This meta-analysis examined 31 studies of antidepressant medication for depressive disorders in children and adolescents across open, placebo-controlled, and active comparator study designs. Consistent with our hypotheses, open studies of antidepressant medications were associated with a significantly higher medication response rate compared to placebo-controlled and comparator RCTs. Contrary to our hypotheses, response rates to antidepressant medication did not differ significantly between placebo-controlled and active comparator study designs. Medication response rates also did not depend upon mean patient age or the amount of contact with research staff.
Mechanisms for change in clinical trials can be conceptualized as comprising medication effects, placebo effects, and non-specific study effects. Medication effects are the specific physiological effects of the medication being studied on the target disorder (e.g., the effect of serotonin reuptake inhibition on MDD). Placebo effects are the psychological and physiological effects on a patient of receiving a treatment that is believed by the patient to be effective for the target disorder. In clinical trials, patient expectancy of therapeutic improvement is believed to be the primary mechanism of placebo effects. Non-specific study effects occur by virtue of studying a patient over time in a research study, and they include the natural history of the patient's condition, therapeutic aspects of the health care context, and the expectations of clinicians and raters in research studies.
Since `effect' denotes a conceptual cause of patient change and the term `response' denotes what is actually observed in a research study, it follows that antidepressant response
results from a combination of medication, placebo, and non-specific study effects
. Differences in placebo and non-specific study effects across studies may explain differences in observed clinical responses to the same medications. For example, adult participants in comparator trials have enhanced expectancy of therapeutic benefit and consequently higher antidepressant response rates based on their certainty of receiving active medication (as opposed to participants in placebo-controlled trials being aware they may receive placebo).8,10,56
This appears not to be the case for children and adolescents with depression, since in this analysis of antidepressant studies for pediatric MDD, medication response in placebo-controlled and comparator trials did not differ significantly.
One interpretation of these findings is that children and adolescents do not generate the same treatment expectancies as do adult RCT participants, and consequently differences in patient expectancy do not cause differential medication response rates across study designs. Younger patients entering clinical studies may not receive the same information disclosure as adults and may not be as cognitively capable of understanding what information they do receive. We attempted to evaluate this interpretation by testing whether increasing patient age was associated with greater differences in medication response between placebo-controlled and comparator trials, but we found no evidence for a patient age × study type interaction. Even greater levels of cognitive sophistication than that possessed by adolescents may be required to generate expectancies about therapeutic improvement based on study design.
Rather than expectancy-based placebo effects, high placebo response rates in pediatric MDD trials may be driven by other factors, such as the therapeutic aspects of the trial protocol. The possibility has been discussed in the literature that children and adolescents with depression respond well to frequent and regular meetings with clinicians who foster the therapeutic alliance and bolster confidence and self-esteem.57
Data from this meta-analysis are partially consistent with this hypothesis, since there was an increasingly positive effect of contact with research staff on response to placebo with increasing patient age. Older youths may benefit more from contact with research staff due to their enhanced capacities for self-evaluation, which may improve the therapeutic alliance by facilitating therapist and patient agreement on treatment goals and the tasks of therapy.58–59
However, the effects of therapeutic contact on antidepressant and placebo response appeared to be limited in our analyses, since we did not observe main effects of contact with research staff on antidepressant and placebo response rates.
Some of the studies in our sample included as part of their design extended screening phases and placebo lead-in periods to identify participants whose symptoms responded quickly to contact with health professionals or placebo. While we did not find sufficient information in the published articles to evaluate the effect of extended screening phases and supportive therapy, we did not determine placebo response to be significantly different between studies having a placebo lead-in period and those that did not. This is consistent with findings in studies of adult patients with MDD, where single-blind placebo lead-in periods have not been found to reduce placebo response or influence the detection of drug-placebo differences.60
Another notable finding of this meta-analysis was that medication response rates were higher in open vs. placebo-controlled and comparator studies. One possible explanation for these differences is that open treatment induces more optimistic treatment expectancies than even comparator studies, though patients in comparator studies are also assured of receiving an active treatment for their condition. Since parents may contribute to the outcome ratings on some measures (e.g., CDRS and KSADS), their expectations about treatment outcome also may influence medication response rates in open studies. Furthermore, it is possible that patients entering combined studies of medication and psychotherapy (3/4 comparator studies in this sample had a psychotherapy arm) preferred randomization to psychotherapy, and they were disappointed (and experienced a corresponding “nocebo” effect) when they were randomized to medication. However, the most cogent explanation of this overestimation of treatment effects in open studies may be increased rater bias.61
Given that open studies are conducted without blinding by investigators who are attempting to find a significant effect of medication in order to support further investigation, rater bias may play a significant role.
Finally, a number of limitations should be considered when interpreting the findings of this study. The use of trial-level summary data limited the data available for analysis in this study, as not all authors reported complete information about patient and trial characteristics in their published article. Four studies were excluded because of inadequate reporting of outcome data, and we were not able to analyze antidepressant remission rates (only 8/31 studies provided remission rate data). Additionally, publication bias may have affected which studies were included in these analyses, since some open label studies as well as RCTs failing to demonstrate significant differences between medication and placebo may not have been published. However it is not the efficacy of medication compared to placebo that was investigated in this analysis, so publication bias seems unlikely to have affected the overall patterns of response observed across trials.
A second limitation of this study concerns the analyses of patient age, which were based on the mean ages of participants provided in each study, centered around the grand mean for age across studies. There may be important differences between the responses of children (aged 7–12 years) and adolescents (aged 13–18 years) to antidepressant medications and placebo that would be useful to investigate with a dichotomous variable for patient age (i.e., child vs. adolescent).62
Unfortunately, it was not possible to conduct the analyses in this fashion due to the characteristics of the study sample. Age-grouped data for both children and adolescents were available for some (but not all) of the placebo-controlled trials in our sample, but the comparator trials only enrolled adolescents. Thus, a dichotomous variable made it impossible to assess the primary question of interest regarding patient age, which was whether there was a patient age × study type interaction indicating increased expectancy effects as cognitive development proceeds.
Thirdly, patient and study characteristics other than expectancy, patient age, and contact with research staff may influence response to antidepressant medication and placebo. Family history of affective disorder, severity of depressive symptoms, greater number of depressive episodes, age, sex, ethnicity, number of concurrent psychiatric comorbidities, length of illness, length of current episode, global functioning of the child and family, and suicidal behaviors have all been suggested to influence medication response in children and adolescents.63–65
The number of treatment sites and the duration of the depressive episode at baseline have been found to be associated with increased response to placebo.6
We chose not to include these demographic, clinical, and methodological characteristics in our modeling of antidepressant and placebo response rates. Rather, our primary concern was to determine whether these predictors of medication and placebo response significantly differed between the study types we analyzed, which could confound our primary comparisons. However, we found that only the distribution of medication classes used between studies differed between study types, with open studies more frequently using SNRIs and atypical antidepressants than placebo-controlled (but not comparator) trials. When we repeated the analyses excluding SNRI and atypical antidepressant treatment cells, the overall pattern of results did not change.
In summary, there are many sources of patient change apart from antidepressant medication in clinical trials for depression. In adult depressed patients, expectancy of improvement is a major determinant of responses rates to antidepressants and placebo. In contrast, findings from this multilevel meta-analysis of antidepressant and placebo response rates in pediatric MDD trials suggest that patient expectancy plays a minor role in children and adolescents. Other non-specific study effects, such as the therapeutic effects of contact with research staff, may explain more of the variability in response rates. However, it is impossible for any retrospective analysis to fully differentiate the contributions of medication, expectancy-based placebo effects, and non-specific study effects to clinical outcome. The execution of prospective studies will be critical to answering these questions, and a major significance of this meta-analysis is to suggest novel clinical trial designs with this capability.