Treatment of depression in children and adolescents – Authors' reply

Falk Leichsenring and colleagues raise issues relating to the transitivity, inconsistency, and heterogeneity of our network meta-analysis.1Zhou 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 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.2Del Giovane C Cortese S Cipriani A Combining pharmacological and nonpharmacological interventions in network meta-analysis in psychiatry.JAMA Psychiatry. 2019; 76: 867-868Crossref PubMed Scopus (6) Google Scholar 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). The results of inconsistency and heterogeneity tests were all reported and certainty of evidence was assessed using Confidence In Network Meta-Analysis. We noted that “the quality of evidence is low” and stressed that our results should be interpreted with caution in the conclusion.1Zhou 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 Interpretations of network meta-analyses mainly depend on the effect estimates and their 95% CIs between treatments, rather than the surface under the cumulative ranking curve, which is relatively imprecise, inattentive to the quality of evidence, and not necessarily representative of the true differences between treatments when the differences are small.3Wang Z Carter RE Ranking of the most effective treatments for cardiovascular disease using SUCRA: Is it as sweet as it appears?.Eur J Prev Cardiol. 2018; 25: 842-843Crossref PubMed Scopus (7) Google Scholar For example, fluoxetine plus cognitive-behavioural therapy (CBT) ranks 12th, and CBT ranks 5th for suicidality, although the differences between these two treatments were not significant (0·88, 95% CI 0·21–2·36), and the non-significant result was considered in the interpretation. We agree with Leichsenring and colleagues that dropouts due to adverse events should be examined to take harm into account in the rankings. However, to our knowledge, few psychotherapy trials report data on adverse events,4Linden M Schermuly-Haupt ML Definition, assessment and rate of psychotherapy side effects.World Psychiatry. 2014; 13: 306-309Crossref PubMed Scopus (76) Google Scholar so extant trials provide too little data for safety outcome analysis. Moreover, relatively few studies have reported follow-up effects of treatments, and our findings should certainly be interpreted with caution in regard to longer-term effects (please note that the title of our Article referred to “acute treatment”).1Zhou 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 All these issues related to adverse events and the follow-up effects have been already discussed in the limitations section of our Article.We agree with Marc Diener and colleagues that only a few of the comparisons between fluoxetine or fluoxetine plus CBT and other treatments were significant in our network meta-analysis, including the finding that fluoxetine plus CBT was superior to CBT and psychodynamic therapy. However, fluoxetine or fluoxetine plus CBT were recommended due to the finding that they were significantly more effective than pill placebo or psychological controls (standardised mean difference ranging from –1·73 to –0·51), rather than significant results in relation to other treatments. The small number of trials comparing specific treatments (eg, psychodynamic therapy, problem-solving therapy, and clomipramine) was a limitation of our network meta-analysis, requiring more reliance on the indirect comparisons. There are more challenges in doing paediatric trials than adult trials, because of the paucity of funding and the unique ethical concerns that arise in research with children.5Joseph PD Craig JC Caldwell PH Clinical trials in children.Br J Clin Pharmacol. 2015; 79: 357-369Crossref PubMed Scopus (150) Google Scholar Transitivity is one of the three assumptions on which network meta-analysis rests, and trials in our network meta-analysis were included following our predefined inclusion criteria to ensure reasonably similar characteristics of included patients. Our network meta-analysis is based on the best currently available evidence. It might not be wise to discredit the currently available evidence in the name of non-existent, more perfect evidence. It is our professional obligation to present the totality of evidence, with due caveats, first to provide duly moderated judicious advice for colleagues and patients, and second to point out areas in which stronger evidence is needed to increase confidence. In our network meta-analysis, the available evidence on average favoured fluoxetine (alone or in combination with CBT) for acute treatment of moderate-to-severe depressive disorder in children and adolescents; however, the potential efficacy of other pharmacological and non-pharmacological treatments warrants close attention in future studies. Having access to anonymised participant-level data from randomised controlled trials would allow us to do a personalised analysis and produce results that are easily transferrable to the individual patient.6Tomlinson A Furukawa TA Efthimiou O et al.Personalise antidepressant treatment for unipolar depression combining individual choices, risks and big data (PETRUSHKA): rationale and protocol.Evid Based Ment Health. 2020; 23: 52-56Crossref PubMed Scopus (21) Google Scholar XZ reports travel and accommodation expenses from the Chinese Society of Psychiatry for lectures delivered for the Chinese Society of Psychiatry, outside the submitted work. TAF reports grants and personal fees from Mitsubishi-Tanabe, personal fees from MSD, and personal fees from Shionogi, outside the submitted work. In addition, TAF has a pending patent (2018-177688) concerning smartphone cognitive-behavioural therapy apps, and intellectual properties for Kokoro-app licensed to Tanabe-Mitsubishi. AC has received research and consultancy fees from the Italian Network for Paediatric Trials, from the CARIPLO Foundation, and from the Angelini Pharma, and is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration, and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. PX reports speaker's honoraria from Janssen, outside the submitted work. All other authors declare no 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 Treatment of depression in children and adolescentsOn the basis of their meta-analytic review, Zhou and colleagues1 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. 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 Access