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Journal of Child & Adolescent Mental Health

ISSN: 1728-0583 (Print) 1728-0591 (Online) Journal homepage: http://www.tandfonline.com/loi/rcmh20

Controversies in the use of antidepressants in children and adolescents: A decade since the storm and where do we stand now?

Soraya Seedat

To cite this article: Soraya Seedat (2014) Controversies in the use of antidepressants in children and adolescents: A decade since the storm and where do we stand now?, Journal of Child & Adolescent Mental Health, 26:2, iii-v, DOI: 10.2989/17280583.2014.938497

To link to this article: https://doi.org/10.2989/17280583.2014.938497

Published online: 16 Jul 2014.

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EDITORIAL

Controversies in the use of antidepressants in children and adolescents: A decade since the storm and where do we stand now?

As we focus in this special issue on new developments in diagnosis and treatment (with a particular emphasis on paediatric psychopharmacology), I thought that the time was opportune to pause and reflect on a potentially life-threatening medical condition in children and adolescents: Major Depressive Disorder (MDD). The prevalence of MDD in pre-pubertal children (2.8%) doubles after puberty (5.8% in adolescents 13–18 years of age), is twofold more preponderant in post-pu- bertal girls than boys, and is characterised by episodic recurrences in adolescence and adulthood. About half of all adolescents with current MDD will have a subsequent depressive episode over the next five years. Paediatric MDD is arguably the most important risk factor for suicide and, in fact, accounts for more than half of adolescent suicides. However, it is a potentially preventable and highly treatable cause of other psychiatric morbidity, alcohol and drug use, academic and social impairment, and disability. The World Health Organization has identified adolescent depression as one of the key priority areas for diagnosis and treatment in low and middle income countries, where the burden of the disorder is greatest. Timely recognition and treatment of youth is therefore critical. Over the past decade the use of antidepressants in children and adolescents has raised widespread public concern and debate. Despite the passage of time and the emergence of new evidence (including unpublished data), professional opinions among psychiatrists continue to be divided on issues of antidepressant effectiveness and safety. Currently, there are only two FDA (US Food and Drug Administration)-approved medications for the treatment of paediatric MDD: fluoxe- tine (for children and adolescents aged 7–17 years) and escitalopram (for adolescents aged 12–17 years). Additional evidence from randomised controlled trials (RCTs) indicates that sertraline and citalopram, in children 7–17 years of age, are also beneficial for the treatment of MDD but these agents are not FDA approved. Placebo response rates in trials of paediatric MDD exceed 30%, perhaps not surprising considering the multi-site nature of these RCTs and the inclusion of young patients with less severe depressive symptomatology.

In pondering the evidence that guides the prescription of antidepressants in children and adoles- cents, it is prudent to take a trip down memory lane. In 2003 there were worrying signals from RCTS of paroxetine, indicating a lack of efficacy of this selective serotonin reuptake inhibitor (SSRI) relative to placebo in paediatric depression and an elevated risk of harmful outcomes that included self-harm and suicidal behaviour. The FDA and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) subsequently issued health advisories warning about the increased risk of suicidality with antidepressants in this age group. The FDA then commissioned a widely publicised data review of antidepressant RCTs in child and adolescent MDD. Based on conclu- sions drawn from the review, the FDA requested pharmaceutical companies to include a ‘black box’ warning to the package labelling of all antidepressants about the increased risk of suicidality in children under 18 years (Isacsson and Rich 2014). No completed suicides had occurred in any of the RCTs that were reviewed. In 2007 this was extended to include young adults under 25 years of age. Around the same time, the Treatment for Adolescents with Depression Study (TADS), the first trial to compare the effectiveness of fluoxetine, cognitive behaviour therapy (CBT), their combina- tion, or placebo, in adolescents with MDD, found that fluoxetine was superior to placebo at three months. However, CBT was not superior to placebo. Over time the three active treatments (fluoxe- tine, CBT and fluoxetine + CBT) had comparable efficacy, in response and remission rates (March et al. 2004). Of note, the risk of suicidal ideation and attempts was low across all three treatments.

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Further analysis of TADS data showed that both fluoxetine and combination therapy were at least as cost-effective in the short term as other treatments commonly used in primary care.

The benefits of antidepressants for internalising disorders in youth were also supported by a meta-analysis assessing the efficacy of antidepressants and risk of reported suicidal ideation/ suicide attempts for treatment of paediatric MDD, obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders published in 2007 (Bridge et al. 2007). Antidepressants were superior to placebo and were associated with a 3% increase in suicidal ideation/attempts compared with a 2% rate on placebo. The antidepressant-placebo difference in risk of 1% was not statistically signif- icant and, more importantly, there were no completed suicides in any of the RCTs included in the meta-analysis.

Further interesting (and confusing) data came to light. In the five years preceding the black box warning (1999–2003), there had been an increase in the diagnosis of MDD coupled with an increase in the use of SSRIs across all ages. However, in the five years following the black box warning there had been the opposite effect! There was a notable decrease in the diagnosis of depression and the prescription of antidepressants in countries such as the USA, UK, Sweden, Canada and Australia. More disturbing was an increase in the number of completed suicides in these countries (except UK where there was no difference). Notably, in a recently published study of all cases of suicide in 10–19 year olds in Sweden (Isacsson and Ahlner 2013) that included toxicology data on antidepressants taken immediately before death, there was a substantial increase in suicide cases in the five years after the warning. As this increase was notable in youth who were not on antidepressants, the authors have suggested that “these truly suicidal persons might have been denied antidepressants or abstained from them, due to the ‘black box’ and then committed suicide because of untreated depression” (Isacsson and Ahlner 2013: 6).

So where do we stand with the numerous systematic reviews meta-analyses and new studies that have been published since the black box? First, it needs to be emphasised that there have been no completed suicides in any of the placebo-controlled RCTs of newer generation antide- pressants in children and adolescents. Second, the benefit–risk ratio for the use of antidepres- sants, more specifically fluoxetine, in children and adolescents with moderate-to-severe depression is favourable (Soutullo and Figueroa-Quintana 2013). Close observation and monitoring of youth before and following initiation of treatment, regardless of the type of treatment, should be part and parcel of routine care. Third, CBT or interpersonal therapy should be considered as a first-line in this age group, even in moderate-to-severe paediatric depression. Fourth, adding CBT to an antide- pressant does not appear to improve response in paediatric MDD in the longer term, challenging the often held notion that combining these treatments trumps giving either alone. Fifth, as adoles- cent MDD has a relapsing and remitting course continuing treatment for at least 6 to 12 months after acute phase treatment (antidepressant or CBT) has been demonstrated to prevent relapse. Finally, evidence that antidepressant treatments improving the quality of life among children and adolescents with depressive or anxiety disorders is inconclusive and more research is required in this regard. In summary, evidence relating to the risk–benefit profile of antidepressants is still contradictory and not much has changed since 2003. Closing the knowledge gaps in cost-effective diagnosis, treatment and prevention of child and adolescent MDD, using family based approaches, remains a priority.

References

Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA. 2007. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. Journal of the American Medical Association 297: 1683–1696.

Isacsson G, Ahlner J. 2014. Antidepressants and the risk of suicide in young persons—prescription trends and toxicological analyses. Acta Psychiatrica Scandinavica 129: 296–302.

Isacsson G, Rich CL. 2014. Antidepressant drugs and the risk of suicide in children and adolescents. Paediatric Drugs 16: 115–122.

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March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J; Treatment for Adolescents With Depression Study (TADS) Team. 2004. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. Journal of the American Medical Association 292: 807–820.

Soutullo C, Figueroa-Quintana A. 2013. When do you prescribe antidepressants to depressed children? Current Psychiatry Reports 15: 366–373.

Soraya Seedat Editor-in-Chief, Journal of Child & Adolescent Mental Health email: sseedat@sun.ac.za

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