Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis

Abstract

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.

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-obsessive compulsive disorder (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, pharmacologic variables were explored with regard to effect size, although no correction for multiple comparisons was made with regard to these relationships.

Results: Nine trials involving 1,673 patients and six medications were included. All SSRI/SSNRIs evaluated demonstrated efficacy, and the meta-analytic estimate of effect was of moderate magnitude (Cohen's d = 0.62, confidence interval [CI]: 0.34-0.89, P = .009) and there was evidence of modest heterogeneity (I(2) = 0.29, P = .103). Activation trended toward 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 = .262), discontinuation as a result of an adverse event (P = .132), or suicidality (OR: 1.3, CI: 0.53-3.2, P = .514). Finally, the effect size correlated with the serotonergic specificity of the agent (R = .79, P = .021).

Conclusions: Data for nine SSRI/SSNRIs suggest superiority of antidepressants relative to placebo for the treatment of pediatric anxiety disorders with a moderate effect size.

Keywords: GAD; antidepressants; anxiety; anxiety disorders; child/adolescent; generalized anxiety disorder; pharmacotherapy; separation anxiety.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram.

Figure 2. Funnel plot (A) and forest plot (B) for individual studies of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors in children and adolescents with generalized anxiety disorder, social phobia or separation anxiety disorder

Effect sizes are based on the change in the dimensional anxiety symptom scale from baseline (see methods) and open symbols represent effect sizes and horizontal lines reflect the 95% confidence intervals for each study. Dashed line represents the estimated effect size (Cohen's d=0.62)

Figure 3. Effect size is predicted by serotonergic selectivity in double-blind, placebo-controlled trials of antidepressants in youth with anxiety disorders

Serotonergic specificity is reflected by the ratio of the K_i for norepinephrine to the K_i for serotonin, where K_i is the inhibition constant (in nM), based on radioactive ligand transport competition assays using human specific transporter proteins. Note: potency is inversely related to K_i and, given that concurrent treatment with psychostimulants (which affect norepinephrine and dopamine) was allowed in the trial by March et al, 2008, this study was excluded.