Elsevier

The Lancet

Volume 363, Issue 9418, 24 April 2004, Pages 1341-1345
The Lancet

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Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data

https://doi.org/10.1016/S0140-6736(04)16043-1Get rights and content

Summary

Background

Questions concerning the safety of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression in children led us to compare and contrast published and unpublished data on the risks and benefits of these drugs.

Methods

We did a meta-analysis of data from randomised controlled trials that evaluated an SSRI versus placebo in participants aged 5–18 years and that were published in a peer-reviewed journal or were unpublished and included in a review by the Committee on Safety of Medicines. The following outcomes were included: remission, response to treatment, depressive symptom scores, serious adverse events, suicide-related behaviours, and discontinuation of treatment because of adverse events.

Findings

Data for two published trials suggest that fluoxetine has a favourable risk-benefit profile, and unpublished data lend support to this finding. Published results from one trial of paroxetine and two trials of sertraline suggest equivocal or weak positive risk-benefit profiles. However, in both cases, addition of unpublished data indicates that risks outweigh benefits. Data from unpublished trials of citalopram and venlafaxine show unfavourable risk-benefit profiles.

Interpretation

Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people. Clinical guideline development and clinical decisions about treatment are largely dependent on an evidence base published in peer-reviewed journals. Non-publication of trials, for whatever reason, or the omission of important data from published trials, can lead to erroneous recommendations for treatment. Greater openness and transparency with respect to all intervention studies is needed.

Introduction

Researchers have estimated that 2–6% of children and adolescents in the community suffer from depression,1, 2 and suicide is now the third leading cause of death in 10–19 year olds.3 There is, therefore, a clear need for safe and effective treatments for this group of people. Although evidence of such treatments for depression in children exists,4 the lack of efficacy and poor side-effect profile for tricyclic antidepressants5 leaves selective serotonin reuptake inhibitors (SSRIs) as the only class of antidepressants for pharmacological therapy.

The Expert Working Group of the Committee on Safety of Medicines (CSM) undertook a review of the efficacy and safety of SSRIs in paediatric major depressive disorder. In view of the CSM review, the Medicines and Healthcare products Regulatory Agency (MHRA) released a statement contraindicating the use of all SSRIs other than fluoxetine as new treatment for patients younger than 18 years of age with depressive illness.6 This advice followed an earlier recommendation by the CSM that both paroxetine and venlafaxine should be contraindicated for use in this context.

The CSM review was initiated because of concerns about the safety of SSRIs; in particular, the possibility that these drugs might be associated with an increased risk of suicidal behaviour and that important withdrawal reactions can happen on stopping treatment.7 Similar concerns in the USA about the safety of SSRIs prompted reviews by the US Food and Drug Administration8 and the American College of Neuropsychopharmacology.9 Although both these organisations raised concerns about the validity of the suicide data and called for further analyses, neither recommended contraindicating SSRIs.

In parallel to the reviews described above, in the UK, the National Collaborating Centre for Mental Health (NCCMH), commissioned by the National Institute for Clinical Excellence (NICE), produced a similar review restricted to published evidence for a national clinical guideline that is being developed for the management of depression in children and young people.

In view of the ongoing debate about publication bias and the serious concerns about withholding unfavourable trial data and under-reporting of adverse events,10, 11, 12, 13, 14, 15, 16 we decided to investigate the risk-benefit profile of individual SSRIs using published data, unpublished data, and the combined dataset.

Section snippets

Methods

The full review protocol is available from the authors and will be published in the full guideline on depression in children (for more information, see http://www.nice.org.uk). Briefly, we searched four electronic bibliographic databases (EMBASE, MEDLINE, PsycINFO, CINAHL) and the Cochrane Library for published trials in which any antidepressant was compared with placebo in participants aged 5–18 years who were diagnosed with depression. Every database was searched from inception to April,

Results

Of 5220 potentially relevant papers, 165 were retrieved for more detailed evaluation. Of these, 143 were excluded as clearly not relevant. Further inspection of the remaining papers revealed five randomised controlled trials that met our inclusion criteria (figure). The most usual reason for exclusion was that the study only compared a tricyclic antidepressant with placebo. Further details of the five included studies and reasons for excluding studies are shown in the webtable.

Discussion

Our analysis of published data from two trials22, 23 of fluoxetine suggested a favourable risk-benefit profile for the treatment of depression in children and young people; unpublished safety data17 lent support to this view. Published data from one trial24 of paroxetine and two trials25 of sertraline suggested equivocal or weak positive risk-benefit profiles; however, in both cases, addition of unpublished data17 indicated that risks outweighed benefits. Further, our analyses of unpublished

References (29)

  • American College of Neuropsychopharmacology (ACNP)

    Executive summary: preliminary report of the task force on SSRIs and suicide behaviour in youth

  • GarlandEJ

    Facing the evidence: antidepressant treatment in children and adolescents

    CMAJ

    (2004)
  • HerxheimerA et al.

    Antidepressants and adverse effects in young patients: uncovering the evidence

    CMAJ

    (2004)
  • KondroW et al.

    Drug company experts advised staff to withhold data about SSRI use in children

    CMAJ

    (2004)
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