Re: “A Multicenter Double-Blind,Placebo-Controlled Trial of Escitalopram in Children and Adolescents with Generalized Anxiety Disorder” by Strawn et al.—Concerning Harm–Benefit Ratio in a Recent Trial About Escitalopram for Generalized Anxiety Disorder

To the Editor:

Recently, Strawn et al. (2023) reported on a clinical trial about escitalopram for the treatment of generalized anxiety disorder among children and adolescents. They concluded that “Escitalopram reduced anxiety symptoms and was well tolerated.” This conclusion is not supported by the data presented.

Efficacy, according to the primary outcome, is small, with a standardized mean difference of 0.27 (not reported in the article). None of the six secondary outcomes is statistically significant and the drug–placebo differences are small and even close to zero for the three measures for remission. This raises doubt about clinical significance of the therapeutic effects.

A major concern is suicide risk. In the acute treatment phase, 13 of 136 patients in the escitalopram arm reported suicidal ideation, compared with 2 of 137 in the placebo arm. The authors provided no statistical test, but the odds ratio (OR) is statistically significant, OR = 6.67, 95% confidence interval (CI) = 1.77–47.20, p < 0.01. Strikingly, the findings for suicidal ideation were not discussed at all.

There were also more adverse events other than suicidal ideation with escitalopram than with placebo (55.5% vs. 37.5%), which is statistically significant (OR = 2.07, 95% CI = 1.28–3.37, p < 0.01, not reported in the article). Furthermore, sexual dysfunctions were not systematically assessed but it is known that these are rarely spontaneously reported and occur at much higher rates with antidepressant than with placebo (Serretti and Chiesa, 2009).

Finally, it is well known that adverse events are under-reported in clinical trials (Golder et al., 2016) and methodological biases may lead to an overestimation of efficacy in antidepressant trials (Healy et al., 2018).

Consequently, in this trial, the efficacy of escitalopram is likely not clinically meaningful, and the increase of suicidal ideation and other adverse effects suggests that the drug conveys significant harms. Relative to treatment with placebo, 8% more patients treated with escitalopram developed suicidal ideation (1.5% placebo vs. 9.5% escitalopram) but only 6.2% more patients achieved clinical response (33.3% vs. 39.5%) and 1.5% fewer achieved remission (17.7% vs. 18.8%). Thus, relative to placebo, children and adolescents exposed to escitalopram were more likely to become suicidal than to experience an improvement in anxiety. These results are concerning and the conclusions in the article seem to be misleading.