Agomelatine versus other antidepressive agents for major depression

Giuseppe Guaiana; Sumeet Gupta; Debbie Chiodo; Simon JC Davies; Katja Haederle; Markus Koesters

doi:10.1002/14651858.CD008851.pub2

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Figure 1

Study flow diagram

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 4

Forest plot of comparison: 1 Agomelatine vs SSRI, outcome: 1.1 Response rates

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Figure 5

Forest plot of comparison: 1 Agomelatine vs SSRI, outcome: 1.2 Remission rates

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Figure 6

Forest plot of comparison: 1 Agomelatine vs SSRI, outcome: 1.3 Total drop outs

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Figure 7

Forest plot of comparison: 2 Agomelatine vs SNRI, outcome: 2.1 Response rates

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Figure 8

Forest plot of comparison: 2 Agomelatine vs SNRI, outcome: 2.2 Remission rates

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Figure 9

Forest plot of comparison: 2 Agomelatine vs SNRI, outcome: 2.3 Total drop outs

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Analysis 1.1

Comparison 1 Agomelatine vs SSRI, Outcome 1 Response rates.

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Analysis 1.2

Comparison 1 Agomelatine vs SSRI, Outcome 2 Remission rates.

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Analysis 1.3

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

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Analysis 1.4

Comparison 1 Agomelatine vs SSRI, Outcome 4 Drop out due to inefficacy.

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Analysis 1.5

Comparison 1 Agomelatine vs SSRI, Outcome 5 Drop outs due to side effects.

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Analysis 1.6

Comparison 1 Agomelatine vs SSRI, Outcome 6 Total number of patients with side effects.

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Analysis 1.7

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

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Analysis 1.8

Comparison 1 Agomelatine vs SSRI, Outcome 8 Insomnia.

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Analysis 1.9

Comparison 1 Agomelatine vs SSRI, Outcome 9 Dry mouth.

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Analysis 1.10

Comparison 1 Agomelatine vs SSRI, Outcome 10 Constipation.

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Analysis 1.11

Comparison 1 Agomelatine vs SSRI, Outcome 11 Dizziness.

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Analysis 1.12

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

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Analysis 1.13

Comparison 1 Agomelatine vs SSRI, Outcome 13 Suicide wishes, gestures or attempts.

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Analysis 1.14

Comparison 1 Agomelatine vs SSRI, Outcome 14 Completed suicide.

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Analysis 1.15

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

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Analysis 1.16

Comparison 1 Agomelatine vs SSRI, Outcome 16 Diarrhoea.

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Analysis 1.17

Comparison 1 Agomelatine vs SSRI, Outcome 17 Sexual dysfunction.

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Analysis 1.18

Comparison 1 Agomelatine vs SSRI, Outcome 18 Abnormal liver function tests.

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Analysis 1.19

Comparison 1 Agomelatine vs SSRI, Outcome 19 Depression scales endpoint score.

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Analysis 1.20

Comparison 1 Agomelatine vs SSRI, Outcome 20 Subgroup analysis: dosing ‐ response rates.

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Analysis 1.21

Comparison 1 Agomelatine vs SSRI, Outcome 21 Sensitivity analysis: excluding trials with > 20% drop outs ‐ response rates.

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Analysis 1.22

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

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Analysis 1.23

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

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Analysis 1.24

Comparison 1 Agomelatine vs SSRI, Outcome 24 Sensitivity analysis: excluding trials with imputed SDs.

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Analysis 1.25

Comparison 1 Agomelatine vs SSRI, Outcome 25 Sensitivity analysis: response rates ‐ best case.

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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.

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Analysis 1.28

Comparison 1 Agomelatine vs SSRI, Outcome 28 Sensitivity analysis:remission rates ‐ worst case.

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Analysis 1.29

Comparison 1 Agomelatine vs SSRI, Outcome 29 Sensitivity anal': excluding studies with bipolar participants ‐ response rates.

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Analysis 1.30

Comparison 1 Agomelatine vs SSRI, Outcome 30 Additional subgroup analysis: unpublished vs published trials ‐ response rates.

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Analysis 2.1

Comparison 2 Agomelatine vs SNRI, Outcome 1 Response rates.

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Analysis 2.2

Comparison 2 Agomelatine vs SNRI, Outcome 2 Remission rates.

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Analysis 2.3

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

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Analysis 2.4

Comparison 2 Agomelatine vs SNRI, Outcome 4 Drop out due to inefficacy.

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Analysis 2.5

Comparison 2 Agomelatine vs SNRI, Outcome 5 Drop outs due to side effects.

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Analysis 2.6

Comparison 2 Agomelatine vs SNRI, Outcome 6 Total number of patients with side effects.

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Analysis 2.7

Comparison 2 Agomelatine vs SNRI, Outcome 7 Sleepiness or drowsiness.

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Analysis 2.8

Comparison 2 Agomelatine vs SNRI, Outcome 8 Insomnia.

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Analysis 2.9

Comparison 2 Agomelatine vs SNRI, Outcome 9 Dry mouth.

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Analysis 2.10

Comparison 2 Agomelatine vs SNRI, Outcome 10 Constipation.

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Analysis 2.11

Comparison 2 Agomelatine vs SNRI, Outcome 11 Dizziness.

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Analysis 2.12

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

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Analysis 2.13

Comparison 2 Agomelatine vs SNRI, Outcome 13 Diarrhoea.

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Analysis 2.14

Comparison 2 Agomelatine vs SNRI, Outcome 14 Depression scales endpoint score.

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Analysis 2.15

Comparison 2 Agomelatine vs SNRI, Outcome 15 Subgroup analysis: dosing ‐ response rates.

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Analysis 2.16

Comparison 2 Agomelatine vs SNRI, Outcome 16 Subgroup analysis: severity ‐ response rates.

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Analysis 2.17

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

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Analysis 2.18

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

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Analysis 2.19

Comparison 2 Agomelatine vs SNRI, Outcome 19 Sensitivity analysis: response rates ‐ best case.

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Analysis 2.20

Comparison 2 Agomelatine vs SNRI, Outcome 20 Sensitivity analysis: response rates ‐ worst case.

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Analysis 2.21

Comparison 2 Agomelatine vs SNRI, Outcome 21 Sensitivity analysis: remission rates ‐ best case.

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Analysis 2.22

Comparison 2 Agomelatine vs SNRI, Outcome 22 Sensitivity analysis: remission rates ‐ worst case.

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Summary of findings for the main comparison. Agomelatine compared to SSRI for major depression

Agomelatine compared to SSRI for major depression
Patient or population: patients with major depression Settings: inpatients and outpatients Intervention: agomelatine Comparison: SSRI
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	SSRI	Agomelatine
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	Study population		RR 1.01 (0.95 to 1.08)	3826 (10 studies)	⊕⊝⊝⊝ very low^1,2
	610 per 1000	616 per 1000 (579 to 658)
	Moderate
	557 per 1000	563 per 1000 (529 to 602)
Remission rates 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' on the Clinical Global Impression ‐ Severity; or any other equivalent value on a depression scale defined by the authors Follow‐up: 6 to 12 weeks	Study population		RR 0.83 (0.68 to 1.01)	3826 (10 studies)	⊕⊝⊝⊝ very low^1,2,3	Most of the difference in heterogeneity existed between published and unpublished studies
	363 per 1000	302 per 1000 (247 to 367)
	Moderate
	264 per 1000	219 per 1000 (180 to 267)
Total drop outs Total number of participants who dropped out during the trial as a proportion of the total number of randomised participants Follow‐up: 6 to 12 weeks	Study population		RR 0.95 (0.83 to 1.09)	3826 (10 studies)	⊕⊝⊝⊝ very low^1,2
	189 per 1000	180 per 1000 (157 to 206)
	Moderate
	188 per 1000	179 per 1000 (156 to 205)
Drop out due to inefficacy Number of participants who dropped out due to inefficacy during the trial, as a proportion of the total number of randomised participants Follow‐up: 6 to 12 weeks	Study population		RR 0.99 (0.71 to 1.37)	3377 (9 studies)	⊕⊝⊝⊝ very low^1,2,3
	44 per 1000	43 per 1000 (31 to 60)
	Moderate
	49 per 1000	49 per 1000 (35 to 67)
Drop outs due to side effects Number of participants who dropped out due to side effects during the trial, as a proportion of the total number of randomised participants Follow‐up: 6 to 12 weeks	Study population		RR 0.68 (0.51 to 0.91)	3377 (9 studies)	⊕⊝⊝⊝ very low^1,2
	70 per 1000	47 per 1000 (35 to 63)
	Moderate
	65 per 1000	44 per 1000 (33 to 59)
Total number of participants with side effects Total number of participants experiencing at least one side effect Follow‐up: 6 to 12 weeks	Study population		RR 0.91 (0.84 to 0.98)	2490 (6 studies)	⊕⊝⊝⊝ very low^1,2
	594 per 1000	540 per 1000 (499 to 582)
	Moderate
	611 per 1000	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

Summary of findings for the main comparison. Agomelatine compared to SSRI for major depression

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Summary of findings 2. Agomelatine compared to SNRI for major depression

Agomelatine compared to SNRI for major depression
Patient or population: patients with major depression Settings: inpatients and outpatients Intervention: agomelatine Comparison: SNRI
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	SNRI	Agomelatine
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	Study population		RR 1.06 (0.98 to 1.16)	669 (3 studies)	⊕⊝⊝⊝ very low^1,2
	727 per 1000	771 per 1000 (712 to 843)
	Moderate
	707 per 1000	749 per 1000 (693 to 820)
Remission rates 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' on the Clinical Global Impression ‐ Severity; or any other equivalent value on a depression scale defined by the authors Follow‐up: 6 to 12 weeks	Study population		RR 1.08 (0.94 to 1.24)	669 (3 studies)	⊕⊝⊝⊝ very low^1,2
	454 per 1000	490 per 1000 (427 to 563)
	Moderate
	333 per 1000	360 per 1000 (313 to 413)
Total drop outs Total number of participants who dropped out during the trial as a proportion of the total number of randomised participants Follow‐up: 6 to 8 weeks	Study population		RR 0.4 (0.24 to 0.67)	392 (2 studies)	⊕⊝⊝⊝ very low^1,2
	228 per 1000	91 per 1000 (55 to 153)
	Moderate
	258 per 1000	103 per 1000 (62 to 173)
Drop out due to inefficacy Number of participants who dropped out due to inefficacy during the trial, as a proportion of the total number of randomised participants Follow‐up: 6 weeks	Study population		RR 1.01 (0.21 to 4.94)	332 (1 study)	⊕⊝⊝⊝ very low^1,2
	18 per 1000	18 per 1000 (4 to 89)
	Moderate
	18 per 1000	18 per 1000 (4 to 89)
Drop outs due to side effects Number of participants who dropped out due to side effects during the trial, as a proportion of the total number of randomised participants Follow‐up: 6 to 12 weeks	Study population		RR 0.3 (0.15 to 0.59)	608 (2 studies)	⊕⊝⊝⊝ very low^1,2
	111 per 1000	33 per 1000 (17 to 66)
	Moderate
	109 per 1000	33 per 1000 (16 to 64)
Total number of patients with side effects Total number of participants experiencing at least one side effect	Study population		RR 0.72 (0.44 to 1.18)	611 (2 studies)	⊕⊝⊝⊝ very low^1,2,3
	481 per 1000	346 per 1000 (211 to 567)
	Moderate
	471 per 1000	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 The studies included in our review were conducted in inpatient and outpatient settings. Results may not be generalisable for a primary care setting ² Most studies were funded by the pharmaceutical company that manufactures agomelatine (Servier) ³ There is high heterogeneity

Summary of findings 2. Agomelatine compared to SNRI for major depression

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Comparison 1. Agomelatine vs SSRI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Response rates Show forest plot	10	3826	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.95, 1.08]

1.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.77, 1.09]
1.2 Agomelatine vs fluoxetine	4	1862	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.92, 1.11]
1.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.30]
1.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.95, 1.16]
2 Remission rates Show forest plot	10	3826	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.68, 1.01]

2.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.32, 1.18]
2.2 Agomelatine vs fluoxetine	4	1862	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.55, 1.05]
2.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.80, 1.58]
2.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.94, 1.35]
3 Total drop outs Show forest plot	10	3826	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.83, 1.09]

3.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.80, 1.28]
3.2 Agomelatine vs fluoxetine	4	1862	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.74, 1.26]
3.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.43, 1.21]
3.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.50, 1.32]
4 Drop out due to inefficacy Show forest plot	9	3377	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.71, 1.37]

4.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.64, 1.80]
4.2 Agomelatine vs fluoxetine	3	1413	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.57, 1.65]
4.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.16, 1.68]
4.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.43, 4.21]
5 Drop outs due to side effects Show forest plot	9	3377	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.51, 0.91]

5.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.49, 1.41]
5.2 Agomelatine vs fluoxetine	3	1413	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.50, 1.09]
5.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.14, 1.00]
5.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.15, 1.06]
6 Total number of patients with side effects Show forest plot	6	2490	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.84, 0.98]

6.1 Agomelatine vs paroxetine	2	905	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.78, 0.94]
6.2 Agomelatine vs fluoxetine	2	1141	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.89, 1.11]
6.3 Agomelatine vs sertraline	1	307	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.78, 1.23]
6.4 Agomelatine vs escitalopram	1	137	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.66, 0.99]
7 Sleepiness or drowsiness Show forest plot	5	1868	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.43, 2.15]

7.1 Agomelatine vs paroxetine	2	905	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.32, 1.21]
7.2 Agomelatine vs fluoxetine	1	513	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.78, 3.93]
7.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	4.65 [1.02, 21.16]
7.4 Agomelatine vs escitalopram	1	137	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.02, 1.55]
8 Insomnia Show forest plot	2	1192	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.38, 1.59]

8.1 Agomelatine vs paroxetine	1	572	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.21, 1.38]
8.2 Agomelatine vs fluoxetine	1	620	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.44, 2.88]
9 Dry mouth Show forest plot	5	2349	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.64, 1.40]

9.1 Agomelatine vs paroxetine	2	905	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.51, 1.57]
9.2 Agomelatine vs fluoxetine	2	1133	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.49, 1.89]
9.3 Agomelatine vs sertraline	1	311	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.40, 2.72]
10 Constipation Show forest plot	1	513	Risk Ratio (M‐H, Random, 95% CI)	2.81 [0.75, 10.46]

10.1 Agomelatine vs fluoxetine	1	513	Risk Ratio (M‐H, Random, 95% CI)	2.81 [0.75, 10.46]
11 Dizziness Show forest plot	4	1603	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.64, 1.55]

11.1 Agomelatine vs paroxetine	1	333	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.32, 1.96]
11.2 Agomelatine vs fluoxetine	2	1133	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.71, 1.94]
11.3 Agomelatine vs escitalopram	1	137	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.03, 2.03]
12 Agitation or anxiety Show forest plot	2	1192	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.46, 2.27]

12.1 Agomelatine vs paroxetine	1	572	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.40, 3.62]
12.2 Agomelatine vs fluoxetine	1	620	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.26, 2.70]
13 Suicide wishes, gestures or attempts Show forest plot	1	572	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.17, 4.41]

13.1 Agomelatine vs paroxetine	1	572	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.17, 4.41]
14 Completed suicide Show forest plot	1	572	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.02, 5.49]

14.1 Agomelatine vs paroxetine	1	572	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.02, 5.49]
15 Vomiting or nausea Show forest plot	5	2175	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.33, 1.45]

15.1 Agomelatine vs paroxetine	2	905	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.23, 0.52]
15.2 Agomelatine vs fluoxetine	2	1133	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.30, 7.90]
15.3 Agomelatine vs escitalopram	1	137	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.26, 1.61]
16 Diarrhoea Show forest plot	4	1533	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.46, 1.40]

16.1 Agomelatine vs paroxetine	1	572	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.19, 1.43]
16.2 Agomelatine vs fluoxetine	1	513	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.37, 2.96]
16.3 Agomelatine vs sertraline	1	311	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.25, 1.91]
16.4 Agomelatine vs escitalopram	1	137	Risk Ratio (M‐H, Random, 95% CI)	1.86 [0.35, 9.82]
17 Sexual dysfunction Show forest plot	1	333	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.04, 0.47]

17.1 Agomelatine vs paroxetine	1	333	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.04, 0.47]
18 Abnormal liver function tests Show forest plot	4	1755	Risk Ratio (M‐H, Random, 95% CI)	3.04 [0.90, 10.22]

18.1 Agomelatine vs paroxetine	1	318	Risk Ratio (M‐H, Random, 95% CI)	3.04 [0.32, 28.89]
18.2 Agomelatine vs fluoxetine	2	1124	Risk Ratio (M‐H, Random, 95% CI)	3.02 [0.60, 15.17]
18.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	3.10 [0.13, 75.44]
19 Depression scales endpoint score Show forest plot	10	3457	Std. Mean Difference (IV, Random, 95% CI)	0.00 [‐0.11, 0.12]

19.1 Agomelatine vs paroxetine	3	882	Std. Mean Difference (IV, Random, 95% CI)	0.16 [‐0.11, 0.43]
19.2 Agomelatine vs fluoxetine	4	1816	Std. Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.15, 0.13]
19.3 Agomelatine vs sertraline	1	306	Std. Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.46, ‐0.01]
19.4 Agomelatine vs escitalopram	2	453	Std. Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.26, 0.11]
20 Subgroup analysis: dosing ‐ response rates Show forest plot	10	3826	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.95, 1.08]

20.1 Flexible dosing	6	2255	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.94, 1.12]
20.2 Fixed dosing	4	1571	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.88, 1.07]
21 Sensitivity analysis: excluding trials with > 20% drop outs ‐ response rates Show forest plot	5	1516	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.97, 1.16]

21.1 Agomelatine vs paroxetine	1	280	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.74, 1.17]
21.2 Agomelatine vs fluoxetine	2	785	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.84, 1.27]
21.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.30]
21.4 Agomelatine vs escitalopram	1	138	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.87, 1.54]
22 Sensitivity analysis: excluding imputed response rates Show forest plot	8	3097	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.95, 1.10]

22.1 Agomelatine vs paroxetine	2	909	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.67, 1.21]
22.2 Agomelatine vs fluoxetine	3	1413	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.91, 1.15]
22.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.30]
22.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.95, 1.16]
23 Sensitivity analysis: excluding imputed remission rates Show forest plot	6	2331	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.83, 1.14]

23.1 Agomelatine vs paroxetine	2	909	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.67, 0.97]
23.2 Agomelatine vs fluoxetine	2	785	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.67, 1.45]
23.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.80, 1.58]
23.4 Agomelatine vs escitalopram	1	324	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.93, 1.35]
24 Sensitivity analysis: excluding trials with imputed SDs Show forest plot	8	2524	Std. Mean Difference (IV, Random, 95% CI)	0.01 [‐0.15, 0.16]

24.1 Agomelatine vs paroxetine	3	882	Std. Mean Difference (IV, Random, 95% CI)	0.16 [‐0.11, 0.43]
24.2 Agomelatine vs fluoxetine	3	1207	Std. Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.23, 0.18]
24.3 Agomelatine vs sertraline	1	306	Std. Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.46, ‐0.01]
24.4 Agomelatine vs escitalopram	1	129	Std. Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.55, 0.14]
25 Sensitivity analysis: response rates ‐ best case Show forest plot	10	3826	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.99, 1.11]

25.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.83, 1.11]
25.2 Agomelatine vs fluoxetine	4	1862	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.99, 1.14]
25.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.98, 1.35]
25.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.93, 1.26]
26 Sensitivity analysis: response rates ‐ worst case Show forest plot	10	3826	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.92, 1.04]

26.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.73, 1.07]
26.2 Agomelatine vs fluoxetine	4	1862	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.90, 1.07]
26.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.92, 1.27]
26.4 Agomelatine vs escitalopram	2	462	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.94, 1.13]
27 Sensitivity analysis: remission rates ‐ best case Show forest plot	9	3502	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.72, 1.15]

27.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.48, 1.17]
27.2 Agomelatine vs fluoxetine	4	1862	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.61, 1.30]
27.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.87, 1.69]
27.4 Agomelatine vs escitalopram	1	138	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.74, 2.71]
28 Sensitivity analysis:remission rates ‐ worst case Show forest plot	9	3502	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.57, 0.94]

28.1 Agomelatine vs paroxetine	3	1189	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.29, 1.12]
28.2 Agomelatine vs fluoxetine	4	1862	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.52, 1.05]
28.3 Agomelatine vs sertraline	1	313	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.77, 1.50]
28.4 Agomelatine vs escitalopram	1	138	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.43, 1.43]
29 Sensitivity anal': excluding studies with bipolar participants ‐ response rates Show forest plot	2	617	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.70, 1.03]

29.1 Agomelatine vs paroxetine	2	617	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.70, 1.03]
30 Additional subgroup analysis: unpublished vs published trials ‐ response rates Show forest plot	10	3826	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.95, 1.08]

30.1 Unpublished	4	1336	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.81, 1.00]
30.2 Published	6	2490	Risk Ratio (M‐H, Random, 95% CI)	1.05 [1.00, 1.11]

Comparison 1. Agomelatine vs SSRI

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Comparison 2. Agomelatine vs SNRI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Response rates Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.16]

1.1 Agomelatine vs venlafaxine	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.16]
2 Remission rates Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.94, 1.24]

2.1 Agomelatine vs venlafaxine	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.94, 1.24]
3 Total drop outs Show forest plot	2	392	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.24, 0.67]

3.1 Agomelatine vs venlafaxine	2	392	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.24, 0.67]
4 Drop out due to inefficacy Show forest plot	1	332	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.21, 4.94]

4.1 Agomelatine vs venlafaxine	1	332	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.21, 4.94]
5 Drop outs due to side effects Show forest plot	2	608	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.15, 0.59]

5.1 Agomelatine vs venlafaxine	2	608	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.15, 0.59]
6 Total number of patients with side effects Show forest plot	2	611	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.44, 1.18]

6.1 Agomelatine vs venlafaxine	2	611	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.44, 1.18]
7 Sleepiness or drowsiness Show forest plot	1	334	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.27, 2.14]

7.1 Agomelatine vs venlafaxine	1	334	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.27, 2.14]
8 Insomnia Show forest plot	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.24]

8.1 Agomelatine vs venlafaxine	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.24]
9 Dry mouth Show forest plot	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.13, 1.99]

9.1 Agomelatine vs venlafaxine	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.13, 1.99]
10 Constipation Show forest plot	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.30, 2.53]

10.1 Agomelatine vs venlafaxine	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.30, 2.53]
11 Dizziness Show forest plot	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.06, 0.64]

11.1 Agomelatine vs venlafaxine	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.06, 0.64]
12 Vomiting or nausea Show forest plot	2	609	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.17, 1.08]

12.1 Agomelatine vs venlafaxine	2	609	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.17, 1.08]
13 Diarrhoea Show forest plot	1	332	Risk Ratio (M‐H, Random, 95% CI)	2.70 [0.73, 10.00]

13.1 Agomelatine vs venlafaxine	1	332	Risk Ratio (M‐H, Random, 95% CI)	2.70 [0.73, 10.00]
14 Depression scales endpoint score Show forest plot	3	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.22, 0.08]

14.1 Agomelatine vs venlafaxine	3	668	Std. Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.22, 0.08]
15 Subgroup analysis: dosing ‐ response rates Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.16]

15.1 Flexible dosing	1	332	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.95, 1.23]
15.2 Fixed dosing	2	337	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.94, 1.17]
16 Subgroup analysis: severity ‐ response rates Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.16]

16.1 Agomelatine vs venlafaxine (moderate depression)	1	277	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.93, 1.17]
16.2 Agomelatine vs venlafaxine (severe depression)	2	392	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.96, 1.23]
17 Sensitivity analysis: excluding trials with > 20% drop outs Show forest plot	2	392	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.96, 1.23]

17.1 Agomelatine vs venlafaxine	2	392	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.96, 1.23]
18 Sensitivity analysis: excluding imputed remission rates Show forest plot	2	337	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.93, 1.26]

18.1 Agomelatine vs venlafaxine	2	337	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.93, 1.26]
19 Sensitivity analysis: response rates ‐ best case Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.16]

19.1 Agomelatine vs venlafaxine	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.16]
20 Sensitivity analysis: response rates ‐ worst case Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.97, 1.15]

20.1 Agomelatine vs venlafaxine	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.97, 1.15]
21 Sensitivity analysis: remission rates ‐ best case Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.95, 1.25]

21.1 Agomelatine vs venlafaxine	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.95, 1.25]
22 Sensitivity analysis: remission rates ‐ worst case Show forest plot	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.94, 1.24]

22.1 Agomelatine vs venlafaxine	3	669	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.94, 1.24]

Comparison 2. Agomelatine vs SNRI

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