• Katarina Kopcalic, Justin Arcaro, Antonio Pinto, Shehzad Ali, Corrado Barbui, Chiara Curatoli, Janet Martin, and Giuseppe Guaiana.
• Department of Epidemiology and Biostatistics, Western University, London, Canada.
• Cochrane Db Syst Rev. 2025 Jan 30; 1 (1): CD012942CD012942.

BackgroundGeneralised 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.ObjectivesTo 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 MethodsWe searched the Cochrane Common Mental Health Disorders (CCMD) register, CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers in October 2022.Selection CriteriaWe 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 AnalysisTwo 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 ResultsWe 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' ConclusionsThis 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.Copyright © 2025 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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