Open Access Highly Accessed Research article

Which placebo to cure depression? A thought-provoking network meta-analysis

Florian Naudet123*, Bruno Millet23, Philippe Charlier45, Jean Michel Reymann67, Anne Solène Maria18 and Bruno Falissard189

Author Affiliations

1 INSERM U669, Maison de Solenn, 97 Boulevard de Port Royal, 75679 Paris Cedex 14, France

2 Université de Rennes 1, EA-4712 Behavior and Basal Ganglia Unit, Rennes, France

3 Centre Hospitalier Guillaume Régnier, Service Hospitalo-Universitaire de Psychiatrie, Rennes, France

4 Department of Forensic Medicine and Pathology, University Hospital R. Poincaré (AP-HP, UVSQ), Garches, France

5 Laboratory of Medical Ethics, University of Paris 5, 45 St Pères Street, 75006 Paris, France

6 Centre d’Investigation Clinique CIC-P INSERM 0203, Hôpital de Pontchaillou, Centre Hospitalier Universitaire de Rennes et Université de Rennes 1, Rennes, France

7 Laboratoire de Pharmacologie Expérimentale et Clinique, Faculté de Médecine, CS34317, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France

8 Université Paris-Sud and Université Paris Descartes, UMR-S0669, Paris, France

9 AP-HP, Hôpital Paul Brousse, Département de santé publique, Villejuif, France

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BMC Medicine 2013, 11:230  doi:10.1186/1741-7015-11-230

Published: 25 October 2013



Antidepressants are often considered to be mere placebos despite the fact that meta-analyses are able to rank them. It follows that it should also be possible to rank different placebos, which are all made of sucrose. To explore this issue, which is rather more epistemological than clinical, we designed an unusual meta-analysis to investigate whether the effects of placebo in one situation are different from the effects of placebo in another situation.


Published and unpublished studies were searched for by three reviewers on Medline, the Cochrane Library, Embase,, Current Controlled Trial, in bibliographies, and by mailing key organizations. The following studies in first-line treatment for major depressive disorder were considered to construct an “evidence network”: 1) randomized controlled trials (RCTs) versus placebo on fluoxetine, venlafaxine and 2) fluoxetine versus venlafaxine head-to-head RCTs.

Two network meta-analyses were run to indirectly compare response and remission rates among three different placebos: 1) fluoxetine placebo, 2) venlafaxine placebo, and 3) venlafaxine/fluoxetine placebo (that is, placebo compared to both venlafaxine and fluoxetine). Publication biases were assessed using funnel plots and statistically tested.


The three placebos were not significantly different in terms of response or remission. The antidepressant agents were significantly more efficacious than the placebos, and venlafaxine was more efficacious than fluoxetine. The funnel plots, however, showed a major publication bias.


The presence of significant levels of publication bias indicates that we cannot even be certain of the conclusion that sucrose equals sucrose in trials of major depressive disorder. This result should remind clinicians to step back to take a more objective view when interpreting a scientific result. It is of crucial importance for their practice, far more so than ranking antidepressant efficacy.

Antidepressants; Placebo; Major depressive disorder; Meta-analysis; Publication bias