Cochrane Review: SSRI/SNRI Antidepressants Effective for Generalized Anxiety Disorder

Selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants are safe and effective treatments for generalized anxiety disorder (GAD), according to a 2025 systematic review from the Cochrane Library.[1] Examples of these drugs are the SSRI escitalopram (LEXAPRO and generics) and the SNRIs venlafaxine (EFFEXOR XR and generics) and duloxetine (CYMBALTA, DRIZALMA SPRINKLE and generics).

The evidence supporting this conclusion, however, was limited to short-term (seven months or less) use of the drugs and did not involve comparisons with other drugs or with psychotherapy (talk therapy). For depression, Public Citizen’s Health Research Group has classified many SSRIs and SNRIs as Limited Use or Do Not Use drugs because of adverse effects and limited efficacy.[2]

Background

GAD is a psychiatric disorder that involves intense and persistent feelings of anxiety that extend well beyond normal worries.[3] The cause is unknown, although genetic and environmental factors are likely important contributors. Although the mechanism by which antidepressants work on anxiety is not fully understood, these drugs modulate the neurotransmitters noradrenaline (norepinephrine) and serotonin, both associated with stress-related brain circuitry.

stress-related brain circuitry. The diagnosis of GAD requires the detection of excessive worry lasting at least six months, difficulty controlling that worry, significant social and work impairment, and at least three of these specific symptoms: restlessness, fatigue, inattention, muscle tension, sleep disturbance or irritability.[4] The diagnosis is inappropriate if there is a physical cause that can explain the anxiety.

Approximately 3% of persons in the United States report experiencing GAD within the past year; the disorder is twice as common in women as in men.[5]

Cognitive behavioral therapy is a first-line treatment for GAD;[6] 10 to 15 hour-long sessions are typical. Such psychotherapy includes instruction on the development of relaxation and other coping strategies. If cognitive behavioral therapy does not work or is not an option, for example because of cost or time constraints, treatment with antidepressants may be considered, along with other talk therapy or in combination.[7] Mindfulness therapies are also used.[8]

The Cochrane review

The Cochrane review[9] assessed widely disseminated randomized controlled trials that were completed as of October 2022. Studies were only included if GAD was the primary medical concern being treated, although psychiatric comorbidities (for example, depression) could also be present. Trials were excluded if there was regular use of benzodiazepines, which are often used to treat anxiety.

The review included 37 unique randomized, placebo-controlled trials with 12,226 participants and durations ranging from 4 to 28 weeks. All participants had a GAD that was classified as moderate to severe. Fifteen studies were conducted in the United States, and 14 were multinational.

Across all studies, antidepressants demonstrated a significant benefit: they lowered by at least 50% the score of participants on the Hamilton Anxiety Rating Scale,[10] a 14-item self-assessment with scores ranging from 0 (no signs or symptoms) to 56 (very severe anxiety). In a subset of 7,267 participants, a reduction in the anxiety scale score was 41% more likely in those treated with antidepressants than those treated with placebo; the evidence was rated as “high certainty.”

In another subset of 11,793 participants, dropouts due to adverse effects were significantly more likely in the antidepressant group, occurring in an estimated 1 of every 17 individuals treated with antidepressants; the evidence was also rated as “high certainty.” An estimated one of every seven participants treated with antidepressants achieved at least a 50% improvement on the rating scale.

Accordingly, the Cochrane authors concluded that they “have high confidence that antidepressants are more effective than placebo.” These authors cautioned, however, that the “evidence is not strong enough to create a clinical guideline” for those with other co-occurring medical conditions because such individuals were excluded from the analyses.

Adverse events considered in the trials included sleepiness or drowsiness; agitation or anxiety; and suicidal wishes, gestures or actions. None of the trials assessed falls, hypotension (low blood pressure), memory impairment or withdrawal symptoms. Risk of bias was “uncertain” in 21 of the included studies because the funder or funder’s role was unclear and was “high” in 15 studies because the trial was sponsored by a pharmaceutical company. Although the review included data about eight different classes of antidepressants, essentially all the studies pertained only to SSRIs and SNRIs.

Recent product labels for escitalopram,[11] duloxetine[12] and venlafaxine[13] list the following common adverse effects: dry mouth, insomnia, somnolence (drowsiness), constipation, decreased appetite, hyperhidrosis (sweating), nausea, abnormal ejaculation, impotence, decreased libido and anorgasmia (not reaching sexual climax). Each of these adverse effects occurred at least 5% of the time and at twice the rate with drug use than with placebo.

What You Can Do

If you suffer from severe and unremitting anxiety, consult with a mental health clinician about diagnosis and treatment options, including whether SSRI and SNRI drugs may be helpful. The adverse effects of SSRI and SNRI drugs are a concern, and long-term safety and effectiveness to treat GAD have not been established. Moreover, these drugs have not been rigorously compared with cognitive behavioral therapy either alone or in combination with medication.
 

References

[1] Kopcalic K, Arcaro J, Pinto A, et al. Antidepressants versus placebo for generalised anxiety disorder (GAD). Cochrane Database Syst Rev. 2025;1(1):CD012942.

[2] Do Not Use: duloxetine (CYMBALTA). Worst Pills, Best Pills News. June 2012. https://www.worstpills.org/newsletters/view/795. Accessed April 10, 2025.

[3] National Institute of Mental Health. Generalized Anxiety Disorder: When Worry Gets Out of Control. U.S. Department of Health and Human Services. NIH Publication No. 22-MH-8090. Revised 2022.

[4] Munir S, Takov V. Generalized anxiety disorder. StatPerls. October 17, 2022.

[5] Baldwin D. Generalized anxiety disorder in adults: epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis. UpToDate. January 10, 2025.

[6] Craske M. Generalized anxiety disorder in adults: cognitive behavioral therapy and other psychotherapies. UpToDate. May 1, 2024.

[7] Craske M, Bystritsky A. Generalized anxiety disorder in adults: management. UpToDate. March 28, 2024.

[8] Mindfulness as an alternative to the antidepressant medication escitalopram for anxiety disorder. Worst Pills, Best Pills News. July 2023. https://www.worstpills.org/newsletters/view/1540. Accessed April 8, 2025.

[9] Kopcalic K, Arcaro J, Pinto A, et al. Antidepressants versus placebo for generalised anxiety disorder (GAD). Cochrane Database Syst Rev. 2025;1(1):CD012942.

[10] Hamilton Anxiety Rating Scale. https://psychology-tools.com/test/hamilton-anxiety-rating-scale. 2025. Accessed April 8, 2025.

[11] AbbVie Inc. Label: escitalopram (LEXAPRO). October 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021323s058lbl.pdf. Accessed April 10, 2025.

[12] Eli Lilly and Company. Label: duloxetine (CYMBALTA). August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021427s055s057lbl.pdf. Accessed April 8, 2025.

[13] Norwich Pharmaceutical, Inc. Label: venlafaxine extended-release tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215429s000lbl.pdf. Accessed April 8, 2025.