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Meta-Analysis
. 2021 May 24;5(5):CD013674.
doi: 10.1002/14651858.CD013674.pub2.

New generation antidepressants for depression in children and adolescents: a network meta-analysis

Sarah E Hetrick  1   2 , Joanne E McKenzie  3 , Alan P Bailey  4   5 , Vartika Sharma  1   2 , Carl I Moller  4   5 , Paul B Badcock  4   5   6 , Georgina R Cox  7 , Sally N Merry  8 , Nicholas Meader  9   10
Affiliations
Meta-Analysis

New generation antidepressants for depression in children and adolescents: a network meta-analysis

Sarah E Hetrick et al. Cochrane Database Syst Rev. .

Abstract

Background: Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.

Objectives: To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes.

Search methods: We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020.

Selection criteria: Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs).

Data collection and analysis: Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results.

Main results: Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants.

Authors' conclusions: Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.

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Conflict of interest statement

SH: is a PI on the YoDA‐C study — a trial of CBT and fluoxetine versus CBT and placebo. She is the Joint Co‐ordinating Editor of the Cochrane Common Mental Disorders Group. She is funded by the Auckland Medical Research Foundation and CureKids. JM: no conflicts of interest AB: no conflicts of interest VS: no conflicts of interest CM: no conflicts of interest PB: no conflicts of interest GC: no conflicts of interest SM: led the development of SPARX, a computerised intervention for depression in young people. In the event of successful commercialisation of SPARX, Dr Merry would receive a portion of the profits. NM: is the Deputy Co‐ordinating Editor of the Cochrane Common Mental Disorders Group.

Figures

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Dropouts from each trial (by treatment arm where available)
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Comparison‐adjusted funnel plot individual antidepressants for clinician‐rated depression symptoms (CDRS‐R)
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Comparison‐adjusted funnel plot antidepressant classes for clinician‐rated depression symptoms (CDRS‐R)
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Comparison‐adjusted funnel plot individual antidepressants for suicide‐related outcomes
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Network plot comparing individual antidepressants on depression symptom severity (clinician‐rated) using the Children's Depression Rating Scale (CDRS‐R). Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot effectiveness of individual antidepressants versus placebo CDRS‐R depression scale (ordered by ranking)
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Forest plot on the effectiveness of individual antidepressants on CDRS‐R (sensitivity analysis removing studies at high risk of bias)
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Network plot comparing individual antidepressants on remission or response as defined by trialists. Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot comparing individual antidepressants with placebo on remission/response (ordered by ranking)
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Network plot of individual antidepressants for self‐rated depression. Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot comparing individual antidepressants with placebo for self‐rated depression (CDI)
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Network plot of individual antidepressants on functioning (C‐GAS). Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot comparing individual antidepressants with placebo on the CGAS (sorted by P value)
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Network plot comparing individual antidepressants on suicide‐related outcomes. Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot comparing individual antidepressants with placebo for suicide related outcomes (ordered by ranking)
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Forest plot comparing effectiveness of individual antidepressants with placebo on suicide‐related outcomes (studies at high risk of bias removed)
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Network plot of individual antidepressants for overall adverse outcomes. Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot comparing individual antidepressants versus placebo on overall adverse outcomes
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Network plot comparing antidepressants classes on depression severity (CDRS‐R). Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot effectiveness of antidepressant classes versus placebo CDRS‐R depression scale
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Forest plot comparing effectiveness of antidepressant classes with placebo on CDRS‐R (studies at high risk of bias removed)
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Network plot comparing antidepressants classes for remission/response. Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
26
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Forest plot effectiveness of antidepressant classes versus placebo for remission/response (ordered by ranking)
27
27
Network plot comparing antidepressant classes for suicide‐related outcomes. Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
28
28
Forest plot effectiveness of antidepressant classes versus placebo for suicide related outcomes (ordered by ranking)
29
29
Comparison‐adjusted funnel plot antidepressant classes for suicide‐related outcomes
30
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Forest plot comparing effectiveness of antidepressant classes on suicide‐related behaviour (removing studies at high risk of bias)
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Network plot comparing antidepressants classes on overall adverse outcomes. Nodes are weighted by number of studies and the width of the edges are weighted by the inverse of the variance.
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Forest plot comparing effectiveness of antidepressant classes on overall adverse outcomes
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Wagner 2004 {published data only}
    1. CIT-MD-20. A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of citalopram in children and adolescent outpatients diagnosed with major depressive disorders (MDD) [CIT-MD-18]. Forest Clinical Trial Registry (www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/... ) 2005 (accessed 24 November 2011). [3331177]
    1. Medicines and Healthcare Products Regulatory Agency (MHRA). Citalopram Study 1 ID# CIT-MD-18. medicines.mhra.gov.uk (accessed 20 June 2004). [3331178]
    1. Wagner KD, Robb AS, Findling R, Tiseo P. Citalopram is effective in the treatment of major depressive disorder in children and adolescents: results of a placebo-controlled trial. International Journal of Neuropsychopharmacology 2002;5(Suppl 1):161. [3331179]
    1. Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. American Journal of Psychiatry 2004;161:1079-83. [3331180] - PubMed
    1. Wagner KD, Robb AS, Findling RL, Jin J, Tiseo PJ. Efficacy of citalopram in the treatment of MDD in children and adolescents [Abstract NR328]. In: 155th Annual Meeting of the American Psychiatric Association: New Research Program and Abstracts; 2002 May 18-23; Philadelpheia, PA, USA. 2002:90. [3331181]
Wagner 2006 {published data only}
    1. Forest LL. Forest announces results of recently completed Lexapro pediatric depression clinical trial. healthyplace.com/Communities/Depression/news/children_antidepressants_le... OR frx.com/ (accessed October 2004). [3331183]
    1. Wagner KD, Jonas J, Findling RL, Ventura D, Saikali K. A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of pediatric depression. Journal of the American Academy of Child and Adolescent Psychiatry 2006;45(3):280-8. [3331184] - PubMed
Wagner Trial 1 {published data only}
    1. Pfizer PI. Study A050100. A multicenter 10-week randomized double-blind placebo-controlled flexible dose outpatient study of sertraline in children and adolescents with major depressive disorder. clinicalstudyresults.org/documents/company-study_98_0.pdf 2004 (accessed 24 November 2011). [3331186]
Wagner Trial 1 & 2 (2003) {published data only}
    1. Medicines and Healthcare products Regulatory Agency (MHRA). Sertraline Study 1 ID#1001. medicines.mhra.gov.uk (accessed 20 June 2004). [3331188]
    1. Medicines and Healthcare products Regulatory Agency (MHRA). Sertraline Study 2 ID # 1017. medicines.mhra.gov.uk (accessed 20 June 2004). [3331189]
    1. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. JAMA 2003;290(8):1033-41. [3331190] - PubMed
    1. Wagner KD, Wohlberg C. Efficacy and safety of sertraline for treatment of pediatric major depressive disorder [Abstract NR327]. In: 155th Annual Meeting of the American Psychiatric Association; 2002 May 18-23; Philadelphia, PA. 2002. [3331191]
    1. Wagner KD, Wohlberg CJ, Yang R. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: Reply. JAMA 2004;291(1):42. [3331192] - PubMed
Wagner Trial 2 {published data only}
    1. Pfizer PI. Study A0501017A. Multicenter 10-week randomized double-blind placebo-controlled flexible dose outpatient study of sertraline in children and adolescents with major depressive disorder. clinicalstudyresults.org/documents/company-study_1981_0.pdf 2004 (accessed 24 November 2011). [3331194]
Weihs 2018 {published data only}
    1. NCT01372150. A study of DVS SR in treatment of children and adolescent outpatients with MDD. clinicaltrials.gov/show/NCT01372150 (first received 13 June 2011).
    1. Weihs KL, Murphy W, Abbas R, Chiles D, England RD, Ramaker S, et al. Desvenlafaxine versus placebo in a fluoxetine-referenced study of children and adolescents with major depressive disorder. Journal of Child and Adolescent Psychopharmacology 2018;28(1):36-46. [DOI: 10.1089/cap.2017.0100] - DOI - PMC - PubMed
    1. Weihs KL, Wajsbrot DB, Chiles D, Ramaker S, Chappell P. Letter to the editor: Re: "desvenlafaxine versus placebo in a fluoxetine-referenced study of children and adolescents with major depressive disorder: design, definitions, and ongoing challenges for child and adolescent psychopharmacology research" (Strawn JR, Croarkin PE, Journal of Child & Adolesent Psychopharmacoly 2018;28:(5)363). Journal of Child and Adolescent Psychopharmacology 2019;29(3):245-6. [DOI: 10.1089/cap.2018.0163] - DOI - PubMed

References to studies excluded from this review

Atkinson 2018 extension phase {published data only}
    1. Atkinson S, Thurman L, Ramaker S, Buckley G, Jones SR, England R, et al. Safety, tolerability, and efficacy of desvenlafaxine in children and adolescents with major depressive disorder: results from two open-label extension trials. CNS Spectrums 2019;24(5):496-506. - PubMed
Braconnier 2003 {published data only}
    1. Braconnier A, Coent R, Cohen D. Paroxetine versus clomipramine in adolescents with severe major depression: a double blind, randomized, multicentre trial. Journal of the American Academy of Child and Adolescent Psychiatry 2003;42(1):22-9. [3331196] - PubMed
Cheung 2016 {published data only}
    1. Cheung A, Levitt A, Cheng M, Santor D, Kutcher S, Dubo E, et al. A pilot study of citalopram treatment in preventing relapse of depressive episode after acute treatment. Journal de L'academie Canadienne de Psychiatrie de L'enfant ET de L'adolescent [Journal of the Canadian Academy of Child and Adolescent Psychiatry] 2016;25(1):11-16. - PMC - PubMed
Cornelius 2009 {published data only}
    1. Cornelius JR, Bukstein OG, Wood DS, Kirisci L, Douaihy A, Clark DB. Double-blind placebo-controlled trial of fluoxetine in adolescents with comorbid major depression and an alcohol use disorder. Addictive Behaviors 2009;34(10):905-9. [3331198] - PMC - PubMed
    1. Cornelius JR, Clark DB, Bukstein OG, Salloum IM, Matta J, Wood DS. Alcohol use but not cannabis use reported to contribute to depression in treatment trial of comorbid adolescents. In: Proceedings of the 68th Annual Scientific Meeting of the College on Problems of Drug Dependence; June 17-22 2006. Scottsdale, Arizona, USA, 2006. [3331199]
    1. NCT00027378. Pharmacological Intervention Project (Fluoxetine). clinicaltrials.gov/show/NCT00027378 (first received 1 December 2001).
Cornelius 2010 {published data only}
    1. Cornelius JR, Bukstein OG, Douaihy AB, Clark DB, Chung TA, Daley DC, et al. Double-blind fluoxetine trial in comorbid MDD-CUD youth and young adults. Drug and Alcohol Dependence 2010;112(1-2):39-45. [3331201] - PMC - PubMed
    1. Cornelius JR, Clark DB, Bukstein OG, Salloum IM, Matta J, Wood DS. Alcohol use but not cannabis use reported to contribute to depression in treatment trial of comorbid adolescents. In: Proceedings of the 68th Annual Scientific Meeting of the College on Problems of Drug Dependence; June 17-22. Scottsdale, Arizona, USA, 2006. [3331202]
Cosgrove 1994 {published data only}
    1. Cosgrove PVF. Fluvoxamine in the treatment of depressive illness in children and adolescents. Journal of Psychopharmacology 1994;8(2):118-23. [3331204] - PubMed
Emslie 2008 discontinuation phase {published data only}
    1. Emslie GJ. Predictors and moderators of relapse in depressed youth. Neuropsychiatrie de L'enfance et de L'adolescence 2012;60(5 suppl. 1):S168.
ePOD‐SSRI {published data only}
    1. Bottelier MA, Schrantee AGM, Wingen GA, Ruhe HG, Reneman L. Treatment with fluoxetine in adolescents may aggravate emotional dysregulation: A power analysis for future studies. European Neuropsychopharmacology 2015;25:S461-2.
Findling 2009 {published data only}
    1. Findling RL, Pagano ME, McNamara NK, Stansbrey RJ, Faber JE, Lingler J, et al. The short-term safety and efficacy of fluoxetine in depressed adolescents with alcohol and cannabis use disorders: a pilot randomized placebo-controlled trial. Child and Adolescent Psychiatry and Mental Health 2009;3(1):11. [3331206] - PMC - PubMed
Henkel 2010 {published data only}
    1. Henkel V, Mergl R, Allgaier Ak, Hautzinger M, Kohnen R, Coyne Jc, et al. Treatment of atypical depression: post-hoc analysis of a randomized controlled study testing the efficacy of sertraline and cognitive behavioural therapy in mildly depressed outpatients. European Psychiatry : The Journal of the Association of European Psychiatrists 2010;25(8):491-8. - PubMed
JPRN‐UMIN000016192 {published data only}
    1. JPRN-UMIN000016192. Investigation for the effect of duloxetine on adolescent depression; Ver. 2. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018778 (first received 4 August 2011).
Kennard 2018 {published data only}
    1. Kennard BD, Mayes TL, Chahal Z, Nakonezny PA, Moorehead A, Emslie G J. Predictors and moderators of relapse in children and adolescents with major depressive disorder. Journal of Clinical Psychiatry 2018;79(2):5m10330. [DOI: 10.4088/JCP.15m10330] - DOI - PMC - PubMed
Kennedy 2014 {published data only}
    1. Kennedy S H, Avedisova A, Belaidi C, Picarel-Blanchot F, Bodinat C. Sustained efficacy of agomelatine 10 mg, 25 mg, and 25-50 mg on depressive symptoms and functional outcomes in patients with major depressive disorder. A placebo-controlled study over 6 months. European Neuropsychopharmacology 2016;26(2):378-89. - PubMed
    1. Kennedy S H, Avedisova A, Gimenez-Montesinos N, Belaidi C, de Bodinat C - Agomelatine Study Group. A placebo-controlled study of three agomelatine dose regimens (10 mg, 25 mg, 25-50 mg) in patients with major depressive disorder. European Neuropsychopharmacology 2014;24(4):553-63. - PubMed
Liebowitz 2008 {published data only}
    1. Liebowitz MR, Manley AL, Padmanabhan SK, Ganguly R, Tummala R, Tourian KA. Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder. Current Medical Research and Opinion 2008;24(7):1877-90. - PubMed
Mandoki 1997 {published data only}
    1. Mandoki MW, Tappia MR, Tapia MA, Sumner GS, Parker JL. Veanlafaxine in the treatment of children and adolescents with major depression. Psychopharmacology Bulletin 1997;33(1):149-54. [3331208] - PubMed
NCT00005015 {published data only}
    1. NCT00005015. Fluoxetine for the treatment of major depression in youth with bipolar disorder [Study numbers N01-MH-70008A; N01-MH-70008]. clinicaltrials.gov/ct2/show/NCT00005015 (first received 3 April 2000). [3331210]
NCT00249886 {published data only}
    1. ISRCTN42386710. A double blind placebo controlled discontinuation of citalopram in adolescents with major depression. isrctn.com/ISRCTN42386710 (first received 5 September 2005).
NCT00508859 {published data only}
    1. NCT00508859. Maintenance Study for Adolescent Depression. ClinicalTrials.gov/show/NCT00508859 (first received 30 July 2007).
NCT02871297 {published data only}
    1. EUCTR2008-005356-25-LV. A study to evaluate the long-term safety and tolerability of a product named vortioxetine (used in depression) in children and adolescents. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:200... (first received 6 April 2016).
NCT03436173 {published data only}
    1. NCT03436173. OxSYPan: Oxford study with young people on antidepressants. clinicaltrials.gov/show/nct03436173 (first received 19 February 2018).
Riggs 2007 {published data only}
    1. Riggs PD, Lohman M, Davies R, Mikulich-Gilbertson S, Laudenslager M, Klein C. Randomized controlled trial of fluoxetine/placebo and cognitive behavioral treatments in depressed adolescents with substance use disorders. In: Proceedings of the 67th Annual Scientific Meeting of the College on Problems of Drug Dependence; June 19-23 2005. Orlando, Florida, USA, 2005. [3331212]
    1. Riggs PD, Mikulich-Gilbertson SK, Davies RD, Lohman M, Klein C, Stover SK. A randomized controlled trial of fluoxetine and cognitive behavioral therapy in adolescents with major depression, behavior problems, and substance use disorders. Archives of Pediatrics and Adolescent Medicine 2007;161(11):1026-34. [3331213] - PubMed
    1. Thurstone C, Riggs PD, Orton HD, Libby AM. Fluoxetine for cannabis withdrawal in depressed adolescents. In: Proceedings of the 67th Annual Scientific Meeting of the College on Problems of Drug Dependence; June 19-23 2005. Orlando, Florida, USA, 2005. [3331214]
Sallee 1997 {published data only}
    1. Chabrol H, Peresson G. Pulse clomipramine for depressed adolescents [letter]. American Journal of Psychiatry 1998;155(7):995. [3331216] - PubMed
    1. Sallee FR, Vrindavanam NS, Deas-Nesmith D, Carson SW, Sethuraman G. Pulse intravenous clomipramine for depressed adolescents: double-blind, controlled trial. American Journal of Psychiatry 1997;154(5):668-73. [3331217] - PubMed
    1. Sallee FR. Dr. Sallee replies [letter]. American Journal of Psychiatry 1998;155(7):995. [3331218]
Tashakori 1997 {published data only}
    1. Tashakori A, Arabgol F, Panaghi L, Davari R. The effect of reboxetine in the treatment of depression in children and adolescents. Tehran University Medical Journal 2007;65(8):40-8. [3331220]
Walker 2017 {published data only}
    1. Walker DJ, DelBello MP, Landry J, D'Souza DN, Detke HC. Quality of life in children and adolescents with bipolar I depression treated with olanzapine/fluoxetine combination. Child & Adolescent Psychiatry & Mental Health [Electronic Resource] 2017;11:34. - PMC - PubMed
Wohlfarth 2007 {published data only}
    1. Wohlfarth T, Boer F, den Brink W. Withdrawal of attention rather than pharmacological treatment affects suicide rates in depressed children and adolescents. American Journal of Psychiatry 2007;164(12):1908-10. [3331222] - PubMed

References to studies awaiting assessment

Haneveld 2003 {published data only}
    1. Haneveld JK. Two studies confirm the efficacy of sertraline for the treatment of depression in children and adolescents. Pharmaceutisch Weekblad 2003;138(46):1616-7.

References to ongoing studies

EUCTR2015‐002181‐23 {published data only}
    1. EUCTR2015-002181-23-FI. Efficacy and safety of 2 doses of agomelatine (10mg, 25mg) given orally in children (from 7 to less than 12 years) and adolescents (from 12 to less than 18 years) with moderate to severe Major Depressive Disorder. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 14 December 2015).
Glod 2004 {published data only}
    1. Glod CA, Lynch A, Berkowitz C, Hennen J, Baldessarini RJ. Bupropion versus citalopram versus placebo in adolescents with major depression [Abstract NR484]. 157th Annual Meeting of the American Psychiatric Association; May 1-6 2004 2004. [3331231]
IRCT138901093607N1 {published data only}
    1. IRCT138901093607N1. Comparing the effect of Fluoxetine and Fluvoxamine on child and adolescent depression admitted to Akhavan hospital, Kashan. www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT138901093607N1 (first received 4 June 2010).
JPRN‐JapicCTI‐194585 {published data only}
    1. JPRN-JapicCTI-194585. A clinical trial of MLD-55 in pediatric patients with depression. www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-JapicCTI-194585 (first received 6 January 2016).
NCT00353028 {published data only}
    1. Yamaguchi T. SME3110 (fluvoxamine maleate) in the treatment of depression/depressive state: a post-marketing clinical study in children and adolescents (8 through 18 years of age) - a double-blind, randomized, placebo-controlled study. www.clinicaltrials.gov/ct2/show/NCT00353028 (first received 17 July 2006). [3331233]
NCT00426946 {published data only}
    1. NCT00426946. Reboxetine Treatment in Depressed Children and Adolescents an 8-Week, Open Study. ClinicalTrials.gov/show/NCT00426946 (first received 25 January 2007).
NCT01185977 {published data only}
    1. NCT01185977. Biomarkers of Antidepressant Treatment in Adolescents With Major Depression (The Adolescents MDD Study). clinicaltrials.gov/show/NCT01185977 (first received 20 August 2010).
NCT02129751 {published data only}
    1. NCT02129751. Efficacy and Safety of Bupropion Hydrobromide in Adolescents and Children With Major Depressive Disorder. clinicaltrials.gov/show/NCT02129751 (first received 2 May 2014).
NCT02431806 {published data only}
    1. NCT02431806. Safety and Efficacy of Levomilnacipran ER in Adolescent Patients With Major Depressive Disorder. ClinicalTrials.gov/show/NCT02431806 (first received 1 May 2015).
NCT02709655 {published data only}
    1. EUCTR2008-005353-38-EE. Interventional, randomised, double-blind, placebo-controlled, active reference (fluoxetine), fixed-dose study of vortioxetine in paediatric patients aged 7 to 11 years, with Major depressive disorder (MDD). clinicaltrialsregister.eu/ctr-search/search? Query=eudract_number:2008-005353-38 (first received 25 November 2015).
    1. NCT02709655. Active Reference (Fluoxetine) Fixed-dose Study of Vortioxetine in Paediatric Patients Aged 7 to 11 Years With Major Depressive Disorder (MDD). ClinicalTrials.gov/show/NCT02709655 (first received 16 March 2016).
NCT03315793 {published data only}
    1. JPRN-JapicCTI-173734. A phase 3 clinical trial of duloxetine in children and adolescents with depressive disorder. www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-JapicCTI-173734 (first received 13 October 2017).
    1. NCT03315793. A Study of Duloxetine (LY248686) in Japanese Children and Adolescents With Depressive Disorder. clinicaltrials.gov/show/nct03315793 (first received 20 October 2017).
NCT03569475 {published data only}
    1. NCT03569475. Efficacy, Safety, and Tolerability of Levomilnacipran ER in Pediatric (7-17 Years) With Major Depressive Disorder. clinicaltrials.gov/show/nct03569475 (first received 26 June 2018).

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