Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents: A Systematic Review and Meta-analysis

Abstract

Importance: Depressive disorders (DDs), anxiety disorders (ADs), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are common mental disorders in children and adolescents.

Objective: To examine the relative efficacy and safety of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and placebo for the treatment of DD, AD, OCD, and PTSD in children and adolescents.

Data sources: PubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Database from inception through August 7, 2016.

Study selection: Published and unpublished randomized clinical trials of SSRIs or SNRIs in youths with DD, AD, OCD, or PTSD were included. Trials using other antidepressants (eg, tricyclic antidepressants, monoamine oxidase inhibitors) were excluded.

Data extraction and synthesis: Effect sizes, calculated as standardized mean differences (Hedges g) and risk ratios (RRs) for adverse events, were assessed in a random-effects model.

Main outcomes and measures: Primary outcomes, as defined by authors on preintervention and postintervention data, mean change data, and adverse event data, were extracted independently by multiple observers following PRISMA guidelines.

Results: Thirty-six trials were eligible, including 6778 participants (3484 [51.4%] female; mean [SD] age, 12.9 [5.1] years); 17 studies for DD, 10 for AD, 8 for OCD, and 1 for PTSD. Analysis showed that SSRIs and SNRIs were significantly more beneficial compared with placebo, yielding a small effect size (g = 0.32; 95% CI, 0.25-0.40; P < .001). Anxiety disorder (g = 0.56; 95% CI, 0.40-0.72; P < .001) showed significantly larger between-group effect sizes than DD (g = 0.20; 95% CI, 0.13-0.27; P < .001). This difference was driven primarily by the placebo response: patients with DD exhibited significantly larger placebo responses (g = 1.57; 95% CI, 1.36-1.78; P < .001) compared with those with AD (g = 1.03; 95% CI, 0.84-1.21; P < .001). The SSRIs produced a relatively large effect size for ADs (g = 0.71; 95% CI, 0.45-0.97; P < .001). Compared with participants receiving placebo, patients receiving an antidepressant reported significantly more treatment-emergent adverse events (RR, 1.07; 95% CI, 1.01-1.12; P = .01 or RR, 1.49; 95% CI, 1.22-1.82; P < .001, depending on the reporting method), severe adverse events (RR, 1.76; 95% CI, 1.34-2.32; P < .001), and study discontinuation due to adverse events (RR, 1.79; 95% CI, 1.38-2.32; P < .001).

Conclusions and relevance: Compared with placebo, SSRIs and SNRIs are more beneficial than placebo in children and adolescents; however, the benefit is small and disorder specific, yielding a larger drug-placebo difference for AD than for other conditions. Response to placebo is large, especially in DD. Severe adverse events are significantly more common with SSRIs and SNRIs than placebo.

Figure 1.. Between-Group Analyses Stratified by Disorder

Because there was only 1 study, posttraumatic stress disorder was not included in the overall analysis. POTS indicates Pediatric OCD Treatment Study; RUPP, Research Unit on Pediatric Psychopharmacology Anxiety Study Group; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. ^aOne study reported 2 different dosages of duloxetine. ^bOne study reported 2 trials that were treated independently for analyses. ^cOne study examined 2 forms of dosing. One treatment arm was sertraline at standard dosing and the second treatment arm was sertraline titrated slowly.

Figure 2.. Drug and Placebo Effect Size by Disorder Category

Because there was only 1 study, posttraumatic stress disorder (PTSD) was not included in subgroup analyses. Responses to selective serotonin reuptake inhibitors (SSRIs) were significantly larger in depressive disorders (DDs) and anxiety disorders (ADs) compared with obsessive-compulsive disorder (OCD) (both P < .001). The placebo response was significantly larger in DDs compared with ADs (P < .001) and OCD (P < .001) and significantly larger in ADs compared with OCD (P < .002). SNRI indicates serotonin-norepinephrine reuptake inhibitor.