Newer antidepressants for depression in children and adolescents

Depression is common in young people and can contribute to a variety of negative outcomes, such as poor academic functioning, difficulties in peer and family relationships, increases in substance use, and both attempted and completed suicide. This review contained 19 trials (with a total of 3353 participants) testing the effectiveness of newer generation antidepressants (these are antidepressants developed and used since tricyclic antidepressants were developed). These include the well-known selective serotonin reuptake inhibitors that have an impact primarily on the brain chemical called serotonin, as well as several other newer classes of antidepressants now being used, which aim to target noradrenaline and dopamine as well as serotonin and include selective norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), norepinephrine dopamine reuptake inhibitors (NDRIs), norepinephrine dopamine disinhibitors (NDDIs) and tetracyclic antidepressants (TeCAs)) for the treatment of depression in children and adolescents. Based on 14 of the trials (2490 participants in total), there was evidence that those treated with an antidepressant had lower depression severity scores than those on placebo, however, the size of this difference was small. Based on 17 trials (3229 participants in total), there was evidence of an increased risk (64%) of suicide-related outcomes for those on antidepressants compared with those given placebo. Where rates of adverse events were reported, this was higher for those prescribed an antidepressant. There was no evidence that one particular type of newer generation antidepressant had a larger effect than the others when compared to placebo.

It is unclear how meaningful the results regarding the effectiveness of these medications are in terms of a young person's day-to-day functioning. Children and adolescents with other conditions (such as anxiety, substance use disorder or a conduct disorder) as well as depression, and those at risk of suicide, were often excluded from trials. However, these young people are more representative of the population who present to clinical services, therefore it is not possible to predict how they would respond to antidepressants. There was often insufficient information to judge the quality of the trials accurately. With these limitations, it is difficult to answer questions about the effectiveness and safety of antidepressants for treating depression in children and adolescents. Clinicians need to provide accurate information to children and adolescents, and their families, about the uncertainties regarding the benefits and risks of newer generation antidepressant medication as a treatment option for depression. If a decision to use medication is agreed then fluoxetine might be the medication of first choice given guideline recommendations and, if used, the risk of suicide should be assessed and monitored particularly closely.

Authors' conclusions: 

Caution is required in interpreting the results given the methodological limitations of the included trials in terms of internal and external validity. Further, the size and clinical meaningfulness of statistically significant results are uncertain. However, given the risks of untreated depression in terms of completed suicide and impacts on functioning, if a decision to use medication is agreed, then fluoxetine might be the medication of first choice given guideline recommendations. Clinicians need to keep in mind that there is evidence of an increased risk of suicide-related outcomes in those treated with antidepressant medications.

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Background: 

Depressive disorders are common in young people and are associated with significant negative impacts. Newer generation antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are often used, however evidence of their effectiveness in children and adolescents is not clear. Furthermore, there have been warnings against their use in this population due to concerns about increased risk of suicidal ideation and behaviour.

Objectives: 

To determine the efficacy and adverse outcomes, including definitive suicidal behaviour and suicidal ideation, of newer generation antidepressants compared with placebo in the treatment of depressive disorders in children and adolescents.

Search strategy: 

For this update of the review, we searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) to October 2011. The CCDANCTR includes relevant randomised controlled trials from the following bibliographic databases: CENTRAL (the Cochrane Central Register of Controlled Trials) (all years), EMBASE (1974 -), MEDLINE (1950 -) and PsycINFO (1967 -). We searched clinical trial registries and pharmaceutical company websites. We checked reference lists of included trials and other reviews, and sent letters to key researchers and the pharmaceutical companies of included trials from January to August 2011.

Selection criteria: 

Published and unpublished randomised controlled trials (RCTs), cross-over trials and cluster trials comparing a newer generation antidepressant with a placebo in children and adolescents aged 6 to 18 years old and diagnosed with a depressive disorder were eligible for inclusion. In this update, we amended the selection criteria to include newer generation antidepressants rather than SSRIs only.

Data collection and analysis: 

Two or three review authors selected the trials, assessed their quality, and extracted trial and outcome data. We used a random-effects meta-analysis. We used risk ratio (RR) to summarise dichotomous outcomes and mean difference (MD) to summarise continuous measures.

Main results: 

Nineteen trials of a range of newer antidepressants compared with placebo, containing 3335 participants, were included. The trials excluded young people at high risk of suicide and many co-morbid conditions and the participants are likely to be less unwell than those seen in clinical practice. We judged none of these trials to be at low risk of bias, with limited information about many aspects of risk of bias, high drop out rates and issues regarding measurement instruments and the clinical usefulness of outcomes, which were often variously defined across trials. Overall, there was evidence that those treated with an antidepressant had lower depression severity scores and higher rates of response/remission than those on placebo. However, the size of these effects was small with a reduction in depression symptoms of 3.51 on a scale from 17 to 113 (14 trials; N = 2490; MD -3.51; 95% confidence interval (CI) -4.55 to -2.47). Remission rates increased from 380 per 1000 to 448 per 1000 for those treated with an antidepressant. There was evidence of an increased risk (58%) of suicide-related outcome for those on antidepressants compared with a placebo (17 trials; N = 3229; RR 1.58; 95% CI 1.02 to 2.45). This equates to an increased risk in a group with a median baseline risk from 25 in 1000 to 40 in 1000. Where rates of adverse events were reported, this was higher for those prescribed an antidepressant. There was no evidence that the magnitude of intervention effects (compared with placebo) were modified by individual drug class.