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Original Investigation
August 30, 2017

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

Author Affiliations
  • 1Department of Clinical Psychology & Psychotherapy, University of Basel, Basel, Switzerland
  • 2Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Department of Psychology, Stanford University, Stanford, California
  • 4Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland
  • 5Program in Placebo Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
  • 6Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts
  • 7Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Psychiatry. Published online August 30, 2017. doi:10.1001/jamapsychiatry.2017.2432
Key Points

Question  Is there a scientific justification to prescribe selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for children and adolescents, based on what is known about their efficacy and safety?

Findings  In a systematic review and meta-analysis including 36 trials (6778 participants), selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors were significantly more beneficial compared with placebo in treating common pediatric psychiatric disorders, yet also led to significantly more treatment-emergent and severe adverse events, such as suicide ideation and suicide attempts, as well as study discontinuation due to adverse events. The magnitude of the effect and adverse event profiles were disorder dependent.

Meaning  There is some evidence for the benefit of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in children and adolescents, but owing to the higher risk for severe adverse events, a cautious and individual cost-benefit analysis is of importance.

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.

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