Cochrane review: Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents

Abstract

BackgroundDepressive disorders are common in young people and are associated with significant negative impacts. 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.ObjectivesTo determine the efficacy and adverse outcomes, including definitive suicidal behaviour and suicidal ideation, of SSRIs compared to placebo in the treatment of depressive disorders in children and adolescents.Search strategyWe searched the CCDAN Trials Register, MEDLINE, PSYCHINFO and CENTRAL. Reference lists were checked, letters were sent to key researchers and internet databases searched.Selection criteriaWe included published and unpublished randomised controlled trials.Data collection and analysisTwo or three review authors selected the trials, assessed the quality and extracted trial and outcome data. We used a fixed‐effect meta‐analysis. The relative risk was used to summarise dichotomous outcomes and the mean difference to summarise continuous measures.Main resultsTwelve trials were eligible for inclusion, with ten providing usable data. At 8‐12 weeks, there was evidence that children and adolescents 'responded' to treatment with SSRIs (RR 1.28, 95% CI 1.17 to 1.41). There was also evidence of an increased risk of suicidal ideation and behaviour for those prescribed SSRIs (RR 1.80, 95% CI 1.19 to 2.72). Fluoxetine was the only SSRI where there was consistent evidence from three trials that it was effective in reducing depression symptoms in both children and adolescents (CDRS‐R treatment effect ‐5.63, 95% CI ‐7.38 to ‐3.88), and 'response' to treatment (RR 1.86, 95% CI 1.49 to 2.32). Where rates of adverse events were reported, this was higher for those prescribed SSRIs.Authors' conclusionsCaution is required to interpret the results. First, there were methodological issues, including high attrition, issues regarding measurement instruments and clinical usefulness of outcomes, often variously defined across trials. Second, patients seen in clinical practice are likely to be more unwell, and at greater risk of suicide, compared to those in the trials, and it is unclear how this group would respond to SSRIs. This needs to be considered, along with the evidence of an increased risk of suicide related outcomes in those treated with SSRIs. It is unclear what the effect of SSRIs is on suicide completion. While untreated depression is associated with the risk of completed suicide and impacts on functioning, it is unclear whether SSRIs would modify this risk in a clinically meaningful way.Plain language summarySelective serotonin reuptake inhibitors (new generation antidepressants) for depressive disorders in children and adolescentsDepressive disorders are common in young people and have significant negative impacts. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for the treatment of depressive disorder in children and adolescents. The review of 12 trials highlighted limitations with the data, making it difficult to answer questions about the effectiveness and safety of SSRIs in clinical practice. Overall, there was evidence of greater reduction in depressive symptoms to a predetermined level deemed a "response" on SSRI compared to placebo. However, response was variously defined across trials making interpretation of this outcome difficult. Fluoxetine was the only SSRI where there was consistent evidence from three trials showing that it was effective in reducing symptoms of depressive disorder in both children and adolescents. Those receiving fluoxetine had a greater improvement, scoring on average 5.63 lower on the Children's Depression Rating Scale‐Revised (CDRS‐R) scale (range 17‐113) than those on placebo. It is unclear whether this small difference is a meaningful outcome for children and adolescents with depressive disorders. Nor is it apparent how children and adolescents with co‐morbid conditions and at risk of suicide would respond to SSRIs, given this group were largely excluded from the trials.There is evidence that those prescribed SSRIs are at an increased risk of suicidal ideation and attempts (RR 1.80, 95% CI 1.19 to 2.72) consistent with a number of similar reviews in the area. Additionally, there was an increased risk of other adverse events. It is unclear how this relates to the risk of suicide completion. The trials were not designed to measure any of the suicide related outcomes adequately. At the same time, untreated depression is associated with the risk of completed suicide and impacts on academic and social functioning, however, it is not clear whether treatment with an SSRI will modify this risk in a clinically meaningful way for children and young people.Clinicians need to provide accurate information to children and adolescents and their families about the uncertainties regarding the benefits and risks of SSRI medication for depressive disorders.

Escitalopram in the Treatment of Major Depressive Disorder in Adolescent Patients†

“…Interpretation of efficacy results in clinical trials of antidepressants is further complicated by a significantly (p = 0.002) higher placebo response rate in paediatric patients with MDD (49.6%) than those with obsessive compulsive disorder (31.0%) or other anxiety disorders (39.6%). [8] Despite these difficulties and a general lack of evidence for the clinical efficacy of antidepressant treatment (with the exception of the SSRI fluoxetine) in children and adolescents, [9,10] the consensus of treatment guidelines [2,11,12] is that antidepressant therapy is needed in some paediatric patients with MDD, particularly those with moderate to severe disease.…”

Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents

“…The majority of guidelines on the treatment of depressive disorders in young people recommend the judicious use of medication, specifically selective serotonin reuptake inhibitors (SSRIs), in the context of careful monitoring of symptoms and side effects (AACAP 2007;Cheung 2008a;NICE 2005;Zuckerbrot 2007). The SSRI for which there is the most consistent evidence of a statistically significant reduction in depressive symptoms compared with placebo is fluoxetine (Hetrick 2007;Richmond 2005;Whittington 2004). The Committee on the Safety of Medicines (CSM) (CSM 2004) and the Food and Drug Administration (FDA) (FDA 2004) recommend it as the preferred SSRI for use in young people, and the National Institute for Health and Clinical Excellence (NICE) guidelines state specifically that fluoxetine should be the first antidepressant medication option (NICE 2005).…”

“…A number of randomised controlled trials (RCTs) are available to guide treatment decisions for adult depressive disorder, but the evidence-base for the treatment of child and adolescent depressive disorder is much less established. Nevertheless, an increasing number of RCTs of psychological interventions and antidepressant medications are being undertaken in this population, and several Cochrane reviews of treatments for depressive disorders in children and adolescents are already available or underway (Hazell 2002;Hetrick 2007;Watanabe 2004). Findings from RCTs have suggested that some psychological therapies might be more effective than a variety of control comparators.…”

Treatment duration with selective serotonin reuptake inhibitors among children and adolescents in Finland: a nationwide register study

“…The DDD was assumed to be the dose for liquid dose forms. The basis of this assumption was that there is a range of different drug strengths available in Finland, thereby negating the need for dividing tablets or capsules, and that the recommended daily dose of SSRI treatment is similar for children, adolescents, and adults [13,30]. The discontinuation date was based on the period covered by the last prescription.…”