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

How well do newer formulations of antidepressants work for children and adolescents with clinical depression?

Children and adolescents (6 to 18 years) with depression (also called ‘major depressive disorder’) experience a range of negative impacts in all areas of their lives and have an increased risk of suicide, suicidal thinking and suicide attempts. Antidepressants have been shown to reduce symptoms of depression, but can also increase the risk of suicide-related outcomes.

Who will be interested in this research?

The research in this Cochrane Review will interest:

- people who decide policy, and influence decisions about the prescription of antidepressant medicines to children and adolescents;

- people who prescribe these medicines to children and adolescents;

- children and adolescents with depression; and

- those who support and care for them (including their parents and caregivers and clinicians who provide treatment).

What did we want to find out?

We wanted to find out how well newer formulations (called ‘new generation’) antidepressants work to improve depression in children and adolescents aged 6 to 18 years. New generation antidepressants are those that have been developed recently. They are sometimes referred to as ‘second-‘ and ‘third-generation’ antidepressants; they do not include older formulations (tricyclic antidepressants or monoamine oxidase inhibitors).

We wanted to know how these antidepressants affect:

- symptoms of depression;

- recovery: no longer meeting diagnostic criteria for major depressive disorder;

- response or remission: scores on a scale indicating an important reduction in depression or no longer experiencing depression;

- ability to function in daily life;

- suicide-related outcomes; and

- whether they cause any unwanted effects in children and adolescents.

What did we do?

We searched for studies that tested new generation antidepressants on children or adolescents (or both) who had been diagnosed with a major depressive disorder. We identified 26 such studies. We then assessed the trustworthiness of those studies, and synthesized the findings across the studies.

What does the evidence from the review tell us?

Most newer antidepressants probably reduce depression symptoms better than a placebo (a 'dummy' treatment that does not contain any medicine but looks identical to the medicine being tested). However, the reduction is small and may not be experienced as important by children and adolescents, their parents and caregivers, or clinicians. When different medications are compared against each other, there may be only small and unimportant differences between most of them for the reduction of symptoms.

Our findings reflect what happens on average to individuals, but some individuals may experience a greater response. This might lead to recommendations being made for the use of antidepressants for some individuals in some circumstances. Our findings suggest that sertraline, escitalopram, duloxetine and fluoxetine can be used if medication is being considered.

The impact of medication on depression symptoms should be closely monitored by those prescribing the medication, especially as suicide-related thinking and behaviour may be increased in those taking these medications. Close monitoring of suicide-related behaviours is vital in those treated with new generation antidepressants.

What should happen next?

The studies that provided this evidence largely excluded children and adolescents who:

- were already thinking about suicide and wanting to take their own lives (i.e. had suicidal ideation);

- were self-harming;

- had other mental health conditions; and

- had psychosocial difficulties.

Future research should aim to understand the impacts of these medicines in children and adolescents with these problems, who are more typical of those who request clinical services.

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.

Read the full abstract...

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.


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 strategy: 

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.