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Cited by 367Treatment of Major DepressionPsychotherapy Techniques and ApplicationsMental Health Treatment and Access

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

Open access
Zhou, Xinyu, Teng, Teng, Zhang, Yuqing, Del Giovane, Cinzia, Furukawa, Toshi A, Weisz, John R, Li, Xuemei, Cuijpers, Pim +13 more·2020·The Lancet Psychiatry
DOI 10.1016/s2215-0366(20)30137-1PMC PMC7303954
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Abstract

Background Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents.Methods We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841.Findings From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (-0·78, 95% CrI -1·55 to -0·01) and psychodynamic therapy (-1·14, -2·20 to -0·08), but not more effective than fluoxetine alone (-0·22, -0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from -1·73 to -0·51); and only interpersonal therapy was more effective than all psychological controls (-1·37 to -0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as "low" to "very low" in terms of confidence of evidence according to Confidence In Network Meta-Analysis.Interpretation Despite 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.Funding National Key Research and Development Program of China.

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Crossref · 10.1016/s2215-0366(20)30137-1

Cites

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Statistics

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Claims the paper makes

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  • Findingown data

    The update drew on 71 RCTs and 9510 young people with depressive disorders, allocated to 28 active treatments or four control arms.

    “This updated analysis is based on 71 RCTs, which included 9510 children and adolescents with depressive disorders randomly assigned to 28 active interventions or four control conditions.”
    Quote in the paperSubstantial claim
  • Findingnone given

    This work is the first broad systematic review and network meta-analysis of every eligible randomised trial that compared an active treatment-medication, psychotherapy, or both-with another active treatment or a control condition for short-term management of paediatric depressive disorders.

    “Our study provides the first comprehensive systematic review and network meta-analysis of all available RCTs, comparing any active interventions (antidepressant, psychotherapy, and their combination) with another or control conditions for the acute treatment of depressive disorders in children and adolescents.”
    Quote in the paperSubstantial claim
  • Findingreasoning

    High risk of bias in a study was linked to a lower dropout rate.

    “and that studies with high risk of bias were associated with a lower dropout rate.”
    Quote in the paperNot a substantial claim
  • Findingown data

    For suicidality, venlafaxine carried a higher risk of suicidal behaviour or ideation than pill placebo and ten other interventions in this paediatric depression network.

    “In terms of suicidality, our findings confirmed that venlafaxine is associated with an increased risk of suicidal behaviour or ideation compared with pill placebo and ten other interventions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The network meta-analysis satisfies the transitivity assumption, meaning the included comparisons are sufficiently similar in effect modifiers.
    • The authors state this as an assumption: A single common heterogeneity variance applies to all comparisons in the network.
    • The authors state this as an assumption: Uninformative prior distributions for treatment effects are appropriate for the network meta-analysis models.
  • Findingown data

    Nortriptyline was worse than most active interventions.

    “Nortriptyline was worse than most active interventions; however, the interpretation of this result was limited by the inconsistent loop of nortriptyline versus fluoxetine versus pill placebo.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 31
  • May combine two claims. 31

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    5051 (57.2%) of the sample were female.

    “5051 (57•2%) of the sample population were female.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CINeMA rated 9 (12.5%) of 72 efficacy comparisons as low confidence and 63 (87.5%) as very low; for acceptability, 1 (1.3%) was high, 3 (4.0%) moderate, 13 (17.3%) low, and 58 (77.3%) very low.

    “According to CINeMA, nine (12•5%) of 72 comparisons for the efficacy outcome were rated as low confidence of evidence and 63 (87•5%) as very low, and for the acceptability outcome, one (1•3%) was rated as high confidence of evidence, three (4•0%) as moderate, 13 (17•3%) as low, and 58 (77•3%) as very low (appendix pp 107-125).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Summary effect sizes were mostly medium to large and somewhat uncertain.

    “These summary effect sizes were mostly medium to large with some uncertainty, which might result from the small number of patients included, and wide credible intervals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Median acute treatment duration was 8 weeks (IQR 8-12).

    “The median duration of the acute treatment was 8 weeks (IQR 8-12).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among 9510 patients, 7179 (75.5%) had moderate-to-severe major depressive disorder; baseline severity averaged 58.5 (SD 10.1) on CDRS-R, 23.3 (SD 8.8) on CDI, or 24.7 (11.4) on BDI.

    “7179 (75•5%) of 9510 patients had moderateto severe major depressive disorder, with a mean reported baseline severity score on the Children's Depression Rating ScaleRevised of 58•5 (SD 10•1), Children's Depression Inventory of 23•3 (SD 8•8), or Beck Depression Inventory of 24•7 (11•4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Age ranged from 3 to 20 years (mean 14.0, SD 2.6); two studies included participants up to age 20 but were kept because most participants and the mean age were below 18.

    “The age range was from 3 years to 20 years (mean age 14•0 years, SD 2•6); two studies included participants up to 20 years of age, but were included, because the majority of participants and the mean age were younger than 18 years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Geographic distribution: 41 studies in North America, 12 in Europe, five in Asia, two in Australia, one in South America, seven crosscontinental, and three from other or unspecified regions.

    “41 (57•7%) studies were done in North America, 12 (16•9%) in Europe, five (7•0%) in Asia, two (2•8%) in Australia, and one (1•4%) in South America, seven (9•9%) trials were crosscontinental, and the remaining three (4•2%) were either from other regions or did not specify.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Ten (14.1%) of 71 studies randomized participants to three or more groups.

    “Participants were randomly assigned to three or more groups in ten (14•1%) of 71 studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Recruitment was restricted to outpatients in 41 (55.7%) of the 71 studies.

    “Only outpatients were recruited in 41 (55•7%) of 71 studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Randomization counts were 4081 to antidepressants, 1575 to psychotherapy, 553 to combination treatment, and 3301 to psychological control or pill placebo.

    “4081 participants were randomly assigned to anti depressants, 1575 to psychotherapy, 553 to a combination treatment, and 3301 to a psychological control or pill placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Interpersonal psychotherapy outperformed all psychological controls, but the evidence confidence was very low.

    “We also found that interpersonal psychotherapy was more efficacious than all psychological controls, but with very low confidence of evidence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The review identified 20,366 citations, retrieved 390 full texts, and included 71 RCTs with 9510 patients published between 1986 and 2018.

    “We identified 20 366 citations, retrieved the full text of 390 potentially eligible articles, and included 71 RCTs (9510 patients) published between 1986 and 2018 (figure 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Mean study sample size was 136, with a range of 10 to 529.

    “The mean study sample size was 136 participants and ranged from 10 to 529 (tables”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The network showed some global and local inconsistencies for efficacy, but few for acceptability.

    “Second, in the network, we found some global and local inconsistencies in efficacy outcomes, but few in acceptability outcomes”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Industry funding was present in 24 of 71 studies (33.8%).

    “companies funded 24 (33•8%) of 71 studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Combining fluoxetine with CBT outperformed CBT alone and psychodynamic therapy.

    “Fluoxetine plus CBT was more effective than CBT (SMDs -0•78, 95% CrI -1•55 to -0•01) and psychodynamic therapy (-1•14, -2•20 to -0•08)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Global incoherence testing revealed a significant difference between consistency and inconsistency models for efficacy, but not for acceptability.

    “The test of global incoherence showed a significant difference between the consistency and inconsistency models for efficacy (p<0•0001), but not for acceptability (p=0•5531; appendix p 74).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The network meta-analysis transitivity assumption holds across the various control conditions.

  • May combine two claims.

    Findingown data

    The estimated median heterogeneity variance was 0.49 for efficacy and 0.32 for acceptability.

    “The median heterogeneity variances were estimated at 0•49 (95% CrI 0•37-0•64) for efficacy and 0•32 (0•04-0•61) for acceptability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For efficacy, global I2 was 56%; for acceptability, it was 14%.

    “The global I² values were 56% for efficacy and 14% for acceptability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The original protocol was registered with PROSPERO (CRD42015020841), and protocol changes are listed in the appendix.

    “The appendix (p 39) lists the changes to the original protocol, which is registered with PROSPERO, number CRD42015020841.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The uncertainty may stem from the small number of patients and wide credible intervals.

    “which might result from the small number of patients included, and wide credible intervals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Confidence in the evidence for each network estimate was evaluated with CINeMA software.

    “We assessed the confidence of evidence contributing to each network estimate using the Confidence In Network MetaAnalysis (CINeMA) software.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Salanti, 2014, Evaluating the quality of evidence from a network meta-analysis, PLoS One source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Convergence was checked with trace plots and the Brooks-Gelman-Rubin statistic.

    “To ensure convergence, trace plots and the BrooksGelmanRubin statistic were assessed.24”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Brooks, 1998, General methods for monitoring convergence of iterative simulations, J Comput Graph Stat source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Earlier meta-analyses indicated that psychotherapies, particularly CBT and interpersonal psychotherapy, were more effective than psychological control conditions for child and adolescent depression.

    “especially cognitivebehavioural therapy (CBT) and interpersonal psychotherapy, appeared to be more effective compared with psychological controls in previous metaanalyses.7,8”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Zhou, 2015, Comparative efficacy and acceptability of psychotherapies for depression in children and adolescents: a systematic review and network meta-analysis, World Psychiatry source

      Not checked in the free run.

    • cites [8] Eckshtain, 2020, Meta-analysis: 13-year follow-up of psychotherapy effects on youth depression, J Am Acad Child Adolesc Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Missing continuous outcomes were handled with the last available follow-up value, and missing binary outcomes were handled under an intention-to-treat principle.

    “Missing continuous outcome data were analysed using the last available followup data, and missing dicho tomous outcome data were managed according to the intentiontotreat principle.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Risk of bias in included studies was assessed following the Cochrane Handbook for Systematic Reviews of Interventions.

    “We assessed the studies' risk of bias in accordance with the Cochrane Handbook for Systematic Reviews of Interventions.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Zhou, 2017, Comparative efficacy and acceptability of antidepressants, psychological interventions, and their combination for depressive disorder in children and adolescents: protocol for a network meta-analysis, BMJ Open source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Some antidepressants may raise the risk of suicidality.

    “Previous metaanalyses 10,11 have shown that anti depres sants, except for fluoxetine, do not offer a clear advantage over pill placebo for many individuals, and some antidepressants might increase risk of suicidality.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Cipriani, 2016, Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis, Lancet source

      Not checked in the free run.

    • cites [11] Vitiello, 2018, Twenty years of progress in paediatric psychopharmacology: accomplishments and unmet needs, Evid Based Ment Health source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This pattern may be explained by most psychotherapy trials being rated high risk of bias due to nonblinding and having lower dropout and baseline severity than pharmacological trials.

    “These findings might result from the fact that most psycho therapy trials, which were assessed as high risk of bias due to nonblinding of performance and personnel, had relatively lower dropout rates and baseline severity scores than the pharmacological trials (appendix pp 91-96).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Pre-specified sensitivity analyses for primary outcomes excluded trials with unpublished data, imputed data, fewer than 20 participants, inconsistent treatment durations or time points, and non-blinded assessment.

    “We did pre specified sensitivity analyses for primary outcomes by omitting trials with unpublished data, trials with imputed data, trials with sample sizes smaller than 20, trials with inconsistent treatment durations and selected time points, and trials with nonblinding assessment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    It was unclear whether combining an antidepressant with a psychological intervention was more beneficial than an antidepressant alone.

    “Whether the combination of antidepressant and psychological interventions is more beneficial than antidepressants alone remains unclear.13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Cox, 2012, Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents, Cochrane Database Syst Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Publication bias was assessed with comparison-adjusted funnel plots.

    “We used comparisonadjusted funnel plots to assess publi cation bias.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Chaimani, 2013, Graphical tools for network meta-analysis in STATA, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The difficulty of double-blinding psychotherapy trials compromises network transitivity and limits interpretation of the results.

    “which would affect the transitivity of the whole network and restricts the interpretation of these results.15”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Boutron, 2007, Reporting methods of blinding in randomized trials assessing nonpharmacological treatments, PLoS Med source

      Not checked in the free run.

    • The authors state this as an assumption: The network meta-analysis transitivity assumption holds across the various control conditions.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In adults with major depressive disorder, every antidepressant outperforms pill placebo in efficacy.

    “all antidepressants were more efficacious than pill placebo 27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Cipriani, 2018, Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis, Lancet source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Transitivity was examined by comparing the distributions of clinical and methodological effect modifiers-such as age, sex, baseline depression severity, and treatment duration-across treatment comparisons.

    “To assess transitivity, we compared the distribution of clinical and methodological variables (eg, age, sex, depressive severity at baseline, and treatment duration) that could act as effect modifiers across treatment com parisons.14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Zhou, 2017, Comparative efficacy and acceptability of antidepressants, psychological interventions, and their combination for depressive disorder in children and adolescents: protocol for a network meta-analysis, BMJ Open source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Prior meta-analyses found that, apart from fluoxetine, antidepressants did not clearly outperform pill placebo for many young patients.

    “Previous metaanalyses 10,11 have shown that anti depres sants, except for fluoxetine, do not offer a clear advantage over pill placebo for many individuals, and some antidepressants might increase risk of suicidality.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Cipriani, 2016, Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis, Lancet source

      Not checked in the free run.

    • cites [11] Vitiello, 2018, Twenty years of progress in paediatric psychopharmacology: accomplishments and unmet needs, Evid Based Ment Health source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Patients with subsyndromal depressive symptoms make up a substantial share of real-world clinical settings.

    “They do, however, form a substantial proportion of the patients seen in realworld, clinical settings.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Cheung, 2018, Guidelines for adolescent depression in primary care (GLAD-PC): part II. Treatment and ongoing management, Pediatrics source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Some comparisons had relatively low or high transitivity values, so their confidence was downgraded.

    “we found that some comparisons had relatively low or high values in the transitivity assessment; thus, we downgraded the confidence of these comparisons.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The authors tried to retrieve all unpublished information and contact study authors, but some unpublished studies may still be missing.

    “We did our best to retrieve all available unpublished information and contacted study authors for supple mentary data, but we cannot rule out the possibility that some unpublished studies are still missing.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] de Vries, 2019, Hiding negative trials by pooling them: a secondary analysis of pooled-trials publication bias in FDA-registered antidepressant trials, Psychol Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some adverse effects are expected in psychotherapy trials, including new symptoms and strains in the patient-therapist relationship, but few psychotherapy trials report data on adverse events and suicidality.

    “Some of the adverse effects would also be expected in psychotherapy trials, including the emergence of new symptoms and strains in the patienttherapist relationship, 43 however, few psychotherapy trials report data on adverse events and suicidality.44”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Berk, 2009, The elephant on the couch: side-effects of psychotherapy, Aust N Z J Psychiatry source

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    • cites [44] Linden, 2014, Definition, assessment and rate of psychotherapy side effects, World Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    Published data were checked against protocols or trial register reports, but main outcomes could not be examined at the individual patient level.

    “Although we have checked the published data with their protocols or trial register reports, we were not able to investigate these main outcomes at the individual patient level.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The data from included trials other than Restoring Study 329 are accurate.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Different doses of antidepressants might produce different treatment effects.

    “Sixth, antidepressants with different doses might produce different treatment effects.41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Berney, 2005, Dose-response relationship of recent antidepressants in the short-term treatment of depression, Dialogues Clin Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Unpublished data were obtained for 11 of the 71 included trials (15.5%).

    “We retrieved unpublished information for 11 (15•5%) of the 71 included trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Observational studies were excluded to reduce heterogeneity, but they can provide more real-world evidence on antidepressant effectiveness.

    “We excluded obser vational studies to decrease the hetero geneity in the network metaanalysis; however, obser vational studies can provide more information about realworld evidence on antidepressant effectiveness in the studied population group.46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Kernot, 2019, One step closer to personalised prescribing of antidepressants: using real-world data together with patients and clinicians' preferences, Evid Based Ment Health source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Antidepressants were included without therapeutic dose ranges, but potential dose effects should be considered.

    “Although we included antidepressants without therapeutic dose ranges, we should consider the potential dose effects in this review.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    A hierarchy of informants for depressive rating scales was established before the study, which could reduce outcome bias.

    “However, before the study, we established a hierarchy of informants of depressive rating scales, which could reduce this type of outcome bias.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Few studies addressed relapse prevention, and some adverse effects and psychotherapy responses occur over a prolonged period, so positive results should be interpreted cautiously.

    “Relatively few studies addressed the issue of preventing relapse of depression in children and adolescents, and some of the adverse effects of anti depressants and response to psychotherapy occur over a prolonged period, meaning that positive results need to be interpreted with caution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    In this network meta-analysis, few trials compared the same treatments, and the transitivity assumption across various control conditions was understated.

    “In this network metaanalysis, a small number of trials compared the same treatments, and the assumption of transitivity over various control conditions was under stated.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The network meta-analysis transitivity assumption holds across the various control conditions.

  • May combine two claims.

    Study design and conductown data

    Egger's test indicated no publication bias for most outcomes, but funnel plots showed potential asymmetry.

    “Fourth, despite the Egger's test showing no publication bias for most outcomes, we found some potential asymmetry of funnel plots in this network metaanalysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Despite its limitations, this network meta-analysis is the most comprehensive analysis of the available evidence.

    “Despite these limitations, the findings from this network metaanalysis represent the most comprehensive analysis of the available evidence.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The network meta-analysis transitivity assumption holds across the various control conditions.
    • Rests on an assumption: The data from included trials other than Restoring Study 329 are accurate.

  • May combine two claims.

    Study design and conductown data

    Risk of bias was high in 32 trials (45.1%), moderate in 32 (45.1%), and low in 7 (9.9%).

    “32 trials (45•1%) were rated high on risk of bias, 32 (45•1%) as moderate, and seven (9•9%) as low (appendix pp 49-53).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Data from Restoring Study 329 were used, but the accuracy of data from other included trials could not be assured.

    “We have selected the data from Restoring Study 329 for this review, but we could not assure the accuracy of the data in the other included trials.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The data from included trials other than Restoring Study 329 are accurate.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Using different outcomes from the same trials can introduce pharmaceutical marketing bias.

    “Additionally, different outcomes from the same trials can be a source of pharmaceutical marketing bias.35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Lexchin, 2003, Pharmaceutical industry sponsorship and research outcome and quality: systematic review, BMJ source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Trials shorter than 4 weeks were excluded, which could reduce the effect in the final analysis.

    “In this review, we have excluded trials with treatment duration of less than 4 weeks, which could reduce the effect for the final analysis.”
    Quote in the paperSubstantial claim
53 of 53

  • The paper relies on this without support.

    The existing evidence does not clearly establish that psychotherapy is more effective and safer than antidepressants for child and adolescent depressive disorder.

    “However, the evidence base has not been well established that psychotherapy is more effective and safer than antidepressants in the treatment of child and adolescent depressive disorder, and whether the combination of antidepressants and psychotherapies is more beneficial than antidepressants alone remains unknown.”

  • The paper relies on this without support.

    The network meta-analysis satisfies the transitivity assumption, meaning the included comparisons are sufficiently similar in effect modifiers.

    “To assess transitivity, we compared the distribution of clinical and methodological variables (eg, age, sex, depressive severity at baseline, and treatment duration) that could act as effect modifiers across treatment com parisons.14”

  • The authors state this as an assumption.

    A single common heterogeneity variance applies to all comparisons in the network.

    “A common estimate for the heterogeneity variance was assumed for all comparisons in the entire network, and we assessed the presence of statistical heterogeneity using the magnitude of the heterogeneity variance parameter (τ²) and total I² statistic.”

  • The authors state this as an assumption.

    Uninformative prior distributions for treatment effects are appropriate for the network meta-analysis models.

    “We fitted all models of network metaanalysis with uninformative previous distributions for the treatment effects.”

  • The authors state this as an assumption.

    The network meta-analysis transitivity assumption holds across the various control conditions.

    “the assumption of transitivity over various control conditions was under stated.”
    “in order to support transitivity assumption in the network”

  • The paper relies on this without support.

    The data from included trials other than Restoring Study 329 are accurate.

    “we could not assure the accuracy of the data in the other included trials.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Treatment options for a child or adolescent with IBD who is diagnosed with anxiety or depression can include psychotherapy such as CBT and medications like SSRIs.

    “Treatment options for a child or adolescent with IBD who is diagnosed with anxiety or depression can include psychotherapy such as CBT and medications like selective serotonin reuptake inhibitors (SSRIs) (94).”

    From The 2023 Impact of Inflammatory Bowel Disease in Canada: Mental Health and Inflammatory Bowel Disease (2023) · cites this paper as [94]

    The Introduction describes CBT and SSRIs as treatments studied for depressive disorder in children and adolescents, and the ‘Implications of all the available evidence’ section identifies fluoxetine, alone or with CBT, as a possible choice for moderate-to-severe depression. The paper does not establish these options specifically for children or adolescents with IBD; it mentions anxiety only in comparisons with depression research. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The risk of recurrence after the first two episodes of depression is substantially less than after the third and subsequent episodes.

    “In addition, the risk of recurrence after the first two episodes is substantially less than after the third and subsequent episodes, indicating an early potential for recovery on which interventions should capitalise. 488”

    From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [488]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A selected outcome falls outside the stated time window

    Minor

    The methods say that outcomes unavailable at eight weeks were taken from weeks 4-16, but the trial table lists a selected timepoint of 36 weeks.

  • Outpatient-only trial percentage is incorrect

    Minor

    The stated 41 outpatient-only studies represent 57.7% of 71 studies, not 55.7%.

    Reported 55.7 · recomputed 57.746479

2 of 2

Cites

Flagged first, then by citations

Cited by

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Related

Authors
Zhou, X., Teng, T., Zhang, Y., Del Giovane, C., Furukawa, T. A., Weisz, J. R., Li, X., Cuijpers, P., Coghill, D., Xiang, Y., Hetrick, S. E., Leucht, S., Qin, M., Barth, J., Ravindran, A. V., Yang, L., Curry, J., Fan, L., Silva, S. G., Cipriani, A., & Xie, P.
Affiliations
  • The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
  • Second Affiliated Hospital of Chongqing Medical University (CN)
  • Kyoto University (JP)
  • Harvard University (US)
  • Amsterdam Public Health (NL)
  • The University of Melbourne (AU)
  • University of Auckland (NZ)
  • Technical University of Munich (DE)
  • University of Zurich (CH)
  • Centre for Addiction and Mental Health (CA)
  • Duke University (US)
  • Oxford Health NHS Foundation Trust (GB)
Corresponding author
Xie, Peng
ORCID
Venue
The Lancet Psychiatry
Publisher
Elsevier BV
Published
2020-07
Volume
7
Issue
7
Pages
581-601
ISSN
2215-0366 (ISSN-L)
DOI
10.1016/s2215-0366(20)30137-1
PMC
PMC7303954
OpenAlex
W2959400609
Cited by
367
References
49
Citations by year
2026: 62 · 2025: 66 · 2024: 60 · 2023: 65 · 2022: 61 · 2021: 43 · 2020: 9
FWCI
5.86
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Psychiatry (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
  • VU Research Portal (publishedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • ResearchSpace (University of Auckland) (submittedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • NIHR Oxford Biomedical Research Centre (BRC-1215-20005)
  • NIHR Clinical Research Network Thames Valley and South Midlands
  • College of Agricultural and Life Sciences
  • Janssen Canada
  • Royal Society
  • Angelini Pharma
  • Faculty of Medical and Health Sciences, University of Auckland
  • Fondazione Cariplo
  • National Institute for Health Research (RP-2017-08-ST2-006)
  • National Natural Science Foundation of China (81701342, 81873800)
  • National Basic Research Program of China (2017YFA0505700)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
  • Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
Keywords
antidepressants, psychotherapy, childhood depression, adolescent depression, depressive disorders, fluoxetine, cognitive behavioral therapy, psychodynamic psychotherapy, combination therapy, antidepressant efficacy, treatment acceptability, treatment discontinuation, placebo response, comparative treatment effectiveness, network meta-analysis ranking, treatment-resistant depression, bipolar disorder, psychotic depression, children and adolescents
MeSH terms
Adolescent, Antidepressive Agents, Child, Depressive Disorder, Humans, Psychotherapy, Randomized Controlled Trials as Topic, Evidence-Based Medicine

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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