Published online January 29, 2009 DOI:10.1016/S0140-6736(09)60046-5
Comparative eﬃ cacy and acceptability of 12 new-generationantidepressants: a multiple-treatments meta-analysis
Andrea Cipriani, Toshiaki A Furukawa, Georgia Salanti, John R Geddes, Julian P T Higgins, Rachel Churchill, Norio Watanabe, Atsuo Nakagawa,Ichiro M Omori, Hugh McGuire, Michele Tansella, Corrado Barbui
Conventional meta-analyses have shown inconsistent results for eﬃ cacy of second-generationantidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirectcomparisons, to assess the eﬀects of 12 new-generation antidepressants on major depression.
We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up toNov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatmentof unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, ﬂuoxetine, ﬂuvoxamine,milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportionof patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treatbasis.
Mirtazapine, escitalopram, venlafaxine, and sertraline were signiﬁcantly more eﬃ cacious 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), andreboxetine (2·03, 1·95, 1·89, and 1·85, respectively). Reboxetine was signiﬁcantly less eﬃ cacious than all the other antidepressants tested. Escitalopram and sertraline showed the best proﬁle of acceptability, leading to signiﬁcantlyfewer discontinuations than did duloxetine, ﬂuvoxamine, paroxetine, reboxetine, and venlafaxine.
Clinically important diﬀerences exist between commonly prescribed antidepressants for both eﬃ cacyand acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatmentfor moderate to severe major depression in adults because it has the most favourable balance between beneﬁts,acceptability, and acquisition cost.
In the past 20 years, several new drugs have beenintroduced for the treatment of depression, many of which are structurally related and share similar putativemechanisms of action. As with statins for the preventionof coronary events,
the extent to which these agents varyin terms of eﬃ cacy and acceptability is unclear. Moreover,some of the new drugs are so-called me-too drugs
—ie,chemically similar to existing drugs with expiring patentsrather than genuine advances in treatment. Systematicreviews have already highlighted some diﬀerences ineﬃ cacy between second-generation antidepressants.
We report an overview of all randomised controlledtrials that compared 12 new-generation antidepressantsin terms of eﬃ cacy and acceptability in the acute-phasetreatment of major depression. We used multiple-treat-ments meta-analysis,
also known as mixed-treatmentcomparisons meta-analysis or network meta-analysis,which allows the integration of data from direct (whentreatments are compared within a randomised trial) andindirect comparisons (when treatments are comparedbetween trials by combining results on how eﬀective theyare compared with a common comparator treatment).
We aimed to provide a clinically useful summary of theresults of the multiple-treatments meta-analysis that canbe used to guide treatment decisions.
Study selection and data collection
At the beginning of this project, we drafted a studyprotocol and subsequently made it freely available to thepublic on our institutional website before carrying outthe ﬁnal analyses. Furthermore, with the publication of this paper the overall data set will be in the publicdomain.For our analysis, we included only randomised controlledtrials that compared any of the following 12 new-generationantidepressants (bupropion, citalopram, duloxetine,escitalopram, ﬂuoxetine, ﬂuvoxamine, milnacipran, mirta-zapine, paroxetine, reboxetine, sertraline, and venlafaxine)as monotherapy in the acute-phase treatment of adultswith unipolar major depression. We excluded placebogroups where present and randomised controlled trials of women with post-partum depression.
To identify the relevant studies, we reviewed theCochrane collaboration depression, anxiety, and neurosisreview group controlled trials registers (CCDANDTR-studies and CCDANCTR-references) up to Nov 30, 2007.
January 29, 2009DOI:10.1016/S0140-6736(09)60046-5See
Department of Medicine andPublic Health, Section of Psychiatry and ClinicalPsychology, University of Verona, Italy
(A Cipriani PhD,C Barbui MD, Prof M Tansella MD)
Department of Psychiatry andCognitive-Behavioral Medicine,Nagoya City UniversityGraduate School of MedicalSciences, Nagoya, Japan
(Prof T A Furukawa MD,N Watanabe PhD, I M Omori PhD)
Department of Hygiene andEpidemiology, University of Ioannina School of Medicine,Greece
(G Salanti PhD)
Department of Psychiatry,University of Oxford, UK
(A Cipriani, Prof J R Geddes MD)
MRC Biostatistics Unit Instituteof Public Health, University of Cambridge, UK
(J P T Higgins PhD)
CochraneDepression, Anxiety andNeurosis Review Group,Institute of Psychiatry, London,UK
(H McGuire MA)
Departmentof Community based Medicine,University of Bristol, UK
(R Churchill PhD)
Department of Neuropsychiatry, School of Medicine, Keio University,Tokyo, Japan
(A Nakagawa MD)Correspondence to:Dr Andrea Cipriani, Departmentof Medicine and Public Health,Section of Psychiatry and ClinicalPsychology, University of Verona,Policlinico “G B Rossi”, Piazzale LA Scuro, 10, 37134, Verona, Italy
see http://www.psychiatry.univr.it/docs/Research%20Activities/MTM_Protocol.pdf For the