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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder

JA Bridge, B Birmaher, S Lyengar, RP Barbe, and DA Brent.

Review published: 2009.

Link to full article: [Journal publisher]

CRD summary

The review found that number of study sites was the best predictor of placebo response in short-term randomised controlled trials of second-generation antidepressants in children and adolescents with major depressive disorder. The authors' conclusions are appropriate but, due to shortcomings in the review process and the relatively small number of studies, the reliability of the conclusions is not clear.

Authors' objectives

To investigate the characteristics and predictors of response to placebo in short-term randomised controlled trials of antidepressants for major depressive disorder in children and adolescents


PubMed was searched from January 1988 to July 2006; search terms were reported. Potential relevant studies were identified by searching reference lists of identified studies, regulatory reports, proceedings of three scientific meetings and clinical trial registries and contact with individual investigators.

Study selection

Studies were eligible if they were randomised controlled trials (RCTs) in young people aged six to 18 years of age with major depressive disorder that included serotonin reuptake inhibitors (SSRIs) and other second generation antidepressants compared with placebo. Studies were included only if response data (measured by the improvement item on the Clinical Global Impression scale) were available for both participants treated with placebo and those treated with antidepressants.

In the included studies, median age of participants was 12.3 years (range 12.0 to 15.6 years). The median proportion of females was 0.53 (range 0.46 to 0.66). Approximately three quarters of participants were white. The proportion of participants having their first episode of depression ranged from 48% to 88%. Duration of depression ranged from three to 27 months. The most frequently assessed drugs were fluoxetine (dose range 10mg to 40mg) and paroxetine (dose range 10mg to 50mg); other drugs were assessed in single trials and these included sertraline (50mg to 200mg), citalopram (20mg to 40mg), escitalopram (10mg to 20mg), venlafaxine (37.5mg to 225mg), nefazodone (100mg to 600mg) and mirtazapine (15 to 45mg). All comparisons were with placebo. Half of the studies used a placebo run-in period. Duration of treatment ranged from eight to 12 weeks. Response to treatment was defined as an end-of-treatment rating of 2 or less (much improved or very much improved on the Clinical Global Impression improvement item), which indicated a clinically significant reduction in depressive symptoms to the extent that the patient no longer was classified as having a psychiatric disorder. Most studies were published between 1997 and 2007; the remaining studies were unpublished.

The authors did not state how study selection was performed.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Data were extracted on potential predictors of response, which included: number of study sites; number of patients randomised; mean number of participants per study site; location of trial; baseline severity of illness; age of participants; duration of treatment; duration of illness; study location; placebo run-in period; gender of participants; ethnicity of participants; participants who had first episode major depressive disorder; year of publication of study; and year of study completion.

The authors did not state how data extraction was performed.

Methods of synthesis

Pearson correlation coefficients (r) and linear regression were used to assess the associations between continuous variables. Spearman rank correlations (rs) were calculated to assess associations between continuous and dichotomous variables. All statistical tests were two tailed and p values ≤0.05 were considered statistically significant. No correction was made for multiple comparisons. Sensitivity analysis was undertaken by withdrawal of individual trials and recalculating r and rs to determine whether a single trial unduly influenced overall results. The effect of placebo response on the antidepressant-placebo difference in efficacy was tested using either risk differences and Hedge's g (indicating the scalar change in symptoms from baseline to end of treatment).

Results of the review

Twelve RCTs (n=2,862) were included. Sample sizes of the studies ranged from 96 to 376.

Three site selection variables had significant positive associations with placebo response in univariate analyses: number of patients randomised (12 studies); number of study sites (12 studies); and number of participants per study site (11 studies). The mean Children's Depression Rating Scale - Revised (CDRS-R) score at baseline had a significant inverse association with placebo response in univariate analyses. In multiple linear regression analysis, only number of study sites remained significantly associated with placebo response (β=0.59, t=2.46, df=6, p=0.05, partial r=0.71).

Placebo response was not significantly different between children and adolescents, but with the exclusion of one fluoxetine trial in sensitivity analysis, younger children had higher placebo response rates than older adolescents (response rate in children 54.3% versus response rate in adolescents 44.9%; Χ2=5.87; p=0.02), but this relationship was not found when other trials were excluded in sensitivity analysis.

Higher placebo response rates in more recent studies were associated with an increasing trend toward large multisite trials and by publication delays and failures to publish some negative trials.

Authors' conclusions

The authors concluded that placebo response in controlled antidepressant trials of paediatric depression was strongly correlated with number of study sites in the trials.

CRD commentary

The review addressed a clear research question. Inclusion criteria were appropriate. One electronic database was searched, but authors made other attempts to find potentially relevant published and unpublished studies. It was unclear whether there was a restriction to language, so language bias could not be ruled out. Publication bias was not formally assessed. The authors did not report the methods used to select studies or extract data; thus, reviewer bias and error in the review process could not be ruled out. A lack of quality assessment of the included studies made it difficult to assess the reliability of the data. Methods of analysis, both univariate and multivariate, to assess associations with placebo response were appropriate. The authors acknowledged that they had been unable to examine the potential impact of other factors that could impact on placebo response, such as history of non response to SSRIs, history of abuse, family history of psychiatric disorder and comorbid psychiatric disorders. The small number of included studies did not give sufficient power to examine statistical interactions between variables and the authors acknowledged that null results should be interpreted with caution. It was unclear whether results based on the participants in the included studies were applicable to real world populations. The authors' conclusions reflect the evidence base and are appropriate but, due to lack of quality assessment, potential shortcomings in the review process from lack of reporting methods and the relatively small number of studies, the reliability of the conclusions is not clear.

Implications of the review for practice and research

Practice: The authors stated that there was a role for supportive therapy or a brief trial of specialised psychotherapy as first-line treatment options for mild depression.

Research: The authors stated that future trials should focus on identifying the level of clinical severity of depression at which first-line treatments with medication, psychotherapy or their combination were warranted.


NIMH grant K01 MH-69948 and grant P30 MH-66371.

Bibliographic details

Bridge JA, Birmaher B, Lyengar S, Barbe RP, Brent DA. Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. American Journal of Psychiatry 2009; 166(1): 42-49. [PubMed: 19047322]

Indexing Status

Subject indexing assigned by NLM


Adolescent; Age Factors; Child; Depressive Disorder, Major /diagnosis /drug therapy /psychology; Humans; Multicenter Studies as Topic; Personality Assessment; Placebo Effect; Publication Bias; Randomized Controlled Trials as Topic; Treatment Outcome



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 19047322


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