Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: A systematic review and meta-analysis

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Abstract

To evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with depressive disorder, the main electronic databases and the reference lists of retrieved articles and reviews were searched up to January 2007. Randomized controlled studies (RCT) were assessed for methodological quality, taking into consideration the specific diagnostic and severity evaluation tools used, and a meta-analysis on the efficacy of SSRIs compared placebo was undertaken. In all, 13 studies were included, covering a total of 2530 children and adolescents. Eleven studies met the criteria for inclusion in the meta-analysis. The pooled odds ratio was 1.57 (95% C.I. 1.29–1.91). Only fluoxetine appeared to offer a moderately significant benefit profile (OR = 2.39). All studies differed in diagnostic tools and primary efficacy measures. SSRI treatment, especially with fluoxetine, may be effective on child and adolescent depression. Nevertheless, additional RCTs with sound methodological designs, validated diagnostic instruments, large sample sizes, and consistent outcomes are necessary to determine the role of SSRIs, alone or in combination with psychological interventions in the treatment of depression in children and adolescents.

Introduction

The existence of major depressive disorder (MDD) in youths has been a controversial topic since the beginning of the 80s (Puig-Antich et al., 1985a, Puig-Antich et al., 1985b). Research over the past 25 years, however, has clearly demonstrated that children and adolescents can experience clinical episodes of depression, according to standard DSM-IV criteria for the disorder, including recurring (Kovacs et al., 1984, Rao et al., 1993) and persistent functional impairment, even after recovery (Puig-Antich et al., 1985a, Puig-Antich et al., 1985b). Children and adolescents are diagnosed with major depression when they experience persistent depressed or irritable moods and markedly diminished interest or pleasure in all or almost all activities for at least 2 weeks (APA, 1994). At least four of the following nine symptoms must be present in order for the diagnosis to be made: weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, lack of concentration, or thoughts of death or suicidal ideation/attempts. Differently from adults, symptoms of melancholia, delusion and high-risk suicidal attempts are less prevalent in young children and increase with age, while symptoms such as anxiety, behavioural activation and perhaps auditory and visual dysperceptions are more common in children (AACAP, 1998). About 40 to 70% of depressed children and adolescents also show coexisting psychiatric disorders, including anxiety, disruptive behaviour, and eating disorders and substance abuse (Angold et al., 1999). These comorbid conditions have been reported to lead to poorer treatment response, to a more intense functional impairment, and to increased use of mental health services (Birmaher et al., 1996, Brent et al., 1998, Emslie et al., 1998).

The prevalence of MDD is estimated to be approximately 2% in children, increasing up to 8% in adolescents (Kashani et al., 1987, Fleming and Offord, 1990, Lewinsohn et al., 1994, Ford et al., 2003). This disorder can be severe and often has a recurrent (about 30% of cases) or chronic course, extending into adult life and causing disability and social, academic, and occupational impairment. The most serious complication is suicide, which ranks third as a cause of death among adolescents in the USA (Vitiello and Swedo, 2004; www.cdc.gov/ncipc/wisqars). As many as 3–7% of depressed adolescents will commit suicide within 10–20 years of their initial episode of major depression (Rao et al., 1993, Weissman et al., 1999, Fombonne et al., 2001).

Non-pharmacological interventions, such as cognitive-behavioural therapy and other psychotherapies, have been shown to be effective in improving the symptoms, at least in mild or moderate depressive disorder (Harrington et al., 1998, Compton et al., 2004). For severe or resistant depression, pharmacological treatment may be needed. Nevertheless, the prescription prevalence in children and adolescents has been increasing in the last few years (Schirm et al., 2001, Clavenna et al., 2004, Murray et al., 2004). Due to the poor efficacy of tricyclic drugs and their association with significant adverse effects (Hazell et al., 2002), selective serotonin reuptake inhibitors (SSRIs) are used more frequently, even though their risk–benefit profile has been the basis of debate among the scientific community and lay people since 2000 (Ambrosini, 2000). Despite the lively debate and the conflicting conclusions on the analyses of the published and unpublished data on the risks and benefits of SSRIs, the U.S. Food and Drug Administration (FDA; Food and Drug Administration Website, 2007) issued a “black box” warning about the risk of suicidal thoughts and hostility induced by these drugs. At present, according to available guidelines (American Academy of Child and Adolescent Psychiatry, 1998, National Institute for Health and Clinical Excellence, 2005), fluoxetine is the only drug approved for paediatric use in depressed children over 8 years old both in the USA and Europe. Regulatory decisions were based more on analyses of the seriousness of the risks of suicidal ideation or attempts than on the drugs' efficacy over placebo. In fact, the FDA report (http://www.fda.gov/cder/drug/antidepressants) did not provide data on the efficacy of SSRIs (Sharp and Hellings, 2006). Similarly, the majority of the reviews that followed were focused reanalyses of published and unpublished findings on the suicidal risks of the drug treatments (Whittington et al., 2004, Jureidini et al., 2004, Courtney, 2004, Mann et al., 2006, Wallance et al., 2006).

All the trials considered in the regulatory revisions have, in the meantime, been published. A systematic review and a meta-analysis of randomised controlled trials on the effectiveness of SSRIs in improving the symptoms in depressed children and adolescents, with a particular focus on diagnostic tools and outcome measures used to evaluate treatment efficacy, were thus conducted a recent paper on predictors and moderators of efficacy, as well as the few long-term follow up data available, will also be discussed.

Section snippets

Definitions and inclusion criteria

The systematic review was restricted to studies using SSRI therapy in children and adolescents with depressive disorder or depressive symptoms. Studies were eligible if they were randomised controlled trials and described subjects diagnosed by using standardised criteria. Studies involving only adults were excluded.

Search strategy

The search was performed independently by 2 reviewers (TU, AC) using the Cochrane Library's Central Register of Controlled Trials (issue 1, 2007) and the Embase (1974–January 2007),

Search results

The electronic search strategy, after accurate evaluation of the abstracts by all the authors and, in cases of disagreement as to whether an article was relevant, retrieval of the full original article, identified 60 potentially relevant published studies. In all, 26 were duplicate titles indexed in multiple databases and were excluded. Of the 34 resulting studies, 12 were excluded because depression was not the primary diagnosis of the enrolled patients. Four additional studies were retrieved

Discussion

A total of 13 randomised controlled trials on the effects of SSRI treatment in children and adolescents on depression symptoms were identified in this systematic review, and 11 were included in the meta-analysis. As reported in recent systematic reviews (Whittington et al., 2004, Jureidini et al., 2004, Wallance et al., 2006, Papanikolaou et al., 2006, Moreno et al., 2007), the 13 randomised controlled trials considered were different in methodological approaches (enrolled population, sample

Role of the funding source

Funding for this study was provided in part by the Sardinian Public Health Secretariat (DGL 62/44–2005; grant to TU and AZ). The Sardinian Public Health Secretariat had no role in study design, in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Contributors

MB was responsible for initiation, design and direction of the review. MB and AZ wrote the protocol. TU and AC retrieved the studies, extracted and analysed the data. All authors interpreted and discussed the results. TU and AC wrote the first draft of the manuscript, which was discussed and implemented by all authors.

Conflict of interest

AZ has been reimbursed by Lilly for attending an international scientific meeting, has been paid by Lilly for speaking and for consulting work, and by UCB , Shire, Cephalon, and Astra Zeneca for consulting work. AZ has also received research grants from Lilly (Atomoxetine for ADHD). AC holds a fellowship granted by Boehringer Ingelheim Italia. Ethical approval: Not required.

Acknowledgements

We thank Giusy Petruzzelli for obtaining original articles and Daniela Miglio and Chiara Pandolfini for editorial assistance.

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