Selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors for anxiety, obsessive-compulsive, and stress disorders: A 3-level network meta-analysis

PLoS Med. 2021 Jun 10;18(6):e1003664. doi: 10.1371/journal.pmed.1003664. eCollection 2021 Jun.


Background: Anxiety, obsessive-compulsive, and stress-related disorders frequently co-occur, and patients often present symptoms of several domains. Treatment involves the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), but data on comparative efficacy and acceptability are lacking. We aimed to compare the efficacy of SSRIs, SNRIs, and placebo in multiple symptom domains in patients with these diagnoses over the lifespan through a 3-level network meta-analysis.

Methods and findings: We searched for published and unpublished randomized controlled trials that aimed to assess the efficacy of SSRIs or SNRIs in participants (adults and children) with diagnosis of any anxiety, obsessive-compulsive, or stress-related disorder in MEDLINE, PsycINFO, Embase, and Cochrane Library from inception to 23 April 2015, with an update on 11 November 2020. We supplemented electronic database searches with manual searches for published and unpublished randomized controlled trials registered in publicly accessible clinical trial registries and pharmaceutical companies' databases. No restriction was made regarding comorbidities with any other mental disorder, participants' age and sex, blinding of participants and researchers, date of publication, or study language. The primary outcome was the aggregate measure of internalizing symptoms of these disorders. Secondary outcomes included specific symptom domains and treatment discontinuation rate. We estimated standardized mean differences (SMDs) with 3-level network meta-analysis with random slopes by study for medication and assessment instrument. Risk of bias appraisal was performed using the Cochrane Collaboration's risk of bias tool. This study was registered in PROSPERO (CRD42017069090). We analyzed 469 outcome measures from 135 studies (n = 30,245). All medications were more effective than placebo for the aggregate measure of internalizing symptoms (SMD -0.56, 95% CI -0.62 to -0.51, p < 0.001), for all symptom domains, and in patients from all diagnostic categories. We also found significant results when restricting to the most used assessment instrument for each diagnosis; nevertheless, this restriction led to exclusion of 72.71% of outcome measures. Pairwise comparisons revealed only small differences between medications in efficacy and acceptability. Limitations include the moderate heterogeneity found in most outcomes and the moderate risk of bias identified in most of the trials.

Conclusions: In this study, we observed that all SSRIs and SNRIs were effective for multiple symptom domains, and in patients from all included diagnostic categories. We found minimal differences between medications concerning efficacy and acceptability. This three-level network meta-analysis contributes to an ongoing discussion about the true benefit of antidepressants with robust evidence, considering the significantly larger quantity of data and higher statistical power when compared to previous studies. The 3-level approach allowed us to properly assess the efficacy of these medications on internalizing psychopathology, avoiding potential biases related to the exclusion of information due to distinct assessment instruments, and to explore the multilevel structure of transdiagnostic efficacy.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Anti-Anxiety Agents / adverse effects
  • Anti-Anxiety Agents / therapeutic use*
  • Anxiety / diagnosis
  • Anxiety / drug therapy*
  • Anxiety / psychology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Network Meta-Analysis
  • Obsessive-Compulsive Disorder / diagnosis
  • Obsessive-Compulsive Disorder / drug therapy*
  • Obsessive-Compulsive Disorder / psychology
  • Randomized Controlled Trials as Topic
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Serotonin and Noradrenaline Reuptake Inhibitors / adverse effects
  • Serotonin and Noradrenaline Reuptake Inhibitors / therapeutic use*
  • Trauma and Stressor Related Disorders / diagnosis
  • Trauma and Stressor Related Disorders / drug therapy*
  • Trauma and Stressor Related Disorders / psychology
  • Treatment Outcome


  • Anti-Anxiety Agents
  • Serotonin Uptake Inhibitors
  • Serotonin and Noradrenaline Reuptake Inhibitors

Grants and funding

This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES -, Finance Code 001 –, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq -, Finance Code 001, Brazilian federal government agencies, and Fundo de Incentivo à Pesquisa/Hospital de Clínicas de Porto Alegre (FIPE/HCPA). This funding was awarded to GAS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.