Skip to content

Slee A, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019;393:768-777. PMID 30712879

One-paragraph summary

A systematic review and random-effects network meta-analysis of randomised trials in adult outpatients with GAD, drawing on MEDLINE, Web of Science, the Cochrane Library, ClinicalTrials.gov, CNKI, Wanfang, Drugs@FDA and commercial pharmaceutical registries (PROSPERO CRD42018087106). From 1,992 screened studies, 89 trials published between 1 January 1994 and 1 August 2017 were included, randomising 25,441 patients to 22 active drugs or placebo. Primary outcomes were efficacy (mean difference in change in Hamilton Anxiety Scale score) and acceptability (all-cause discontinuation). Duloxetine (MD −3.13, 95% CrI −4.13 to −2.13), pregabalin (−2.79, −3.69 to −1.91), venlafaxine (−2.69, −3.50 to −1.89) and escitalopram (−2.45, −3.27 to −1.63) were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone and agomelatine were also efficacious and well tolerated, but on small samples. Quetiapine had the largest effect (−3.60, −4.83 to −2.39) with poor tolerability (discontinuation OR 1.44, 1.16–1.80); paroxetine and benzodiazepines were likewise effective but poorly tolerated.

Key findings

  • A reference ranking of GAD pharmacotherapy that included Chinese-language and regulatory-registry sources.
  • Efficacy and tolerability come apart: the single most efficacious agent is the least well tolerated.
  • The authors' clinical conclusion is often overlooked and is load-bearing: "The failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy."
  • Effects are expressed in HAM-A points, and the spread between the best drug and placebo is ~2.5–3.6 points — narrower than a single published HAM-A severity band (mild 8–14, moderate 15–23, severe ≥24; Matza 2010, PMID 20718076).

Limitations

  • Network meta-analysis assumes transitivity across trials that differ in era (1994–2017), comorbidity policy, and placebo-response magnitude.
  • Several of the "efficacious and well tolerated" agents rest on small samples, as the authors state.
  • HAM-A change is a continuous surrogate; the Cochrane responder analysis of an overlapping literature reports RR 1.41 and NNTB 7 (Kopcalic 2025, PMID 39880377), and the two framings imply different clinical stories that nobody has reconciled.
  • Comorbidity is not stratified, so the ranking cannot answer what works in GAD without depression.

Why it matters

Before this paper, choosing a drug for GAD was guided mainly by class-level guidance and indirect reasoning. After it, there is a published ordering with credible intervals that guidelines, formularies and later networks all cite. It is also the clearest single illustration of GAD's core pharmacological problem: against a placebo arm that improves by more than one standard deviation (d_av 1.23; Bschor 2024, PMID 38809560), even the best drug moves the HAM-A by about three points. Whether that is a treatment worth having is a measurement question as much as a clinical one — which is why this knowledge base pairs the ranking with screening and measurement rather than presenting it alone.

Cited by wiki pages

  • ssri-and-snri-pharmacotherapy.md
  • pregabalin-benzodiazepines-and-others.md
  • treatment-resistant-gad.md
  • screening-and-measurement.md
  • guidelines.md
  • clinical-trials-landscape.md
  • red-flags-and-safety-concerns.md
  • overview.md