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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

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Locher, Cosima, Koechlin, Helen, Zion, Sean R., Werner, Christoph, Pine, Daniel S., Kirsch, Irving, Kessler, Ronald C., Kossowsky, Joe·2017·JAMA Psychiatry

DOI 10.1001/jamapsychiatry.2017.2432PMC PMC5667359

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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 Study Selection: Published and unpublished randomized clinical trials of SSRIs or SNRIs in youths with DD, AD, OCD, or PTSD were included.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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Authors: Locher, C., Koechlin, H., Zion, S. R., Werner, C., Pine, D. S., Kirsch, I., Kessler, R. C., & Kossowsky, J.
Affiliations: University of Basel (CH)
Boston Children's Hospital (US)
Stanford University (US)
National Institute of Mental Health (US)
Beth Israel Deaconess Medical Center (US)
Harvard University (US)
Corresponding author: Kossowsky, Joe
ORCID: Locher, Cosima
Koechlin, Helen
Zion, Sean R.
Werner, Christoph
Pine, Daniel S.
Kirsch, Irving
Kessler, Ronald C.
Kossowsky, Joe
Venue: JAMA Psychiatry
Publisher: American Medical Association (AMA)
Published: 2017-10-01
Volume: 74
Issue: 10
Pages: 1011
ISSN: 2168-622X (ISSN-L)
DOI: 10.1001/jamapsychiatry.2017.2432
PMC: PMC5667359
OpenAlex: W2752088033
Cited by: 360
References: 90
Citations by year: 2026: 28 · 2025: 32 · 2024: 50 · 2023: 42 · 2022: 37 · 2021: 46 · 2020: 44 · 2019: 48 · 2018: 30 · 2017: 3
FWCI: 23.87
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: JAMA Psychiatry (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (ZIA‐MH002781)
U.S. National Library of Medicine (T15LM007092)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
Health Sciences › Medicine › Psychiatry and Mental health › Mental Health Treatment and Access
Keywords: selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, children and adolescents, depression, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, placebo response, adverse drug reactions, antidepressant efficacy, antidepressant safety, treatment-resistant depression, treatment-emergent mania, suicidal ideation
MeSH terms: Serotonin and Noradrenaline Reuptake Inhibitors, Adolescent, Mental Disorders, Child, Female, Humans, Male, Treatment Outcome, Selective Serotonin Reuptake Inhibitors

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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

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