Elsevier

The Lancet

Volume 373, Issue 9665, 28 February–6 March 2009, Pages 746-758
The Lancet

Articles
Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis

https://doi.org/10.1016/S0140-6736(09)60046-5Get rights and content

Summary

Background

Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression.

Methods

We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis.

Findings

Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1·39, 1·33, 1·30 and 1·27, respectively), fluoxetine (1·37, 1·32, 1·28, and 1·25, respectively), fluvoxamine (1·41, 1·35, 1·30, and 1·27, respectively), paroxetine (1·35, 1·30, 1·27, and 1·22, respectively), and reboxetine (2·03, 1·95, 1·89, and 1·85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine.

Interpretation

Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.

Funding

None.

Introduction

In the past 20 years, several new drugs have been introduced for the treatment of depression, many of which are structurally related and share similar putative mechanisms of action. As with statins for the prevention of coronary events,1 the extent to which these agents vary in terms of efficacy and acceptability is unclear. Moreover, some of the new drugs are so-called me-too drugs2—ie, chemically similar to existing drugs with expiring patents rather than genuine advances in treatment. Systematic reviews have already highlighted some differences in efficacy between second-generation antidepressants.3, 4, 5, 6, 7, 8, 9

We report an overview of all randomised controlled trials that compared 12 new-generation antidepressants in terms of efficacy and acceptability in the acute-phase treatment of major depression. We used multiple-treatments meta-analysis,10 also known as mixed-treatment comparisons meta-analysis or network meta-analysis, which allows the integration of data from direct (when treatments are compared within a randomised trial) and indirect comparisons (when treatments are compared between trials by combining results on how effective they are compared with a common comparator treatment).11 We aimed to provide a clinically useful summary of the results of the multiple-treatments meta-analysis that can be used to guide treatment decisions.

Section snippets

Study selection and data collection

At the beginning of this project, we drafted a study protocol and subsequently made it freely available to the public on our institutional website before carrying out the final analyses. Furthermore, with the publication of this paper the overall data set will be in the public domain.

For our analysis, we included only randomised controlled trials that compared any of the following 12 new-generation antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,

Results

The electronic searches yielded 345 potentially relevant studies, of which 274 potentially eligible articles were analysed. We excluded 172 reports that did not meet eligibility criteria (figure 1). We identified a further 15 unpublished trials eligible for our meta-analysis from pharmaceutical industry websites. Overall, we used 117 trials from 1991 to 2007 for the multiple-treatments meta-analysis.21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,

Discussion

Our analysis was based on 117 studies including 25 928 individuals randomly assigned to 12 different new-generation antidepressants. Our findings might help to choose among new-generation antidepressants for acute treatment of major depression. Some antidepressants differed both statistically and clinically. In terms of response, mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. In terms of

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