Depression is common in young people with prevalence estimated to be around 2.8% in children and 5.7% in adolescents, and it has been identified as the leading cause of disability in 10-24 year olds (Costello et al., 2006; Gore et al., 2011). During such a critical developmental period the impact can be significant; there are enduring associations between depression in young people and poor physical and mental health, social functioning, educational/occupational outcomes, and quality of life. Depression in young people is also associated with a considerable increase in suicide risk (Cash et al., 2009).
We know that early, effective treatment can reduce the risk of negative long-term outcomes (Peters et al., 2016), but knowing which treatments should be used is far from straightforward. There has been ongoing concern about the effectiveness of treatments in young people, both antidepressants and psychological treatments (see recent blogs by Catherine Harmer on Zhou et al., 2020 and David Halford on Cuijpers et al., 2020).
Clinical guidelines suggest that antidepressants are recommended for use in young people with moderate-to-severe depression who do not respond to (or who are unable to engage with) psychological therapies, although medication can be used as a first-line treatment in more severe depression (NICE 2019). Despite these guidelines, rates of antidepressant prescriptions in young people have risen substantially over recent years (Jack et al 2020).
Within this context, establishing both the benefits and the risks of antidepressants in young people is critically important.
This week, Sarah Hetrick and colleagues published a Cochrane review of the effectiveness and safety of antidepressants in children and adolescents. In this review, they used a network meta-analysis (NMA) approach to investigate the effectiveness and safety of antidepressants in 6-18 year olds with depression.
The researchers restricted their review to ‘newer generation antidepressants’ and their analysis included trials using Selective Serotonin Reuptake Inhibitors (SSRIs; fluoxetine, sertraline, escitalopram, citalopram, paroxetine, vilazodone, vortioxetine), Selective Norepinephrine Reuptake Inhibitors (SNRIs; duloxetine, venlafaxine, desvenlafaxine) and tetracyclic antidepressants (TeCAs; mirtazapine).
In total, data from 26 randomised controlled trials were included in the analysis. Most of these trials were of SSRIs, but there were also two trials of SNRIs and two trials of mirtazapine. The treatment period of all included trials was 6-12 weeks.
- All antidepressant classes were associated with a reduction in depression symptoms compared with placebo. However, these differences were small and the size of the drug-placebo differences did not reach the criteria set by the authors for clinical importance (5 point difference on the Children’s Depression Rating Scale, CDRS-R) and are therefore labelled as “small and unimportant”
- The largest differences in depression symptoms between antidepressants and placebo were seen for sertraline and fluoxetine, which were associated with a 3.5 and 2.8 point difference on the CDRS-R respectively
- The differences between the antidepressants were small, but the analysis suggested a possible ranking of medication class: SSRIs followed by TeCAs and then SNRIs.
- There were no completed suicides in any of the trials. The number of suicide-related events (suicidal thoughts and related behaviours) was small in most trials and confidence intervals were high for all comparisons
- There was some evidence that SSRIs and SNRIs might slightly increase the odds of suicide-related outcomes (suicidal thoughts and behaviours) compared with placebo. This pattern was seen with fluoxetine, sertraline, paroxetine and, particularly, venlafaxine. Conversely, there was some evidence that escitalopram may slightly reduce the odds of suicide-related outcomes.
The findings of this review are consistent with other recent analyses pooling efficacy data across trials of antidepressants in children and adolescents. The take home message being that antidepressants reduce symptoms of depression more than placebo, but that the size of this effect is small.
The review also highlights that antidepressants may slightly increase the chance of suicidal thoughts and behaviours, although this evidence is uncertain because the incidence of these was very small across the trials.
Overall it is hard to make any clear conclusions about suicide-related outcomes. Results are contradictory with some data showing reduced risk, some showing no change, and some showing an increased risk. (Hetrick et al., 2021)
Strengths and limitations
This review represents an extremely careful and thorough analysis of the evidence that we have from clinical trials, about the effects of antidepressants in young people. The authors have taken a systematic and transparent approach to identify relevant trials, extracting data, and assessing the quality of the evidence available.
The use of a network meta-analysis (NMA) allows a comparison of the effectiveness of different treatments and allows comparisons between multiple treatments simultaneously, even when medications have not been directly compared in head-to-head clinical trials. This allowed the authors to not only compare the effects of each antidepressant with placebo, but also to estimate the relative ranking of different antidepressants.
As ever with these kinds of analyses, the conclusions that can be drawn are limited by the quality of the evidence that exists. The authors note that the trials have a high degree of methodological shortcomings, which makes interpreting the findings challenging.
One particular concern is the extent to which the participants included in the trials are representative of those seen in clinical practice. The majority of trials exclude patients who are at risk of suicide and those who have comorbid disorders, which makes an assessment of the ‘real-world’ clinical effects of these treatments difficult to establish, and in particular the effects on suicidality. There were no completed suicides in the trials included in this analysis and the rate of suicidal thoughts and related behaviours was very low, making it difficult to say anything conclusive about the effect of antidepressant treatment on suicide risk.
The effects of antidepressants are considered over a short time period (6-12 weeks) and we know very little about the longer-term effects of antidepressant treatment in young people and children; not just in terms of symptom change, but also on functional outcomes and quality of life.
Finally, defining the criteria for clinically meaningful change is challenging; the authors define this in terms of a minimum fixed point change on a clinical scale (i.e. 5 points on the CDRS-R), which is a commonly used approach. However, clinically important improvements are known to be dependent on initial depression severity and thus ratio scales (i.e. percentage reduction in scores from baseline) may be a better way of assessing meaningful improvement (Button et al 2015; Kounali et al 2020).
Explaining small effect sizes…
One thing this analysis cannot tell us is why the size of the difference between antidepressants and placebo is small. There are a number of possible explanations. It could be that the drug only induces small changes in symptoms, so small that they are perhaps not even clinically meaningful. Another explanation is that responses across people may vary (some of them show a large response to the medication, while others don’t experience many benefits at all) and when you pool the data together this results in small effect size. There is also the possibility that aspects of the trial methodology artificially inflate the size of the placebo response (e.g. clinical contact/supportive care over and above what would usually be given in routine clinical practice), which may diminish the true estimation of antidepressant efficacy for young people (Walkup et al., 2017). This analysis doesn’t tell us which of these explanations is more accurate, but it is important to consider given the very different clinical implications.
When making difficult treatment decisions, the message “antidepressants are unlikely to make much of a difference but they may slightly improve your symptoms” is very different to “some people find this medication really helps them, although they don’t work for everyone”.
Implications for practice
The findings from this new Cochrane review (Hetrick et al., 2021) echo previous reviews suggesting that antidepressants may be associated with small reductions in depression symptoms in children and adolescents. Interestingly, they highlight that these reductions are seen with a range of antidepressants, which suggests the clinical guidelines recommending only fluoxetine may be too narrow. The evidence presented indicates that some young people may experience an increase in suicidal thinking and behaviour during SSRI treatment and highlights the need for careful clinical monitoring when antidepressants are prescribed to young people.
Whilst analyses like these are useful summaries of the data, they leave many questions unanswered and highlight the paucity of our current knowledge base. Many of the outstanding questions about antidepressants are not well answered within the clinical trial methodology and there is a need for experimental, mechanistic work to further unpick the biological and psychological effects of antidepressants in young people. This approach can be particularly helpful in identifying which patients will respond better to treatment and how to combine different treatments by understanding unwanted effects of treatment, and defining targets for future treatment development. Given that antidepressants are increasingly being prescribed to young people and currently remain an often utilised clinical approach, it is critical that we improve our understanding of these medications in this age group. This will allow decision making by clinicians, young people and their families that is based on a solid scientific understanding of their effects.
Statement of interests
Susannah Murphy has received consultancy fees and research funding to the University of Oxford from pharmaceutical companies to develop novel treatments for depression in adults.
Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, Li X, Cuijpers P, Coghill D, Xiang Y, Hetrick SE, Leucht S, Qin M, Barth J, Ravindran AV, Yang L, Curry J, Fan L, Silva SG, Cipriani A, Xie P. 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. Lancet Psychiatry. 2020 Jul;7(7):581-601
Cuijpers, P., Karyotaki, E., Eckshtain, D., Ng, M. Y., Corteselli, K. A., Noma, H., … & Weisz, J. R. (2020). Psychotherapy for depression across different age groups: A systematic review and meta-analysis. JAMA Psychiatry. Doi:10.1001/jamapsychiatry.2020.0164
Button KS, Kounali D, Thomas L, Wiles NJ, Peters TJ, Welton NJ, Ades AE, Lewis G. Minimal clinically important difference on the Beck Depression Inventory–II according to the patient’s perspective. Psychol Med. 2015 Nov;45(15):3269-79. doi: 10.1017/S0033291715001270
Cash_SJ, Bridge_JA. Epidemiology of youth suicide and suicidal behavior. Current Opinion in Pediatrics 2009;21(5):613-9. [DOI: 10.1097/MPO.0b013e32933063e1]
Costello_JE, Erkanli_A, Angold_A. Is there an epidemic of child or adolescent depression? Journal of Child Psychology and Psychiatry, and Allied Disciplines 2006;47(12):1263-71.
Gore_FM, Bloem_PJ, Patton_GC, Ferguson_J, Joseph_V, CoJey_C, et al. Global burden of disease in young people aged 10-24 years: a systematic analysis. Lancet 2011;377(9783):2093-102
Jack RH, Hollis C, Coupland C, et al. Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998–2017: A population-based cohort study. PLOS Medicine 2020; 17: e1003215
Kounali D, Button KS, Lewis G, Gilbody S, Kessler D, Araya R, Duffy L, Lanham P, Peters TJ, Wiles N, Lewis G. How much change is enough? Evidence from a longitudinal study on depression in UK primary care. Psychol Med. 2020 Nov 3:1-8. doi: 10.1017/S0033291720003700.
National Institute for Health and Care Excellence. Depression in children and young people: identification and management (NICE guideline NG134). 2019.
Peters AT, Jacobs RH, Feldhaus C, et al. Trajectories of Functioning Into Emerging Adulthood Following Treatment for Adolescent Depression. Journal of Adolescent Health 2016; 58: 253–9
Stallwood E, Monsour A, Rodrigues C, Monga S, Terwee C, Offringa M, Butcher NJ. Systematic Review: The Measurement Properties of the Children’s Depression Rating Scale-Revised in Adolescents With Major Depressive Disorder. J Am Acad Child Adolesc Psychiatry. 2021 Jan;60(1):119-133. doi: 10.1016/j.jaac.2020.10.009. Epub 2020 Oct 29. PMID: 33130251
Walkup JT. Antidepressant Efficacy for Depression in Children and Adolescents: Industry- and NIMH-Funded Studies. AJP 2017; 174: 430–7