The current study shows that response to placebo differs among internalized disorders in children and adolescents. Compared to anxiety disorders including OCD, MDD appears to respond better to placebo during double-blind placebo-controlled trials of medication. This is evidenced for both children and adolescents, and is not influenced by response over time. The main limitation of this study is the fact that we pooled all placebo arms from studies that varied in their methodologies (e.g. inclusion criteria, initial placebo washout period, definition of responders, and duration of treatment). However, several positive points should be kept in mind. First, in contrast to what has been shown in adult mood disorders 
, we did not find a correlation between placebo response rate and year of publication despite apparent variability in both placebo rates and publication dates. Second, age did not show any major influence on placebo response rates in children and adolescents. Third, most of the data used in these analyses came from studies on SSRIs that were conducted in the late nineties and early 2000s, after several consensus conferences and guidelines had been done on youth psychopharmacological trials. Therefore, the methodologies were very similar for these studies 
. Fourth, when CGI was used to define placebo response rates (either as primary or secondary variables), we obtained the same results. As a consequence, we consider the current results to have validity, and feel that they might reflect differential psychopathology between MDD and anxiety disorders. Other limitations should also be noted: (1) most of the studies were sponsored by drug industry, and, in many studies, broad inclusion criteria were used (e.g., including youths with comorbid anxiety in depression trials and vice versa
; excluding suicidal youths from depression trials); (2) Pooled analysis does not address the fact that MDD is likely to be highly heterogeneous and that some patients may differ in their response to non-specific professional attention (as evidenced in the wide range of placebo response rate across studies, ); (3) Three studies conducted before 1980 did not use DSM-III (or greater) criteria and may have had substantial differences in the disorders' definitions. However, they only accounted for 48 patients total to analyses.
It is not in the scope of this paper to carefully review the main psychological theories regarding MDD, OCD, and AD-non-OCD. However, given that children and adolescents with MDD appear to be more responsive to placebo than other youths with internalized conditions, highlighting differential psychopathology (a point called pharmaceutical dissection), may help with the formulation of hypotheses about this pattern. summarizes the different theoretical views according to psychoanalytic theory, cognitive/behavioral theory, and family/systems theory. The following factors appear to clearly differentiate depression from anxiety disorders in all three theoretical views. First, whether it is called self-esteem or narcissism, a child needs to encounter positive experiences of love, particularly in interactions with his early caregivers, that may help him construct more self-confidence or a stronger sense of self during development. Second, when this does not occur, such as when early life adversities occur, the child becomes vulnerable to a variety of loss experiences that he may encounter in everyday life. Third, this vulnerability to loss manifests in a specific search for adult recognition, care, and love as it may restore the negative views on himself. Fourth, fear is the main emotional dimension in AD, but does not appear much in theories about the psychopathology of depression, unless depression is secondary to, and comorbid with, an AD 
. On the contrary, when loss is involved in the psychopathology of an AD, it is at the level of threatened loss of the object-relationship, and not at the level of real experiences of loss 
. Several empirical studies support these distinctions. Loss events are significantly more prevalent among MDD than AD, both in youth 
and in adults 
. Furthermore, the importance of early life adversities distinguishes youth MDD from adult MDD 
Main psychological theories regarding depression, obsessive compulsive disorder, and anxiety disorders (general anxiety, phobia, separation anxiety, and panic disorder)
Despite the limitations cited previously, several speculations can be made to explain why placebo response rates are higher in juvenile MDD than in anxiety disorders. When entering a double-blind placebo-controlled trial, many aspects of the patient's psychosocial background are considered, since they may account for treatment outcome, compliance, and protocol acceptance. Whether intended or not, the clinician's intervention may aid in restoring self-esteem or narcissism in the depressed child or adolescent. Furthermore, the intervention may encourage openness to transference movements that may be intense at the first meeting, and provide a “positive mirror” 
. Indeed, the formation of a therapeutic alliance is essential to the child's participation in a research efficacy trial. The trial protocol with its frequent and regular meetings offers the child a unique opportunity to restore his feelings of self-esteem and confidence in the adult world, resulting in an unintentional psychotherapeutic dynamic irrespective of the orientation of the clinician. We hypothesize that this phenomenon may partially explain the higher placebo response in youth MDD as compared to other internalized disorders. Alternative hypotheses are also valid. First, in addition to more classical common factors (such as therapeutic relationship, a patient's expectation of help, and treatment rituals), Frank's proposal that all psychotherapies have the shared feature of reducing demoralization may also be claimed 
. Frank stated that all psychotherapies seek to change despair to hope, fear to courage, powerlessness to mastery, and demoralizing meanings to favorable ones. Youth with MDD may be more sensitive to support and interest as well as more demoralized than individuals with anxiety disorders; therefore, they may be more sensitive to this aspect of treatment. Second, the high placebo response rates found in child and adolescent depression can also be discussed in terms of the practical significance of clinical trials. Double-blind placebo-controlled trials are based on the assumption that drug effects and placebo effects are additive. The high placebo response rates in youth MDD that lead to small drug/placebo differences, have called into question the validity of the assumption of additivity. In this case, antidepressant drugs have substantial pharmacological effects that are either duplicated or masked by placebos 
. Alternative methods of clinical trials should be developed to test models other than additive ones. Third, it is possible that some children and adolescents included in the pharmaceutical trials were not depressed given the broad criteria used in many studies. Finally, we cannot exclude that differences in placebo arms between disorders may reflect differences in the probability of spontaneous improvement. Most data regarding the natural history of MDD, however, do not support this hypothesis as MDD in children and adolescents appears to be a chronic and disabling condition 
To summarize, MDD in children and adolescents appears to be more responsive to placebo conditions than do other internalized disorders, highlighting differential psychopathology. We hypothesize that a non-specific response, through an unintentional psychotherapeutic process, occurs in the placebo arms of double-blind placebo-control trials, and that this non-specific response is higher in child and adolescent MDD.