314
16.2 %
0.98 [ 0.88, 1.10 ]
1124
1131
68.9 %
1.03 [ 0.94, 1.12 ]
1 Flexible dosing
CAGO2303
Quera-Salva 2011
Shu 2013
Subtotal (95% CI)

2 Fixed dosing
CL3-022
68/133
77/137
6.4 %
0.91 [ 0.73, 1.14 ]
CL3-023
71/142
74/138
6.3 %
0.93 [ 0.74, 1.17 ]
CL3-024
155/301
79/148
8.5 %
0.96 [ 0.80, 1.16 ]
Loo 2002a
243/425
81/147
9.9 %
1.04 [ 0.88, 1.23 ]
1001
570
31.1 %
0.97 [ 0.88, 1.07 ]
100.0 %
1.01 [ 0.95, 1.08 ]
Subtotal (95% CI)

Total (95% CI)
2125
1701

0.5
0.7
Favours SSRI
1.5
Favours agomelatine

100
Analysis 1.21. Comparison 1 Agomelatine vs SSRI, Outcome 21 Sensitivity analysis: excluding trials with >
20% drop outs - response rates.
Review:

Outcome: 21 Sensitivity analysis: excluding trials with > 20% drop outs - response rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
71/142
74/138
14.0 %
0.93 [ 0.74, 1.17 ]
142
138
14.0 %
0.93 [ 0.74, 1.17 ]
68/133
77/137
14.4 %
0.91 [ 0.73, 1.14 ]
177/252
164/263
38.0 %
1.13 [ 1.00, 1.27 ]
385
400
52.4 %
1.03 [ 0.84, 1.27 ]
CL3-023
Subtotal (95% CI)

CL3-022
Hale 2010
Subtotal (95% CI)

Kasper 2010
105/154
98/159
24.6 %
1.11 [ 0.94, 1.30 ]
154
159
24.6 %
1.11 [ 0.94, 1.30 ]
44/71
36/67
9.0 %
1.15 [ 0.87, 1.54 ]
71
67
9.0 %
1.15 [ 0.87, 1.54 ]
752
764
100.0 %
1.06 [ 0.97, 1.16 ]
Subtotal (95% CI)

Quera-Salva 2011
Subtotal (95% CI)

Total (95% CI)

0.5
0.7
Favours SSRI
1.5
Favours agomelatine

101
Analysis 1.22. Comparison 1 Agomelatine vs SSRI, Outcome 22 Sensitivity analysis: excluding imputed
response rates.
Review:

Outcome: 22 Sensitivity analysis: excluding imputed response rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
70/169
91/168
7.9 %
0.76 [ 0.61, 0.96 ]
243/425
81/147
12.0 %
1.04 [ 0.88, 1.23 ]
594
315
19.8 %
0.90 [ 0.67, 1.21 ]
CAGO2303
Loo 2002a
Subtotal (95% CI)

CL3-022
68/133
77/137
8.1 %
0.91 [ 0.73, 1.14 ]
Hale 2010
177/252
164/263
16.7 %
1.13 [ 1.00, 1.27 ]
Shu 2013
205/314
209/314
18.2 %
0.98 [ 0.88, 1.10 ]
699
714
43.0 %
1.02 [ 0.91, 1.15 ]
Subtotal (95% CI)

Kasper 2010
105/154
98/159
12.3 %
1.11 [ 0.94, 1.30 ]
154
159
12.3 %
1.11 [ 0.94, 1.30 ]
136/164
128/160
19.4 %
1.04 [ 0.93, 1.15 ]
Quera-Salva 2011
44/71
36/67
5.4 %
1.15 [ 0.87, 1.54 ]
Subtotal (95% CI)
235
227
24.8 %
1.05 [ 0.95, 1.16 ]
100.0 %
1.02 [ 0.95, 1.10 ]
Subtotal (95% CI)

Corruble 2013

Total (95% CI)
1682
1415

0.5
0.7
Favours SSRI
1.5
Favours agomelatine

102
Analysis 1.23. Comparison 1 Agomelatine vs SSRI, Outcome 23 Sensitivity analysis: excluding imputed
remission rates.
Review:

Outcome: 23 Sensitivity analysis: excluding imputed remission rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
70/169
91/168
21.4 %
0.76 [ 0.61, 0.96 ]
Loo 2002a
96/425
37/147
14.6 %
0.90 [ 0.65, 1.25 ]
594
315
36.0 %
0.81 [ 0.67, 0.97 ]
Subtotal (95% CI)

CL3-022
18/133
25/137
6.9 %
0.74 [ 0.42, 1.29 ]
Hale 2010
79/252
73/263
18.4 %
1.13 [ 0.86, 1.48 ]
385
400
25.2 %
0.98 [ 0.67, 1.45 ]
Subtotal (95% CI)


Kasper 2010
49/154
45/159
14.1 %
1.12 [ 0.80, 1.58 ]
154
159
14.1 %
1.12 [ 0.80, 1.58 ]
100/164
87/160
24.7 %
1.12 [ 0.93, 1.35 ]
164
160
24.7 %
1.12 [ 0.93, 1.35 ]
1297
1034
100.0 %
0.97 [ 0.83, 1.14 ]
Subtotal (95% CI)

Corruble 2013
Subtotal (95% CI)

Total (95% CI)
0.5
0.7
Favours SSRI
1.5
Favours agomelatine
(Continued . . . )

103
(. . .
Study or subgroup
Agomelatine
SSRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI

0.5
0.7
Favours SSRI
1.5
Favours agomelatine
Analysis 1.24. Comparison 1 Agomelatine vs SSRI, Outcome 24 Sensitivity analysis: excluding trials with
imputed SDs.
Review:

Outcome: 24 Sensitivity analysis: excluding trials with imputed SDs
Study or subgroup
Agomelatine
Std.
Mean
Difference
SSRI
Weight
IV,Random,95% CI
Std.
Mean
Difference
Mean(SD)
Mean(SD)
IV,Random,95% CI
CAGO2303
162
17.1 (7.38)
163
14 (7.53)
12.9 %
0.41 [ 0.20, 0.63 ]
CL3-023
141
13 (8)
137
12.2 (8.1)
12.5 %
0.10 [ -0.14, 0.33 ]
Loo 2002a
135
12.77 (8.23)
144
13.09 (8.37)
12.5 %
-0.04 [ -0.27, 0.20 ]
37.8 %
0.16 [ -0.11, 0.43 ]
Subtotal (95% CI)
438
444

CL3-022
129
14.5 (8.2)
133
13.3 (7.6)
12.2 %
0.15 [ -0.09, 0.39 ]
CL3-024
295
12.69 (8.21)
146
12.5 (7.4)
13.6 %
0.02 [ -0.17, 0.22 ]
Hale 2010
247
11.1 (7.3)
257
12.7 (8.5)
14.2 %
-0.20 [ -0.38, -0.03 ]
40.0 %
-0.02 [ -0.23, 0.18 ]
Subtotal (95% CI)
671
536

-0.5
-0.25
Favours agomelatine
0.25
0.5
Favours SSRI
(Continued . . . )

104
(. . .
Study or subgroup
Agomelatine
Std.
Mean
Difference
SSRI
Mean(SD)
Mean(SD)
150
10.3 (7)
156
12.1 (8.3)
Weight
IV,Random,95% CI
Continued)
Std.
Mean
Difference
IV,Random,95% CI
Kasper 2010
Subtotal (95% CI)
150
12.8 %
-0.23 [ -0.46, -0.01 ]
12.8 %
-0.23 [ -0.46, -0.01 ]
9.4 %
-0.21 [ -0.55, 0.14 ]
61
9.4 %
-0.21 [ -0.55, 0.14 ]
1197
100.0 %
0.01 [ -0.15, 0.16 ]
156

Quera-Salva 2011
68
Subtotal (95% CI)
68
11.4 (5.9)
61
12.7 (6.7)

Total (95% CI)
1327

-0.5
-0.25
Favours agomelatine

0.25
0.5
Favours SSRI
105
Analysis 1.25. Comparison 1 Agomelatine vs SSRI, Outcome 25 Sensitivity analysis: response rates - best
case.
Review:

Outcome: 25 Sensitivity analysis: response rates - best case
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
77/169
91/168
5.9 %
0.84 [ 0.68, 1.04 ]
CL3-023
72/142
74/138
5.5 %
0.95 [ 0.76, 1.18 ]
251/425
81/147
9.3 %
1.07 [ 0.91, 1.27 ]
736
453
20.6 %
0.96 [ 0.83, 1.11 ]
Loo 2002a
Subtotal (95% CI)

CL3-022
72/133
77/137
5.9 %
0.96 [ 0.78, 1.19 ]
CL3-024
161/301
79/148
7.8 %
1.00 [ 0.83, 1.20 ]
Hale 2010
182/252
164/263
15.2 %
1.16 [ 1.03, 1.31 ]
Shu 2013
218/314
209/314
18.0 %
1.04 [ 0.94, 1.16 ]
1000
862
46.9 %
1.06 [ 0.99, 1.14 ]
Subtotal (95% CI)

109/154
98/159
9.9 %
1.15 [ 0.98, 1.35 ]
154
159
9.9 %
1.15 [ 0.98, 1.35 ]
136/164
128/160
18.8 %
1.04 [ 0.93, 1.15 ]
Quera-Salva 2011
47/71
36/67
3.7 %
1.23 [ 0.93, 1.63 ]
Subtotal (95% CI)
235
227
22.5 %
1.08 [ 0.93, 1.26 ]
Kasper 2010
Subtotal (95% CI)


Corruble 2013

0.5
0.7
Favours SSRI
1.5
Favours agomelatine
(Continued . . . )

106
(. . .
Study or subgroup
Agomelatine
Total (95% CI)
SSRI
n/N
n/N
2125
1701
Risk Ratio
MH,Random,95%
CI
Weight
100.0 %
Continued)
Risk Ratio
MH,Random,95%
CI
1.05 [ 0.99, 1.11 ]

0.5
0.7
Favours SSRI
1.5
Favours agomelatine
Analysis 1.26. Comparison 1 Agomelatine vs SSRI, Outcome 26 Sensitivity analysis: response rates - worst
case.
Review:

Outcome: 26 Sensitivity analysis: response rates - worst case
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
70/169
96/168
6.6 %
0.72 [ 0.58, 0.91 ]
CL3-023
71/142
75/138
6.5 %
0.92 [ 0.73, 1.15 ]
243/425
84/147
10.2 %
1.00 [ 0.85, 1.18 ]
736
453
23.3 %
0.88 [ 0.73, 1.07 ]
Loo 2002a
Subtotal (95% CI)

CL3-022
68/133
81/137
6.9 %
0.86 [ 0.70, 1.07 ]
CL3-024
155/301
80/148
8.6 %
0.95 [ 0.79, 1.15 ]
Hale 2010
177/252
170/263
14.2 %
1.09 [ 0.96, 1.23 ]
Shu 2013
205/314
215/314
15.4 %
0.95 [ 0.85, 1.06 ]
0.5
0.7
Favours SSRI
1.5
Favours agomelatine
(Continued . . . )

107
(. . .
Study or subgroup
Subtotal (95% CI)
Agomelatine
SSRI
n/N
n/N
1000
862
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
45.0 %
0.98 [ 0.90, 1.07 ]

105/154
100/159
10.3 %
1.08 [ 0.92, 1.27 ]
154
159
10.3 %
1.08 [ 0.92, 1.27 ]
136/164
128/160
16.1 %
1.04 [ 0.93, 1.15 ]
Quera-Salva 2011
44/71
42/67
5.2 %
0.99 [ 0.76, 1.28 ]
Subtotal (95% CI)
235
227
21.3 %
1.03 [ 0.94, 1.13 ]
100.0 %
0.98 [ 0.92, 1.04 ]
Kasper 2010
Subtotal (95% CI)

Corruble 2013

Total (95% CI)
2125
1701

0.5
0.7
Favours SSRI
1.5
Favours agomelatine

108
Analysis 1.27. Comparison 1 Agomelatine vs SSRI, Outcome 27 Sensitivity analysis: remission rates - best
case.
Review:

Outcome: 27 Sensitivity analysis: remission rates - best case
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
16/169
37/168
8.6 %
0.43 [ 0.25, 0.74 ]
CL3-023
33/142
36/138
10.8 %
0.89 [ 0.59, 1.34 ]
104/425
37/147
12.3 %
0.97 [ 0.70, 1.35 ]
736
453
31.6 %
0.75 [ 0.48, 1.17 ]
Loo 2002a
Subtotal (95% CI)

CL3-022
22/133
25/137
9.0 %
0.91 [ 0.54, 1.53 ]
CL3-024
73/301
65/148
13.2 %
0.55 [ 0.42, 0.72 ]
Hale 2010
84/252
73/263
13.4 %
1.20 [ 0.92, 1.56 ]
Shu 2013
88/314
84/314
13.5 %
1.05 [ 0.81, 1.35 ]
1000
862
49.0 %
0.89 [ 0.61, 1.30 ]
Subtotal (95% CI)

Kasper 2010
53/154
45/159
12.2 %
1.22 [ 0.87, 1.69 ]
154
159
12.2 %
1.22 [ 0.87, 1.69 ]
18/71
12/67
7.2 %
1.42 [ 0.74, 2.71 ]
71
67
7.2 %
1.42 [ 0.74, 2.71 ]
1961
1541
100.0 %
0.91 [ 0.72, 1.15 ]
Subtotal (95% CI)

Quera-Salva 2011
Subtotal (95% CI)

Total (95% CI)
0.5
0.7
Favours SSRI
1.5
Favours agomelatine
(Continued . . . )

109
(. . .
Study or subgroup
Agomelatine
SSRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI

0.5
0.7
Favours SSRI
1.5
Favours agomelatine
Analysis 1.28. Comparison 1 Agomelatine vs SSRI, Outcome 28 Sensitivity analysis:remission rates - worst
case.
Review:

Outcome: 28 Sensitivity analysis:remission rates - worst case
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
9/169
42/168
7.1 %
0.21 [ 0.11, 0.42 ]
CL3-023
32/142
37/138
11.0 %
0.84 [ 0.56, 1.27 ]
Loo 2002a
96/425
40/147
12.5 %
0.83 [ 0.60, 1.14 ]
736
453
30.6 %
0.57 [ 0.29, 1.12 ]
CAGO2303
Subtotal (95% CI)

CL3-022
18/133
29/137
9.0 %
0.64 [ 0.37, 1.09 ]
CL3-024
67/301
66/148
13.1 %
0.50 [ 0.38, 0.66 ]
Hale 2010
79/252
79/263
13.4 %
1.04 [ 0.81, 1.35 ]
Shu 2013
75/314
90/314
13.3 %
0.83 [ 0.64, 1.08 ]
1000
862
48.9 %
0.74 [ 0.52, 1.05 ]
Subtotal (95% CI)
0.5
0.7
Favours SSRI
1.5
Favours agomelatine
(Continued . . . )

110
(. . .
Study or subgroup
Agomelatine
SSRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI

Kasper 2010
49/154
47/159
12.2 %
1.08 [ 0.77, 1.50 ]
154
159
12.2 %
1.08 [ 0.77, 1.50 ]
15/71
18/67
8.2 %
0.79 [ 0.43, 1.43 ]
71
67
8.2 %
0.79 [ 0.43, 1.43 ]
1961
1541
100.0 %
0.73 [ 0.57, 0.94 ]
Subtotal (95% CI)

Quera-Salva 2011
Subtotal (95% CI)

Total (95% CI)

0.5
0.7
Favours SSRI
1.5
Favours agomelatine

111
Analysis 1.29. Comparison 1 Agomelatine vs SSRI, Outcome 29 Sensitivity anal: excluding studies with
bipolar participants - response rates.
Review:

Outcome: 29 Sensitivity anal: excluding studies with bipolar participants - response rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
70/169
91/168
49.9 %
0.76 [ 0.61, 0.96 ]
CL3-023
71/142
74/138
50.1 %
0.93 [ 0.74, 1.17 ]
311
306
100.0 %
0.84 [ 0.70, 1.03 ]
Total (95% CI)

0.5
0.7
Favours SSRI
1.5
Favours agomelatine

112
Analysis 1.30. Comparison 1 Agomelatine vs SSRI, Outcome 30 Additional subgroup analysis: unpublished
vs published trials - response rates.
Review:

Outcome: 30 Additional subgroup analysis: unpublished vs published trials - response rates
Study or subgroup
Agomelatine
SSRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
CAGO2303
70/169
91/168
6.2 %
0.76 [ 0.61, 0.96 ]
CL3-022
68/133
77/137
6.4 %
0.91 [ 0.73, 1.14 ]
CL3-023
71/142
74/138
6.3 %
0.93 [ 0.74, 1.17 ]
CL3-024
155/301
79/148
8.5 %
0.96 [ 0.80, 1.16 ]
745
591
27.4 %
0.90 [ 0.81, 1.00 ]
1 Unpublished
Subtotal (95% CI)

2 Published
Corruble 2013
136/164
128/160
17.5 %
1.04 [ 0.93, 1.15 ]
Hale 2010
177/252
164/263
14.6 %
1.13 [ 1.00, 1.27 ]
Kasper 2010
105/154
98/159
10.3 %
1.11 [ 0.94, 1.30 ]
Loo 2002a
243/425
81/147
9.9 %
1.04 [ 0.88, 1.23 ]
44/71
36/67
4.2 %
1.15 [ 0.87, 1.54 ]
205/314
209/314
16.2 %
0.98 [ 0.88, 1.10 ]
1380
1110
72.6 %
1.05 [ 1.00, 1.11 ]
100.0 %
1.01 [ 0.95, 1.08 ]
Quera-Salva 2011
Shu 2013
Subtotal (95% CI)

Total (95% CI)
2125
1701

0.5
0.7
Favours SSRI
1.5
Favours agomelatine

113
Analysis 2.1. Comparison 2 Agomelatine vs SNRI, Outcome 1 Response rates.

Review:
Comparison: 2 Agomelatine vs SNRI

Outcome: 1 Response rates
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
113/137
111/140
53.9 %
1.04 [ 0.93, 1.17 ]
Lemoine 2007
126/165
118/167
42.2 %
1.08 [ 0.95, 1.23 ]
19/30
16/30
3.8 %
1.19 [ 0.77, 1.83 ]
332
337
100.0 %
1.06 [ 0.98, 1.16 ]
1 Agomelatine vs venlafaxine
Martinotti 2012
Total (95% CI)
Total events: 258 (Agomelatine), 245 (SNRI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

114
Analysis 2.2. Comparison 2 Agomelatine vs SNRI, Outcome 2 Remission rates.

Review:

Outcome: 2 Remission rates
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
100/137
94/140
78.8 %
1.09 [ 0.93, 1.27 ]
Lemoine 2007
54/165
49/167
18.2 %
1.12 [ 0.81, 1.54 ]
8/30
10/30
3.1 %
0.80 [ 0.37, 1.74 ]
332
337
100.0 %
1.08 [ 0.94, 1.24 ]
Martinotti 2012
Total (95% CI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

115
Analysis 2.3. Comparison 2 Agomelatine vs SNRI, Outcome 3 Total drop outs.

Review:

Outcome: 3 Total drop outs
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
15/165
36/167
82.1 %
0.42 [ 0.24, 0.74 ]
3/30
9/30
17.9 %
0.33 [ 0.10, 1.11 ]
195
197
100.0 %
0.40 [ 0.24, 0.67 ]
Lemoine 2007
Martinotti 2012
Total (95% CI)

0.1 0.2
0.5
Favours agomelatine
10
Favours SNRI
Analysis 2.4. Comparison 2 Agomelatine vs SNRI, Outcome 4 Drop out due to inefficacy.
Review:

Outcome: 4 Drop out due to inefficacy
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Lemoine 2007
3/165
3/167
100.0 %
1.01 [ 0.21, 4.94 ]
Total (95% CI)
165
167
100.0 %
1.01 [ 0.21, 4.94 ]

0.05
0.2
Favours agomelatine
20
Favours SNRI

116
Analysis 2.5. Comparison 2 Agomelatine vs SNRI, Outcome 5 Drop outs due to side effects.
Review:

Outcome: 5 Drop outs due to side effects
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
3/137
12/139
30.5 %
0.25 [ 0.07, 0.88 ]
Lemoine 2007
7/165
22/167
69.5 %
0.32 [ 0.14, 0.73 ]
Total (95% CI)
302
306
100.0 %
0.30 [ 0.15, 0.59 ]

0.1 0.2
0.5
Favours agomelatine
10
Favours SNRI

117
Analysis 2.6. Comparison 2 Agomelatine vs SNRI, Outcome 6 Total number of patients with side effects.
Review:

Outcome: 6 Total number of patients with side effects
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
28/137
52/140
44.0 %
0.55 [ 0.37, 0.82 ]
Lemoine 2007
85/166
96/168
56.0 %
0.90 [ 0.74, 1.09 ]
303
308
100.0 %
0.72 [ 0.44, 1.18 ]
Total (95% CI)

0.5
0.7
Favours agomelatine
1.5
Favours SNRI
Analysis 2.7. Comparison 2 Agomelatine vs SNRI, Outcome 7 Sleepiness or drowsiness.

Review:

Outcome: 7 Sleepiness or drowsiness
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Lemoine 2007
6/166
8/168
100.0 %
0.76 [ 0.27, 2.14 ]
Total (95% CI)
166
168
100.0 %
0.76 [ 0.27, 2.14 ]

0.2
0.5
Favours agomelatine
Favours SNRI

118
Analysis 2.8. Comparison 2 Agomelatine vs SNRI, Outcome 8 Insomnia.

Review:

Outcome: 8 Insomnia
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Lemoine 2007
1/165
4/167
100.0 %
0.25 [ 0.03, 2.24 ]
Total (95% CI)
165
167
100.0 %
0.25 [ 0.03, 2.24 ]

0.02
0.1
Favours agomelatine
10
50
Favours SNRI

119
Analysis 2.9. Comparison 2 Agomelatine vs SNRI, Outcome 9 Dry mouth.

Review:

Outcome: 9 Dry mouth
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Lemoine 2007
3/165
6/167
100.0 %
0.51 [ 0.13, 1.99 ]
Total (95% CI)
165
167
100.0 %
0.51 [ 0.13, 1.99 ]

0.1 0.2
0.5
Favours agomelatine
10
Favours SNRI
Analysis 2.10. Comparison 2 Agomelatine vs SNRI, Outcome 10 Constipation.

Review:

Outcome: 10 Constipation
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Lemoine 2007
6/165
7/167
100.0 %
0.87 [ 0.30, 2.53 ]
Total (95% CI)
165
167
100.0 %
0.87 [ 0.30, 2.53 ]

0.5
0.7
Favours agomelatine
1.5
Favours SNRI

120
Analysis 2.11. Comparison 2 Agomelatine vs SNRI, Outcome 11 Dizziness.

Review:

Outcome: 11 Dizziness
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Lemoine 2007
3/165
16/167
100.0 %
0.19 [ 0.06, 0.64 ]
Total (95% CI)
165
167
100.0 %
0.19 [ 0.06, 0.64 ]

0.05
0.2
Favours agomelatine
20
Favours SNRI

121
Analysis 2.12. Comparison 2 Agomelatine vs SNRI, Outcome 12 Vomiting or nausea.

Review:

Outcome: 12 Vomiting or nausea
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
16/137
24/140
50.2 %
0.68 [ 0.38, 1.23 ]
Lemoine 2007
12/165
46/167
49.8 %
0.26 [ 0.15, 0.48 ]
302
307
100.0 %
0.42 [ 0.17, 1.08 ]
Total (95% CI)

0.2
0.5
Favours agomelatine
Favours SNRI
Analysis 2.13. Comparison 2 Agomelatine vs SNRI, Outcome 13 Diarrhoea.

Review:

Outcome: 13 Diarrhoea
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Lemoine 2007
8/165
3/167
100.0 %
2.70 [ 0.73, 10.00 ]
Total (95% CI)
165
167
100.0 %
2.70 [ 0.73, 10.00 ]

0.1 0.2
0.5
Favours agomelatine
10
Favours SNRI

122
Analysis 2.14. Comparison 2 Agomelatine vs SNRI, Outcome 14 Depression scales endpoint score.
Review:

Outcome: 14 Depression scales endpoint score
Study or subgroup
Agomelatine
Std.
Mean
Difference
SNRI
Weight
IV,Random,95% CI
Std.
Mean
Difference
Mean(SD)
Mean(SD)
IV,Random,95% CI
Kennedy 2008
137
10.1 (7.8)
139
9.8 (7.9)
41.4 %
0.04 [ -0.20, 0.27 ]
Lemoine 2007
165
9.9 (6.6)
167
11 (7.4)
49.6 %
-0.16 [ -0.37, 0.06 ]
Martinotti 2012
30
14.17 (7.15)
30
14.77 (6.96)
9.0 %
-0.08 [ -0.59, 0.42 ]
100.0 %
-0.07 [ -0.22, 0.08 ]
Total (95% CI)
332
336

-0.5
-0.25
Favours agomelatine

0.25
0.5
Favours SNRI
123
Analysis 2.15. Comparison 2 Agomelatine vs SNRI, Outcome 15 Subgroup analysis: dosing - response rates.
Review:

Outcome: 15 Subgroup analysis: dosing - response rates
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
126/165
118/167
42.2 %
1.08 [ 0.95, 1.23 ]
165
167
42.2 %
1.08 [ 0.95, 1.23 ]
113/137
111/140
53.9 %
1.04 [ 0.93, 1.17 ]
19/30
16/30
3.8 %
1.19 [ 0.77, 1.83 ]
167
170
57.8 %
1.05 [ 0.94, 1.17 ]
100.0 %
1.06 [ 0.98, 1.16 ]
1 Flexible dosing
Lemoine 2007
Subtotal (95% CI)

2 Fixed dosing
Kennedy 2008
Martinotti 2012
Subtotal (95% CI)

Total (95% CI)
332
337

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

124
Analysis 2.16. Comparison 2 Agomelatine vs SNRI, Outcome 16 Subgroup analysis: severity - response
rates.
Review:

Outcome: 16 Subgroup analysis: severity - response rates
Study or subgroup
Agomelatine
SNRI
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
1 Agomelatine vs venlafaxine (moderate depression)

Kennedy 2008
113/137
111/140
53.9 %
1.04 [ 0.93, 1.17 ]
137
140
53.9 %
1.04 [ 0.93, 1.17 ]
126/165
118/167
42.2 %
1.08 [ 0.95, 1.23 ]
19/30
16/30
3.8 %
1.19 [ 0.77, 1.83 ]
195
197
46.1 %
1.09 [ 0.96, 1.23 ]
100.0 %
1.06 [ 0.98, 1.16 ]
Subtotal (95% CI)

2 Agomelatine vs venlafaxine (severe depression)
Lemoine 2007
Martinotti 2012
Subtotal (95% CI)

Total (95% CI)
332
337

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

125
Analysis 2.17. Comparison 2 Agomelatine vs SNRI, Outcome 17 Sensitivity analysis: excluding trials with >
20% drop outs.
Review:

Outcome: 17 Sensitivity analysis: excluding trials with > 20% drop outs
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
126/165
118/167
91.7 %
1.08 [ 0.95, 1.23 ]
19/30
16/30
8.3 %
1.19 [ 0.77, 1.83 ]
195
197
100.0 %
1.09 [ 0.96, 1.23 ]
Lemoine 2007
Martinotti 2012
Total (95% CI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

126
Analysis 2.18. Comparison 2 Agomelatine vs SNRI, Outcome 18 Sensitivity analysis: excluding imputed
remission rates.
Review:

Outcome: 18 Sensitivity analysis: excluding imputed remission rates
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
100/137
93/140
96.2 %
1.10 [ 0.94, 1.28 ]
8/30
10/30
3.8 %
0.80 [ 0.37, 1.74 ]
167
170
100.0 %
1.09 [ 0.93, 1.26 ]
Kennedy 2008
Martinotti 2012
Total (95% CI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

127
Analysis 2.19. Comparison 2 Agomelatine vs SNRI, Outcome 19 Sensitivity analysis: response rates - best
case.
Review:

Outcome: 19 Sensitivity analysis: response rates - best case
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
113/137
111/140
53.9 %
1.04 [ 0.93, 1.17 ]
Lemoine 2007
126/165
118/167
42.2 %
1.08 [ 0.95, 1.23 ]
19/30
16/30
3.8 %
1.19 [ 0.77, 1.83 ]
332
337
100.0 %
1.06 [ 0.98, 1.16 ]
Martinotti 2012
Total (95% CI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

128
Analysis 2.20. Comparison 2 Agomelatine vs SNRI, Outcome 20 Sensitivity analysis: response rates - worst
case.
Review:

Outcome: 20 Sensitivity analysis: response rates - worst case
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
113/137
112/140
54.5 %
1.03 [ 0.92, 1.15 ]
Lemoine 2007
126/165
118/167
41.7 %
1.08 [ 0.95, 1.23 ]
19/30
16/30
3.8 %
1.19 [ 0.77, 1.83 ]
332
337
100.0 %
1.06 [ 0.97, 1.15 ]
Martinotti 2012
Total (95% CI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

129
Analysis 2.21. Comparison 2 Agomelatine vs SNRI, Outcome 21 Sensitivity analysis: remission rates - best
case.
Review:

Outcome: 21 Sensitivity analysis: remission rates - best case
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
100/137
93/140
78.5 %
1.10 [ 0.94, 1.28 ]
Lemoine 2007
54/165
49/167
18.4 %
1.12 [ 0.81, 1.54 ]
8/30
10/30
3.1 %
0.80 [ 0.37, 1.74 ]
332
337
100.0 %
1.09 [ 0.95, 1.25 ]
Martinotti 2012
Total (95% CI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine

130
Analysis 2.22. Comparison 2 Agomelatine vs SNRI, Outcome 22 Sensitivity analysis: remission rates - worst
case.
Review:

Outcome: 22 Sensitivity analysis: remission rates - worst case
Study or subgroup
Agomelatine
SNRI
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Kennedy 2008
100/137
94/140
78.8 %
1.09 [ 0.93, 1.27 ]
Lemoine 2007
54/165
49/167
18.2 %
1.12 [ 0.81, 1.54 ]
8/30
10/30
3.1 %
0.80 [ 0.37, 1.74 ]
332
337
100.0 %
1.08 [ 0.94, 1.24 ]
Martinotti 2012
Total (95% CI)

0.5
0.7
Favours SNRI
1.5
Favours agomelatine
CONTRIBUTIONS OF AUTHORS
GG: conceived the idea, supervised protocol writing, and wrote part of the review
SG: wrote the protocol and extracted data from studies
DC: read the protocol and the review, and provided methodological input
SJCD: wrote the descriptions of the condition and of the intervention, and provided content supervision
KH: helped with data extraction and with revision of the review
MK: extracted data from studies, wrote part of the review and also analysed the data
DECLARATIONS OF INTEREST
Giuseppe Guaiana: none known
Sumeet Gupta: none known
Debbie Chiodo: none known
Simon JC Davies: none known
Katja Haederle: none known
Markus Koesters: none known
131
SOURCES OF SUPPORT
Internal sources
None, Not specified.
External sources
None, Not specified.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Since we judged that it would have not made much difference in data analysis and interpretation, the analysis for the fixed-effect model
was calculated only for the main outcomes that were included in the Summary of findings tables.
The protocol did not list continuous data as an outcome. We amended the analysis and we included continuous data as a secondary
outcome.
We did not run any meta-regression analyses, as the low number of studies available made these analyses obsolete.
In the protocol phase, we thought of grouping all antidepressants together. At the review stage, we decided to group the antidepressants
by classes (SSRI, SNRI and others).
In order to assess publication bias better, we added a subgroup analysis (Analysis 1.30), that examined differences in outcomes for
agomelatine in published versus unpublished studies.

132

Agomelatine Versus Other Antidepressive Agents For Major Depression

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Agomelatine Versus Other Antidepressive Agents For Major Depression

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Agomelatine versus other antidepressive agents for major

Agomelatine versus other antidepressive agents for major depression (Review)

Agomelatine versus other antidepressive agents for major depression (Review)

Agomelatine versus other antidepressive agents for major

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Families and friends of people who suffer from major depression.

Agomelatine versus other antidepressive agents for major depression (Review)

Agomelatine versus other antidepressive agents for major depression (Review)

Agomelatine compared to SSRI for major depression

Illustrative comparative risks* (95% CI)

610 per 1000

Quality of the evidence

616 per 1000

563 per 1000

Agomelatine versus other antidepressive agents for major depression (Review)

on the Clinical Global Impression - Severity; or any

Total drop outs

Drop out due to inefficacy

189 per 1000

302 per 1000

219 per 1000

180 per 1000

179 per 1000

Drop outs due to side ef- Study population

Agomelatine versus other antidepressive agents for major depression (Review)

the total number of randomised participants

Total number of partici- Study population

540 per 1000

556 per 1000

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Agomelatine versus other antidepressive agents for major depression (Review)

Criteria for considering studies for this review

1. Selective serotonin reuptake inhibitors (SSRIs; fluoxetine,

Our primary outcome measure for efficacy was:

Our secondary outcome measures included:

Agomelatine versus other antidepressive agents for major depression (Review)

3. drop-out rates due to side effects: i.e. number of

Search methods for identification of studies

The Cochrane Depression, Anxiety and Neurosis

We contacted experts in the field for information on unpublished

We checked the reference lists of all included studies, relevant

Data collection and analysis

Agomelatine versus other antidepressive agents for major depression (Review)

then two review authors independently assessed each for inclusion,

1. Agomelatine versus SSRIs

in order to obtain further information. We agreed to report nonconcurrence in quality assessment.

For binary outcomes we calculated a standard estimation of the

(a) Summary statistics

Assessment of risk of bias in included studies

(b) Endpoint versus change data

(1) Cross-over trials

Agomelatine versus other antidepressive agents for major depression (Review)

(2) Studies with multiple treatment groups

without these studies. If the data had been log-transformed for

Dealing with missing data

We presented skewed and qualitative data descriptively.

(4) Missing statistics

Assessment of reporting biases

Agomelatine versus other antidepressive agents for major depression (Review)