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
Open accessAbstract
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 Study Selection: Published and unpublished randomized clinical trials of SSRIs or SNRIs in youths with DD, AD, OCD, or PTSD were included.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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Many patients do not respond to first-line SSRIs, and most experience significant side effects from them.
“Unfortunately, current therapeutic tools have failed to reduce the prevalence of depression, with many patients not responding to, and most having significant side effects from, first-line treatments such as selective serotonin reuptake inhibitors (SSRIs)”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Locher et al., 2017
The Introduction identifies SSRIs as first-line pharmaceutical treatments for the pediatric disorders studied. The Discussion reports a small, disorder-dependent benefit, and Results > Side Effect Analysis finds more adverse events with antidepressants than placebo. Neither passage establishes that many patients fail to respond to SSRIs or that most experience significant side effects; the study also concerns children and adolescents, not patients generally. No page numbers were provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAntidepressant-treated glutamate levels are positively correlated with Hamilton Depression Rating Scale scores.
“While this reduction does not lower glutamate levels to the same concentration as healthy controls, it has been shown that antidepressant-treated glutamate levels are positively correlated with Hamilton Depression Rating Scale scores187.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [187]
Antidepressants are indicated for depressive disorders, anxiety disorders, PTSD, premenstrual dysphoric disorder, OCD, bulimia nervosa, and binge-eating disorder.
“Antidepressants are indicated and used for depressive disorders, anxiety disorders, posttraumatic stress disorder, premenstrual dysphoric disorder, obsessive-compulsive disorder, bulimia nervosa, and binge-eating disorder, among others.[3][4][5]”
From Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review (2019) · cites this paper as [4]
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- [25]Hedges LV Olkin I Statistical methods for meta-analysis Academic press 2014
- [75]Rutherford BR Sneed JR Tandler JM Rindskopf D Peterson BS Roose SP Deconstructing pediatric depression trials: An analysis of the effect of expectancy and theurapeutic contact J Am Acad Child Adolesc Psychiatry 2011 50 8 782 795 21784298 PMC3143372
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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
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2017-10-01
- Volume
- 74
- Issue
- 10
- Pages
- 1011
- ISSN
- 2168-622X (ISSN-L)
- 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 › Treatment of Major Depression
- Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Social Sciences › Psychology › Social Psychology › 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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