Are Child and Adolescent Responses to Placebo Higher in Major Depression than in Anxiety Disorders? A Systematic Review of Placebo-Controlled Trials David Cohen 1,2 *, Emmanuelle Deniau 1 , Alejandro Maturana 3 , Marie-Laure Tanguy 4 , Nicolas Bodeau 1 , Re ´ al Labelle 5,6 , Jean-Jacques Breton 6 , Jean-Marc Guile 2,6 1 Department of Child and Adolescent Psychiatry, Universite ´ Pierre et Marie Curie, GH Pitie ´-Salpe ´trie ` re, AP-HP, Paris, France, 2 CNRS UMR 8189, Laboratoire Psychologie et Neurosciences Cognitives, Paris, France, 3 Department of Child and Adolescent Psychiatry, Universite ´ of Chile, Santiago, Chile, 4 Department of Biostatistics, Universite ´ Pierre et Marie Curie, Paris, France, 5 Department of Psychology, UQAM, Montre ´al, Canada, 6 Department of Child and Adolescent Psychiatry, Universite ´ de Montre ´al, Montre ´al, Canada Abstract Background: In a previous report, we hypothesized that responses to placebo were high in child and adolescent depression because of specific psychopathological factors associated with youth major depression. The purpose of this study was to compare the placebo response rates in pharmacological trials for major depressive disorder (MDD), obsessive compulsive disorder (OCD) and other anxiety disorders (AD-non-OCD). Methodology and Principal Findings: We reviewed the literature relevant to the use of psychotropic medication in children and adolescents with internalized disorders, restricting our review to double-blind studies including a placebo arm. Placebo response rates were pooled and compared according to diagnosis (MDD vs. OCD vs. AD-non-OCD), age (adolescent vs. child), and date of publication. From 1972 to 2007, we found 23 trials that evaluated the efficacy of psychotropic medication (mainly non-tricyclic antidepressants) involving youth with MDD, 7 pertaining to youth with OCD, and 10 pertaining to youth with other anxiety disorders (N = 2533 patients in placebo arms). As hypothesized, the placebo response rate was significantly higher in studies on MDD, than in those examining OCD and AD-non-OCD (49.6% [range: 17–90%] vs. 31% [range: 4–41%] vs. 39.6% [range: 9–53], respectively, ANOVA F = 7.1, p = 0.002). Children showed a higher stable placebo response within all three diagnoses than adolescents, though this difference was not significant. Finally, no significant effects were found with respect to the year of publication. Conclusion: MDD in children and adolescents appears to be more responsive to placebo than other internalized conditions, which highlights differential psychopathology. Citation: Cohen D, Deniau E, Maturana A, Tanguy M-L, Bodeau N, et al. (2008) Are Child and Adolescent Responses to Placebo Higher in Major Depression than in Anxiety Disorders? A Systematic Review of Placebo-Controlled Trials. PLoS ONE 3(7): e2632. doi:10.1371/journal.pone.0002632 Editor: Phillipa J. Hay, James Cook University, Australia Received January 23, 2008; Accepted June 3, 2008; Published July 9, 2008 Copyright: ß 2008 Cohen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: DC was an investigator in two pharmaceutical trials funded by Smith Kline Beecham (2001) and Sanofi-Synthe ´labo (2006). He is currently the principal investigator of a trial on adolescent OCD funded by Lundbeck. Other authors have no disclosure to declare. Sponsors cited above had no influence in the design, collection, analysis and interpretation of the data. Competing Interests: The authors have declared that no competing interests exist. * E-mail: david.cohen@psl.aphp.fr Introduction Child and adolescent depression has been a public health concern for some time because of its high implication in suicidal acts and youth morbidity [1,2]. During the 1980s, the arrival of the selective serotonin reuptake inhibitors (SSRIs), which are associated with far fewer side effects than tricyclics or monoamine oxidase inhibitors, was viewed as an important step in the treatment of affective disorders, first in adults, and then in children and adolescents. In the early 1990s, SSRI use in children and adolescents increased rapidly in developed countries, sometimes to a higher proportion than the prevalence rate of depression in this age range [3]. However, placebo-controlled trials rarely demon- strated the superiority of non-tricyclic antidepressants over placebo mainly because of high placebo response rates, which make the establishment of drug efficacy difficult. Treatment effects must be substantial to be differentiated from placebo. The establishment of SSRI efficacy was easier in child and adolescent obsessive compulsive disorder (OCD) [4,5] and anxiety disorders (AD- nonOCD) [6]. In a previous report [7], we hypothesized that the response to placebo was high in child and adolescent depression because of specific psychopathological factors associated with youth MDD that promote psychotherapeutic effects in pharmacological trials. This hypothesis was based on several points. First, MDD in children and adolescents is not identical to that in adults or young adults [8,9]. In particular, early risk factor profiles of adolescent depression are very different from those of young adult depression [9]. Additionally, the establishment of a therapeutic alliance is a primary objective in any care-giving with a child or adolescent, and it should be formed with both the child and his or her parents [10]. Therapeutic alliance is a familiar concept for pediatric or PLoS ONE | www.plosone.org 1 July 2008 | Volume 3 | Issue 7 | e2632