Treatment of depression in children and adolescents

On the basis of their meta-analytic review, Zhou and colleagues1Zhou X Teng T Zhang Y et al.Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis.Lancet Psychiatry. 2020; 7: 581-601Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar conclude that "fluoxetine (alone or in combination with CBT [cognitive behavioural therapy]) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents." However, the meta-analysis has several statistical and methodological flaws that belie this and other conclusions. First, the authors' own data indicate that the conclusions about the superiority of fluoxetine are unjustifiable. Almost none of the comparisons between fluoxetine or fluoxetine plus CBT and other treatments are significant. Furthermore, the confidence intervals of most interventions versus pill placebo overlap with that of fluoxetine and fluoxetine plus CBT, indicating that none should be considered superior to any other. Second, the meta-analysis gives false impressions of the precision of individual effects. Take, for example, the conclusion regarding the relative inefficacy of psychodynamic therapy compared with fluoxetine plus CBT (d=1·14). A total of two trials examined psychodynamic therapy.2Goodyer IM Reynolds S Barrett B et al.Cognitive behavioural therapy and short-term psychoanalytical psychotherapy versus a brief psychosocial intervention in adolescents with unipolar major depressive disorder (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled superiori.Lancet Psychiatry. 2016; 4: 109-119Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 3Trowell J Joffe I Campbell J et al.Childhood depression: a place for psychotherapy. An outcome study comparing individual psychodynamic psychotherapy and family therapy.Eur Child Adolesc Psychiatry. 2007; 16: 157-167Crossref PubMed Scopus (129) Google Scholar To conclude from such a small number of studies and number of patients that psychodynamic therapy shows inferior outcomes to fluoxetine plus CBT is an example of a well-known methodological problem—ie, the reductionistic fallacy (inappropriately drawing group-level conclusions from individual-level sample data). Finally, a third problem with the network meta-analysis presented by Zhou and colleauges1Zhou X Teng T Zhang Y et al.Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis.Lancet Psychiatry. 2020; 7: 581-601Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar involves the assumption of transitivity (ie, that studies share similar characteristics relevant to estimating an effect size, permitting the comparison of treatments that have never been directly contrasted).4Keefe JR Heightened risk of false positives in a network meta-analysis of social anxiety.Lancet Psychiatry. 2015; 2: 292-293Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar Most psychological treatments in the meta-analysis have never been compared with pill placebo or fluoxetine, meaning that establishing transitivity is vital. In the example of psychodynamic therapy, the authors suggest that psychodynamic therapy is non-significantly inferior to pill placebo (d=–0·41), even though in the two included trials, psychodynamic therapy performed comparably to family therapy (d=–0·03 vs placebo) and CBT (d=0·05); the direct findings from the individual trials appear to contradict the results drawn from the indirect evidence of the network analyses. Although the authors argue that inconsistency was within tolerated bounds, consistency tests are very underpowered under conditions like the present analysis;5Veroniki AA Mavridis D Higgins JPT Salanti G Characteristics of a loop of evidence that affect detection and estimation of inconsistency: a simulation study.BMC Med Res Methodol. 2014; 14: 12Crossref Scopus (42) Google Scholar the assessed inconsistency is likely an underestimate. Consistency is also impossible to estimate if there are no direct comparisons. The authors' conclusions could have the unfortunate consequence of patients not receiving other treatments that have shown efficacy, and not just fluoxetine. Access to effective evidence-based mental health care is challenging enough, and recommending that clinicians provide one treatment over others, when those other treatments are just as useful, only exacerbates the situation. MJD has received remuneration for doing webinars on evidence-based psychodynamic therapy, as well as proceeds from the sales of the recorded webinar. The authors declare no other known potential competing interests. Treatment of depression in children and adolescentsIn their network meta-analysis of treatments for children and adolescents with depression, Xinyu Zhou and colleagues1 suggested that fluoxetine with or without cognitive-behavioural therapy (CBT) might be the best choice. This conclusion, however, seems to be questionable due to methodological problems of their meta-analysis. In network meta-analyses, valid conclusions from indirect comparisons can only be drawn if the assumptions of transitivity and consistency hold.2,3 Full-Text PDF Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysisDespite the scarcity of high-quality evidence, fluoxetine (alone or in combination with CBT) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents. However, the effects of these interventions might vary between individuals, so patients, carers, and clinicians should carefully balance the risk-benefit profile of efficacy, acceptability, and suicide risk of all active interventions in young patients with depression on a case-by-case basis. Full-Text PDF Open AccessTreatment of depression in children and adolescents – Authors' replyFalk Leichsenring and colleagues raise issues relating to the transitivity, inconsistency, and heterogeneity of our network meta-analysis.1 Actually, these problems are common and difficult to avoid in a network meta-analysis, especially in the presence of pharmacological and non-pharmacological treatments, and thoughtful discussion of the potential biases can maximise transparency and avoid errors in its interpretation.2 In our network meta-analysis, stringent inclusion criteria were used in order to limit violation of the transitivity assumption, and then multiple subgroup and meta-regression analyses were pre-planned and explore the potential effect modifiers (eg, sex ratio, mean age, and sponsorship). Full-Text PDF