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Meta-Analysis
. 2009 Jul 8;2009(3):CD006529.
doi: 10.1002/14651858.CD006529.pub2.

Milnacipran versus other antidepressive agents for depression

Atsuo Nakagawa  1 , Norio Watanabe, Ichiro M Omori, Corrado Barbui, Andrea Cipriani, Hugh McGuire, Rachel Churchill, Toshi A Furukawa
Affiliations
Meta-Analysis

Milnacipran versus other antidepressive agents for depression

Atsuo Nakagawa et al. Cochrane Database Syst Rev. .

Abstract

Background: Although pharmacological and psychological interventions are both effective for major depression, antidepressant drugs are frequently used as first-line treatment in primary and secondary care settings. Milnacipran, a dual serotonin-norepinephrine reuptake inhibitor (SNRI), is one of the antidepressant drugs that clinicians use for routine depression care.

Objectives: To assess the evidence for the efficacy, acceptability and tolerability of milnacipran in comparison with tricyclic antidepressants (TCAs), heterocyclics, SSRIs and other newer antidepressive agents in the acute-phase treatment of major depression.

Search strategy: The Cochrane Collaboration Depression, Anxiety & Neurosis review group Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References) were electronically searched in August 2008. References of relevant trials and other reviews were also checked. Trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished trials were hand-searched in 2007. All relevant authors were contacted for supplemental data. No language restriction was applied.

Selection criteria: Randomised controlled trials comparing milnacipran with any other active antidepressive agents (including non-conventional agents such as herbal products like hypericum) as monotherapy in the acute phase of major depression were selected.

Data collection and analysis: Two reviewers independently checked eligibility, assessed methodological quality and extracted data from the eligible trials using a standardised data extraction form. The number of participants who responded to treatment or those who achieved remission were calculated on an intention-to-treat basis. Random-effects meta-analyses were conducted, combining data from the included trials.

Main results: A total of 16 randomised controlled trials (n=2277) were included in the meta-analysis.Despite the size of this sample, the pooled 95% confidence intervals were rather wide and there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressive agents. However, compared with TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse events (OR 0.55; 95%CI 0.35 to 0.85). There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events of sleepiness/ drowsiness, dry mouth or constipation compared with TCAs.

Authors' conclusions: Currently, there is inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events (acceptability) and the rates of experiencing adverse events (tolerability). Information about other clinically meaningful outcomes such as cost-effectiveness and social functioning, including the ability to return to work, is lacking. Further study is needed to answer whether milnacipran would be the better choice of antidepressant for acute major depression.

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Conflict of interest statement

AN, NW, AC, CB, HMG, RC: none declared TAF has received several research grants and fees for speaking from some pharmaceutical companies, which market antidepressants (paroxetine, fluvoxamine, milnacipran, trazodone, mianserin), antipsychotics (risperidone, olanzapine, quetiapine, paliperidone, asenapine), nootropics (donepezil) and anxiolytics (loflazepate, tandospirone).

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Forest plot of comparison: 1 Response at acute phase (6‐12 weeks), outcome: 1.1 Milnacipran vs TCAs.
4
4
Forest plot of comparison: 2 Response at early phase (1‐4 weeks), outcome: 2.1 Milnacipran vs TCAs.
5
5
Forest plot of comparison: 12 Patients with at least some adverse events (Tolerability), outcome: 12.1 Milnacipran vs TCAs.
6
6
Forest plot of comparison: 3 Response at follow‐up phase (4‐6 months), outcome: 3.1 Milnacipran vs TCAs.
7
7
Forest plot of comparison: 2 Response at early phase (1‐4 weeks), outcome: 2.3 Milnacipran vs Hererocyclics.
8
8
Forest plot of comparison: 1 Response at acute phase (6‐12 weeks), outcome: 1.2 Milnacipran vs SSRIs.
9
9
Forest plot of comparison: 2 Response at early phase (1‐4 weeks), outcome: 2.2 Milancipran vs SSRIs.
1.1
1.1. Analysis
Comparison 1 Response at acute phase (6‐12 weeks), Outcome 1 Milnacipran vs TCAs.
1.2
1.2. Analysis
Comparison 1 Response at acute phase (6‐12 weeks), Outcome 2 Milnacipran vs SSRIs.
2.1
2.1. Analysis
Comparison 2 Response at early phase (1‐4 weeks), Outcome 1 Milnacipran vs TCAs.
2.2
2.2. Analysis
Comparison 2 Response at early phase (1‐4 weeks), Outcome 2 Milancipran vs SSRIs.
2.3
2.3. Analysis
Comparison 2 Response at early phase (1‐4 weeks), Outcome 3 Milnacipran vs Heterocyclics.
3.1
3.1. Analysis
Comparison 3 Response at follow‐up phase (4‐6 months), Outcome 1 Milnacipran vs TCAs.
4.1
4.1. Analysis
Comparison 4 Remission at acute phase (6‐12 weeks), Outcome 1 Milnacipran vs TCAs.
4.2
4.2. Analysis
Comparison 4 Remission at acute phase (6‐12 weeks), Outcome 2 Milnacipran vs SSRIs.
5.1
5.1. Analysis
Comparison 5 Remission at early phase (1‐4 weeks), Outcome 1 Milnacipran vs TCAs.
5.2
5.2. Analysis
Comparison 5 Remission at early phase (1‐4 weeks), Outcome 2 Milnacipran vs SSRIs.
5.3
5.3. Analysis
Comparison 5 Remission at early phase (1‐4 weeks), Outcome 3 Milnacipran vs Heterocyclics.
6.1
6.1. Analysis
Comparison 6 Remission at follow‐up phase (4‐6 months), Outcome 1 Milnacipran vs TCAs.
7.1
7.1. Analysis
Comparison 7 Depression scale‐end point score at acute phase (6‐12 weeks), Outcome 1 Milnacipran vs TCAs.
7.2
7.2. Analysis
Comparison 7 Depression scale‐end point score at acute phase (6‐12 weeks), Outcome 2 Milnacipran vs SSRIs.
7.3
7.3. Analysis
Comparison 7 Depression scale‐end point score at acute phase (6‐12 weeks), Outcome 3 Milnacipran vs Heterocyclics.
8.1
8.1. Analysis
Comparison 8 Depression scale‐end point score at early phase (1‐4 weeks), Outcome 1 Milnacipran vs TCAs.
8.2
8.2. Analysis
Comparison 8 Depression scale‐end point score at early phase (1‐4 weeks), Outcome 2 Milnacipran vs SSRIs.
8.3
8.3. Analysis
Comparison 8 Depression scale‐end point score at early phase (1‐4 weeks), Outcome 3 Milnacipran vs Heterocyclics.
9.1
9.1. Analysis
Comparison 9 Total dropouts (any reason), Outcome 1 Milnacipran vs TCAs.
9.2
9.2. Analysis
Comparison 9 Total dropouts (any reason), Outcome 2 Milnacipran vs SSRIs.
9.3
9.3. Analysis
Comparison 9 Total dropouts (any reason), Outcome 3 Milnacipran vs Heterocyclics.
10.1
10.1. Analysis
Comparison 10 Dropouts due to inefficacy, Outcome 1 Milnacipran vs TCAs.
10.2
10.2. Analysis
Comparison 10 Dropouts due to inefficacy, Outcome 2 Milnacipran vs SSRIs.
10.3
10.3. Analysis
Comparison 10 Dropouts due to inefficacy, Outcome 3 Milnacipran vs Heterocyclics.
11.1
11.1. Analysis
Comparison 11 Dropouts due to adverse events, Outcome 1 Milnacipran vs TCAs.
11.2
11.2. Analysis
Comparison 11 Dropouts due to adverse events, Outcome 2 Milnacipran vs SSRIs.
11.3
11.3. Analysis
Comparison 11 Dropouts due to adverse events, Outcome 3 Milnacipran vs Heterocyclics.
12.1
12.1. Analysis
Comparison 12 Patients with at least some adverse events (Tolerability), Outcome 1 Milnacipran vs TCAs.
12.2
12.2. Analysis
Comparison 12 Patients with at least some adverse events (Tolerability), Outcome 2 Milnacipran vs SSRIs.
12.3
12.3. Analysis
Comparison 12 Patients with at least some adverse events (Tolerability), Outcome 3 Milnacipran vs Heterocyclics.
13.1
13.1. Analysis
Comparison 13 Adverse events: Sleepiness/ Drowsiness, Outcome 1 Milnacipran vs TCAs.
13.2
13.2. Analysis
Comparison 13 Adverse events: Sleepiness/ Drowsiness, Outcome 2 Milancipran vs SSRIs.
13.3
13.3. Analysis
Comparison 13 Adverse events: Sleepiness/ Drowsiness, Outcome 3 Milnacipran vs Heterocyclics.
14.1
14.1. Analysis
Comparison 14 Adverse events: Insomnia, Outcome 1 Milnacipran vs TCAs.
14.2
14.2. Analysis
Comparison 14 Adverse events: Insomnia, Outcome 2 Milancipran vs SSRIs.
14.3
14.3. Analysis
Comparison 14 Adverse events: Insomnia, Outcome 3 Milnacipran vs Heterocyclics.
15.1
15.1. Analysis
Comparison 15 Adverse events: Dry mouth, Outcome 1 Milnacipran vs TCAs.
15.2
15.2. Analysis
Comparison 15 Adverse events: Dry mouth, Outcome 2 Milancipran vs SSRIs.
15.3
15.3. Analysis
Comparison 15 Adverse events: Dry mouth, Outcome 3 Milnacipran vs Heterocyclics.
16.1
16.1. Analysis
Comparison 16 Adverse events: Constipation, Outcome 1 Milnacipran vs TCAs.
16.2
16.2. Analysis
Comparison 16 Adverse events: Constipation, Outcome 2 Milancipran vs SSRIs.
16.3
16.3. Analysis
Comparison 16 Adverse events: Constipation, Outcome 3 Milnacipran vs Heterocyclics.
17.1
17.1. Analysis
Comparison 17 Adverse events: Urination problems, Outcome 1 Milnacipran vs TCAs.
17.2
17.2. Analysis
Comparison 17 Adverse events: Urination problems, Outcome 2 Milancipran vs SSRIs.
17.3
17.3. Analysis
Comparison 17 Adverse events: Urination problems, Outcome 3 Milnacipran vs Heterocyclics.
18.1
18.1. Analysis
Comparison 18 Adverse events: Hypotention, Outcome 1 Milnacipran vs TCAs.
18.2
18.2. Analysis
Comparison 18 Adverse events: Hypotention, Outcome 2 Milancipran vs SSRIs.
18.3
18.3. Analysis
Comparison 18 Adverse events: Hypotention, Outcome 3 Milnacipran vs Heterocyclics.
19.1
19.1. Analysis
Comparison 19 Adverse events: Agitaion/ anxiety, Outcome 1 Milnacipran vs TCAs.
19.2
19.2. Analysis
Comparison 19 Adverse events: Agitaion/ anxiety, Outcome 2 Milancipran vs SSRIs.
19.3
19.3. Analysis
Comparison 19 Adverse events: Agitaion/ anxiety, Outcome 3 Milnacipran vs Heterocyclics.
20.1
20.1. Analysis
Comparison 20 Adverse events: Suicide wishes/ gestures/ attempts, Outcome 1 Milnacipran vs TCAs.
20.2
20.2. Analysis
Comparison 20 Adverse events: Suicide wishes/ gestures/ attempts, Outcome 2 Milancipran vs SSRIs.
21.1
21.1. Analysis
Comparison 21 Adverse events:Completed suicide, Outcome 1 Milancipran vs SSRIs.
22.1
22.1. Analysis
Comparison 22 Adverse events: Vomitting/ nausea, Outcome 1 Milnacipran vs TCAs.
22.2
22.2. Analysis
Comparison 22 Adverse events: Vomitting/ nausea, Outcome 2 Milancipran vs SSRIs.
22.3
22.3. Analysis
Comparison 22 Adverse events: Vomitting/ nausea, Outcome 3 Milnacipran vs Heterocyclics.
23.1
23.1. Analysis
Comparison 23 Adverse events: Diarrhoea, Outcome 1 Milnacipran vs TCAs.
23.2
23.2. Analysis
Comparison 23 Adverse events: Diarrhoea, Outcome 2 Milancipran vs SSRIs.
24.1
24.1. Analysis
Comparison 24 Subgroup analysis: Response at early phase (1‐4 weeks)‐High dose milnacipran, Outcome 1 vs TCAs.
25.1
25.1. Analysis
Comparison 25 Subgroup analysis: Response at acute phase (6‐12 weeks)‐Flexible dosing, Outcome 1 Milnacipran vs TCAs.
26.1
26.1. Analysis
Comparison 26 Subgroup analysis: Response at early phase (1‐4 weeks)‐Flexible dosing, Outcome 1 Milnacipran vs TCAs.
27.1
27.1. Analysis
Comparison 27 Subgroup analysis: Response at acute phase [6‐12 weeks]‐Outpatient, Outcome 1 Milnacipran vs SSRIs.
28.1
28.1. Analysis
Comparison 28 Subgroup analysis: Response at early phase [1‐4 weeks]‐Outpatient, Outcome 1 Milancipran vs SSRIs.
29.1
29.1. Analysis
Comparison 29 Subgroup analysis: Response at early phase [1‐4 weeks]‐Inpatient, Outcome 1 Milnacipran vs TCAs.
29.2
29.2. Analysis
Comparison 29 Subgroup analysis: Response at early phase [1‐4 weeks]‐Inpatient, Outcome 2 Milancipran vs SSRIs.
30.1
30.1. Analysis
Comparison 30 Subgroup analysis: Response at acute phase [6‐12 weeks]‐Inpatient, Outcome 1 Milnacipran vs TCAs.
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Update of

References

References to studies included in this review

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Clerc 2001 {published data only}
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Leinonen 1997 {published data only}
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Lopez‐Ibor 2004 {published data only}
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Baek 2002a {published data only}
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