Background Randomized, controlled trials have demonstrated that antidepressants are efficacious in the treatment of anxiety disorders in youth. However, there are no recent, systematic analyses of the efficacy, safety or tolerability of these medications in pediatric anxiety disorders. With this in mind, we sought to systematically review and conduct a meta-analysis of double-blind, placebo-controlled-trials of antidepressants in these conditions. Methods A systematic review and meta-analysis of prospective, randomized, parallel-group, controlled trials of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) in pediatric patients with non-OCD anxiety disorders was undertaken using a search of PubMed/Medline (1966–2014). The meta-analysis utilized random-effects models to evaluate change in the Pediatric Anxiety Rating Scale or similar anxiety scale, suicidality and adverse events. Additionally, a series of pharmacologic variables (e.g., serotonin binding) were explored with regard to effect size. Results Data were included from 9 trials involving 1,673 patients and 6 medications, including 5 SSRIs and 3 SSNRI trials. All SSRI/SSNRIs evaluated demonstrated significant efficacy, and the meta-analytic summary estimate was of moderate magnitude (Cohen's d=0.64, confidence interval [CI]: 0.34–0.96, p=0.0017) and there was evidence of modest heterogenity (I2=0.26, p=0.107). Activation trended towards being more likely with antidepressant treatment (OR: 1.86, CI: 0.98–3.53, p=.054), but no increased risk was observed for nausea/abdominal symptoms (p=0.262) or discontinuation as a result of an adverse event (p=0.132). Treatment-emergent suicidality did not differ between antidepressant-treated youth and those who received placebo (OR: 1.3, CI: 0.53–3.2, p=0.514). Conclusions Data for 9 SSRI/SSNRIs suggest superiority to placebo for the treatment of pediatric anxiety disorders with a moderate effect size and a non-significant risk of suicidality.

Adolescents with GAD, who are early in the course of their illness, exhibit abnormalities in neural structures that subserve threat appraisal, modulation of fear responses, attachment, and mentalization.