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Meta-Analysis
. 2025 Jan 30;1(1):CD012942.
doi: 10.1002/14651858.CD012942.pub2.

Antidepressants versus placebo for generalised anxiety disorder (GAD)

Katarina Kopcalic  1 , Justin Arcaro  2 , Antonio Pinto  3 , Shehzad Ali  1 , Corrado Barbui  4 , Chiara Curatoli  5 , Janet Martin  6 , Giuseppe Guaiana  7
Affiliations
Meta-Analysis

Antidepressants versus placebo for generalised anxiety disorder (GAD)

Katarina Kopcalic et al. Cochrane Database Syst Rev. .

Abstract

Background: Generalised anxiety disorder (GAD) is a mental health condition characterised by excessive anxiety and worry about everyday events. GAD is a common disorder and generally affects women twice as often as men. Treatments include various psychological and pharmacological therapies. Among the pharmacological therapies, antidepressants, in particular, selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), are commonly used for the treatment of GAD and many studies have shown their benefit over placebo. Only one systematic review and meta-analysis comparing all antidepressants to placebo has been done in the past. Since then, new data on existing antidepressants have emerged and new antidepressants have been introduced. An updated and more comprehensive review is needed to provide a stronger understanding of the efficacy, acceptability, tolerability, and impact on the quality of life of the various types of antidepressants compared to placebo.

Objectives: To assess the effects of antidepressants in GAD in adults, specifically: to determine the efficacy of antidepressants in alleviating symptoms of GAD compared to placebo and to review the acceptability of antidepressants in GAD in terms of adverse effects, including the general prevalence of adverse effects compared to placebo.

Search methods: We searched the Cochrane Common Mental Health Disorders (CCMD) register, CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers in October 2022.

Selection criteria: We included randomised controlled trials (RCT) or cluster-RCTs that randomly assigned participants to receive either an antidepressant or placebo for the treatment of GAD. There were no restrictions on dose, frequency, intensity, or duration of treatment. The studies included adults of either sex with a primary diagnosis of GAD and without any serious medical comorbidities. Psychiatric comorbidities were allowed as long as GAD was the primary diagnosis. We excluded studies investigating psychotherapies and those that included participants who had regular use of benzodiazepines. There were no restrictions on setting, country, or language.

Data collection and analysis: Two review authors independently checked eligibility and extracted data following standard Cochrane methodological procedures. We assessed risk of bias using the Cochrane RoB 1 tool. A third review author resolved disagreements between the two primary review authors. We extracted study characteristics, participant characteristics, intervention details, settings, and outcome measures regarding efficacy, acceptability, tolerability, and quality of life. We used GRADE to assess the certainty of the evidence.

Main results: We included 37 unique RCTs with 12,226 participants in the review. The studies included adults with moderate-severe GAD and without any serious medical comorbidities. Few studies included participants with secondary psychiatric comorbidities. The double-blind treatment duration ranged from four weeks to 28 weeks. Antidepressants have a benefit over placebo on rate of treatment response measured as a reduction of at least 50% on the Hamilton Anxiety Rating Scale (HAM-A) (risk ratio (RR) 1.41, 95% confidence interval (CI) 1.29 to 1.55; 20 studies, 7267 participants; high-certainty evidence). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 5 to 9). Antidepressants have no difference in acceptability compared to placebo, measured as the number of participants who dropped out during the trial as a proportion of the total number of randomised participants (RR 1.03, 95% CI 0.93 to 1.14; 33 studies, 11,294 participants; high-certainty evidence). Fewer participants dropped out due to a lack of efficacy in the antidepressant group compared to the placebo group (RR 0.41, 95% CI 0.33 to 0.50; 29 studies, 11,007 participants; high-certainty evidence) with an NNTB of 27 (95% CI 24 to 32), and more participants dropped out due to adverse effects in the antidepressant group compared to placebo (RR 2.18, 95% CI 1.81 to 2.61; 32 studies, 11,793 participants; high-certainty evidence) with a number needed to treat for an additional harmful outcome (NNTH) of 17 (95% CI 13 to 112). We observed similar findings when classes of antidepressants were compared with placebo. The certainty of the evidence for the analyses comparing different classes of antidepressants to placebo was high.

Authors' conclusions: This review added to the growing literature on antidepressants in the treatment of GAD. We have high confidence that antidepressants are more effective than placebo at improving treatment response and that antidepressants have similar acceptability to placebo. Fewer participants dropped out due to a lack of efficacy in the antidepressant group compared to the placebo group and more participants dropped out due to adverse effects in the antidepressant group compared to placebo. We are highly confident in this evidence. This review identified some important gaps in the literature on antidepressants for GAD and can be used as a tool to guide future research. Future studies may be more transparent with their methodology and outcome reporting. Future reviews may also include people with comorbidities, and explore other sources of heterogeneity.

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Conflict of interest statement

KK: none.

JA: none.

AP: none.

SA: none.

CB: none. CB is a Cochrane Editor but was not involved in the editorial process for this review.

CC: none.

JM: none.

GG: is a Diplomate of the Academy of Cognitive Therapy. GG is a Cochrane Editor but was not involved in the editorial process for this review.

Update of

  • doi: 10.1002/14651858.CD012942

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    1. EudraCT 2004-001500-13. An 8-week, multicentre, randomised, double-blind, placebo-controlled, flexible dose study of pregabalin (300-600 mg/day) and venlafaxine XR (75-225 mg/day) for the acute treatment of DSM-IV generalized anxiety disorder in outpatients. www.clinicaltrialsregister.eu/ctr-search/search?query=2004-001500-13 (start date 24 January 2005). [EUDRACT NO.: 2004-001500-13]
EudraCT 2004‐002626‐22 {published and unpublished data}
    1. EudraCT 2004-002626-22. Duloxetine 60 to 120 mg once daily compared with placebo in the prevention of relapse in generalized anxiety disorder. www.clinicaltrialsregister.eu/ctr-search/search?query=2004-002626-22 (start date 24 January 2005). [EUDRACT NO.: 2004-002626-22]
EudraCT 2006‐006339‐31 {published and unpublished data}
    1. EudraCT 2006-006339-31. An 8 week, double blind, placebo controlled, phase 3 trial of pregabalin (150 600 mg/day) in the adjunctive treatment of patients with generalized anxiety disorder (GAD) who have not optimally responded to existing therapies. www.clinicaltrialsregister.eu/ctr-search/search?query=2006-006339-31 (start date 8 March 2007). [EUDRACT NO.: 2006-006339-31]
EudraCT 2008‐003421‐17 {published and unpublished data}
    1. EudraCT 2008-003421-17. Efficacy and safety of agomelatine (25 mg/day with potential blinded adjustment at 50 mg/day) for 12 weeks in non-depressed out-patients with generalized anxiety disorder. A 12-week randomised, double-blind, placebo-controlled, with paroxetine (20 mg/day with potential progressive blinded adjustment to 40 mg/day) as validator, 3-arm parallel groups, international multicenter study. www.clinicaltrialsregister.eu/ctr-search/search?query=2008-003421-17 (start date 18 February 2009). [EUDRACT NO.: 2008-003421-17]
Goldstein 2002 {published data only}
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Hackett 2000 {published data only}
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Hong‐Wei 2006 {published data only}
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ISRCTN75061806 {published and unpublished data}
    1. ISRCTN75061806. Efficacy and safety of agomelatine (25-50 mg/day) for 12 weeks in patients with generalized anxiety disorder: a randomised controlled trial. www.isrctn.com/ISRCTN75061806 (first registered 7 August 2012). [ISRCTN: 75061806]
Kapczinski 2016 {unpublished data only}
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    1. Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Schläfke S, et al. Lavender oil preparation Silexan is effective in generalized anxiety disorder – a randomized, double-blind comparison to placebo and paroxetine. International Journal of Neuropsychopharmacology 2014;17(6):859-69. - PubMed
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References to studies awaiting assessment

Allgulander 2007 {published data only}
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Baldwin 2012d {published data only}
    1. Baldwin DS, Schweizer E, Xu Y, Lyndon G. Does early improvement predict endpoint response in patients with generalized anxiety disorder (GAD) treated with pregabalin or venlafaxine XR? European Neuropsychopharmacology: Journal of the European College of Neuropsychopharmacology 2012;22(2):137-42. [DOI: 10.1016/j.euroneuro.2011.07.005] - DOI - PubMed
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Meoni 2001 {published data only}
    1. Meoni P, Salinas E, Brault Y, Hackett D. Pattern of symptom improvement following treatment with venlafaxine XR in patients with generalized anxiety disorder. Journal of Clinical Psychiatry 2001;62(11):888-93. [DOI: 10.4088/jcp.v62n1109] - DOI - PubMed
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Mychaskiw 2009a {published data only}
    1. Mychaskiw MA, Alvir JM, Hoffman DL, Herman BK, Joshi A. Functional and quality of life impairment in generalized anxiety disorder: effect of short-term treatment with pregabalin and venlafaxine-XR. European Psychiatry 2009;1:S535.
Mychaskiw 2009b {published data only}
    1. Mychaskiw MA, Alvir JM, Herman BK, Pallanti S, Joshi A. Insomnia and quality of life in generalized anxiety disorder: impact on clinical presentation and response to pregabalin and venlafaxine-XR. European Psychiatry 2009;1:S534.
NCT00332891 {published and unpublished data}
    1. EudraCT 2005-003180-23. An 8-week, double blind, placebo-controlled, multicenter study with paroxetine (20 mg q24) as positive control, evaluating the efficacy and safety of 2 fixed doses of SR58611A (175 mg q12 and 350 mg q12) in outpatients with generalized anxiety disorder. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:200... (start date 2 February 2006). [EUDRACT NO.: 2005-003180-23-CZ]
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NCT00390650 {published and unpublished data}
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NCT00715039 {published and unpublished data}
    1. NCT00715039. Clinical study assessing a new scale to measure onset of action in generalized anxiety disorder. clinicaltrials.gov/study/NCT00715039 (first posted 15 July 2008). [NCT00715039]
Roberts 2006 {published data only}
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Schweizer 1993 {published data only}
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Shammas 1977 {published data only}
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References to ongoing studies

jRCT2031220156 {published and unpublished data}
    1. jRCT2031220156. A placebo-controlled, randomized, double-blind, multicenter study to evaluate the efficacy and safety of venlafaxine in Japanese outpatients with generalized anxiety disorder. jrct.niph.go.jp/en-latest-detail/jRCT2031220156 (first registered 22 June 2022). [WHO MAIN ID: JPRN-jRCT2031220156] [WEBSITE: https://trialsearch.who.int/Trial2.aspx?TrialID=JPRN-jRCT2031220156]

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