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. 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.

Placebo Response in Pediatric Anxiety Disorders: Implications for Clinical Trial Design and Interpretation

“…Importantly, given this difference and that recent trials of SSNRIs and SSRIs have (1) utilized similar parallel-group designs, (2) have been collected within a more recent time period, and (3) all used Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994) criteria for the anxiety disorders, we utilized this relative homogeneity in design and population to perform several post hoc analyses. Among these trials (n = 9), the effect size (Strawn et al 2015b) decreases with time (R 2 = -0.84, p = 0.004), although no association between the effect size (Cohen's d) and the number of study sites was found ( p = 0.547) (Fig. 2).…”

“…The effect size of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs) in randomized controlled trials of youth (Strawn et al 2015b) is not associated with the number of sites (A), but is related to the year of publication (B). Lines are shown for weighted least squares regression.…”

“…However, these disorders are also amenable to both psychotherapeutic and psychopharmacologic interventions (Connolly and Bernstein 2007;Walkup et al 2008;Strawn et al 2015a;Strawn et al 2015b), and long-term data suggest that successful treatment may result in sustained reductions in anxiety .…”

Assessment and Treatment of Anxiety in Youth With Autism Spectrum Disorders

“…This finding is in contrast to data in TD youth, which support the use of both medications and therapy. [7][8][9] Most primary care providers lack specific training in managing youth with ASD and co-occurring psychiatric conditions. 10 On the basis of this finding, coupled with the lack of anxiety treatments for youth with ASD, the Anxiety Workgroup sought to develop a systematic approach to the assessment and treatment of anxiety that primary care providers use in their clinical practice.…”

Imipramine-induced mania in a child diagnosed with attention-deficit/hyperactivity disorder (ADHD): a case report

“…The term of "behavioural activation" which occurs at higher rates in paediatric patients than adults refers to; hyperactivity, impulsivity, insomnia or disinhibition and, importantly shows a distinct clinical pattern from treatment-emergent mania [22,23]. A metaanalysis including nine RCTs in children and adolescents showed that behavioural activation is strongly associated with antidepressant treatment compared to placebo [24]. Activation appears to be more common in prepubertal children with an average rate of 10.7% than in adolescents (2.1%) [25].…”