Confirmed: Antidepressants Effective for GAD

A new Cochrane review confirmed that antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), are superior to placebo in adults with generalized anxiety disorder (GAD) and have comparable study dropout rates. However, the long-term impact of antidepressants on GAD remains unclear.

“We have high confidence that antidepressants are more effective than placebo at improving treatment response and that antidepressants have similar acceptability to placebo,” the authors, led by Katarina Kopcalic, MSc, Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada, wrote.

The findings were published on January 30 in the Cochrane Database of Systematic Reviews.

Common, Debilitating Disorder

GAD is a common condition and affects women twice as often as men. It is characterized by excessive anxiety and persistent worry about everyday events. It is often accompanied by physical symptoms such as trembling, poor coordination, muscle aches, sweating, nausea, and an exaggerated startle response.

One estimate puts the lifetime prevalence of GAD at 5.1% in the United States. In addition to being more common in women, research showed the prevalence of GAD is also higher among lower socioeconomic groups and those who are widowed, separated, or divorced.

Treatments include psychological approaches including cognitive therapy, applied relaxation, and medications like benzodiazepines and antidepressants.

Guidelines recommend SSRIs and SNRIs as the first-line treatment for GAD. Antidepressants have a more favorable adverse effect profile than benzodiazepines, which are equally effective.

However, antidepressants can have adverse effects such as gastrointestinal side effects, agitation, and sexual dysfunction. In addition, these medications have been linked to suicidal ideation, especially in younger individuals.

There has been no recent systematic review of all antidepressants for GAD. To address this research gap, investigators conducted an extensive literature search for randomized controlled trials (RCTs), evaluating the efficacy of antidepressants vs placebo in individuals with GAD.

Robust Results

The review included 12,226 participants enrolled in 37 RCTs that ranged in duration from 4 to 28 weeks. Most trials were conducted in high-income countries including the United States and European countries.

Participants had no serious medical comorbidities, with no restrictions on dose, frequency, intensity, or duration of treatment. Psychiatric comorbidities were permitted so long as GAD was the primary diagnosis.

The two primary outcomes were the rate of treatment response measured as a ≥ 50% reduction on the Hamilton Anxiety Rating Scale and acceptability as measured by the dropout rate.

Results showed that antidepressants had a 41% higher treatment response than placebo (risk ratio [RR], 1.41; 95% CI, 1.29-1.55; 20 studies; 7267 participants).

There was no difference between antidepressants and placebo in terms of the dropout rate (RR, 1.03; 95% CI, 0.93-1.14; 33 studies; 11,294 participants).

Fewer participants in the antidepressant groups dropped out due to lack of efficacy than those in the placebo groups (RR, 0.41; 95% CI, 0.33-0.50; 29 studies; 11,007 participants). However, more participants in the antidepressant groups discontinued treatment due to adverse effects (RR, 2.18; 95% CI, 1.81-2.61; 32 studies; 11,793 participants).

All classes of antidepressants — SSRIs, SNRIs, and others — demonstrated results similar to those of placebo across all outcomes. The authors expressed “high confidence in the evidence” for all outcomes.

More participants receiving antidepressants reported adverse effects than those receiving placebo. Specifically, antidepressants were more often associated with sleepiness and drowsiness. However, the incidence of agitation and anxiety was similar between the antidepressant and placebo groups.

Potential Limitations

Despite a comprehensive literature search, researchers found no studies comparing monoamine oxidase inhibitors, noradrenergic and specific serotonergic antidepressants, norepinephrine-dopamine reuptake inhibitors, or norepinephrine reuptake inhibitors with placebo.

In addition, no synthesizable data were available for other outcomes, including falls, hypotension, completed suicide, subjective memory impairment, deaths, and the total number of participants experiencing withdrawal.

The inclusion and exclusion criteria may have limited the applicability of the results. For example, people with other medical comorbidities were excluded from the review, and although other psychiatric comorbidities were allowed, only two studies included subjects with such comorbidities.

“Given that many people with GAD also experience other psychiatric and medical comorbidities, the population in this review may not be representative of the typical GAD population,” the investigators noted.

Another limitation was the lack of data on the long-term effects of antidepressants.

“We don’t have enough information on the potential long-term benefits and harms of antidepressants, even though people often take them for years. This is an area that needs further exploration in future trials,” Kopcalic said in a press release.

Kudos, Concerns

Two experts weighed in on the review via the Science Media Center, an independent venture promoting personal views of professionals on science in the news.

Katharina Domschke, MD, PhD, professor of psychiatry and chair of the Department of Psychiatry and Psychotherapy at the University of Freiburg, Freiburg, Germany, described the long-anticipated update on antidepressants vs placebo in GAD as a robust, methodologically sound analysis with highly compelling effect sizes.

“The present results are very important and ought to increase patients’ trust in the efficacy of pharmacological treatment of generalized anxiety disorder,” said Domschke in a release.

Peter Tyrer, FMedSci, professor of community psychiatry at Imperial College London, London, England, emphasized that the evidence supporting the short-term efficacy of antidepressants for GAD is “unequivocal.”

However, he cautioned that long-term treatment — often the standard practice — raises concerns, particularly regarding potential withdrawal difficulties when discontinuing these medications.

Tyrer also noted that while antidepressants are favored over benzodiazepines due to the latter’s risk for dependence, the issue of adverse effects has merely shifted from one drug class to another. He added that while antidepressants may provide temporary relief, they do not necessarily offer a lasting solution.

The review received no external sources of support. Kopcalic, Domschke, and Tyrer reported no relevant disclosures.