Last reviewed:October 2019
Last updated:May  2019
08 May 2019

Comprehensive network meta-analysis provides guidance to inform choice of medication in GAD

  • A comprehensive new network meta-analysis on medications for generalised anxiety disorder has concluded that there are several effective treatment choices available across different classes of medication and that a failure of initial drug therapy might not be a reason to abandon a pharmacological treatment strategy.

  • While treatment decisions may previously have been based on factors such as patient preference, clinician experience, comorbidities, and potential drug interactions, this meta-analysis allows an evidence-based prioritisation of the many treatment options for GAD. 

  • The meta-analysis found that duloxetine, venlafaxine, escitalopram, and pregabalin were effective and relatively well-tolerated. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also effective and well-tolerated but the supporting evidence base was smaller. Quetiapine, paroxetine, and benzodiazepines were effective but poorly tolerated. 

  • The findings were based on 89 trials published between 1994 and 2017, and included more than 25,000 patients randomly assigned to 22 different active drugs or placebo. Outcomes were defined as mean difference in change in Hamilton Anxiety Scale score and acceptability (study discontinuations for any cause). 

  • This topic has been updated to reflect these findings in the context of clinical experience with these drugs, and now recommends duloxetine, venlafaxine, and escitalopram as first-line options, with mirtazapine, sertraline, fluoxetine, paroxetine, buspirone, and agomelatine as alternatives. Quetiapine, benzodiazepines, and pregabalin are second-line options and should generally only be prescribed if first-line options have proved ineffective. Tricyclic antidepressants are not covered by the meta-analysis, but remain a second-line option.

See Management: approachSee Management: treatment algorithm

Original source of update



History and exam

Key diagnostic factors

  • presence of risk factors
  • excessive worry for at least 6 months
  • anxiety not confined to another mental disorder
  • anxiety not due to medication or substance
  • muscle tension
  • sleep disturbance
  • fatigue
  • restlessness
  • irritability
  • poor concentration

Other diagnostic factors

  • headache
  • sweating
  • dizziness
  • gastrointestinal symptoms
  • muscle aches
  • increased heart rate
  • shortness of breath
  • trembling
  • exaggerated startle response
  • chest pain

Risk factors

  • family history of anxiety
  • physical or emotional stress
  • history of physical or emotional trauma
  • diabetes
  • other anxiety disorder
  • adolescence or early adulthood
  • female sex

Diagnostic investigations

Investigations to consider

  • thyroid function tests
  • urine drug screen
  • 24-hour urine for vanillylmandelic and metanephrines
  • pulmonary function tests
  • ECG
  • echocardiogram
  • electroencephalogram (EEG)
Full details

Treatment algorithm


Emeritus Professor Medical Director

Anxiety Treatment and Research Centre

McMaster University and St Joseph’s Hospital




RPS has personally received royalties for articles published in UpToDate (Wolters Kluwer) and the Compendium of Therapeutic Choices, 2nd edition (Canadian Pharmacists Association).

Research Director

Consultant Psychiatrist

Southern District Health Board

Senior Lecturer

Department of Psychological Medicine

Dunedin School of Medicine

Otago University


New Zealand


CG is an author of the Royal Australian and New Zealand College of Psychiatrists clinical practice guideline on social phobia, panic disorder, and generalised anxiety disorder. He is a contributor to the Cochrane Common Mental Disorders group, writing on generalised anxiety disorder, and has authored papers relating to heterogeneity of the database separately to Cochrane work. Otago University has commercial and research relationships with multiple pharmaceutical companies. 

Dr Richard P. Swinson and Dr Christopher Gale would like to gratefully acknowledge Dr Elizabeth Hoge and Dr Phebe Tucker, previous contributors to this topic.

Peer reviewersVIEW ALL

Research Director

University of Alabama

School of Medicine Tuscaloosa Campus

College of Community Health Sciences




LD declares that she has no competing interests.

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