Review of: Slee A et al, Lancet 2019;393(10173):768–777

Study Type: Network meta-analysis

With over 2 dozen choices, how do we pick a medication for generalized anxiety disorder (GAD)? The authors of this network meta-analysis sought to answer this question.

Network meta-analysis allows researchers to gauge treatments that haven’t been directly compared in head-to-head studies. If drug A works better than drug B and B works better than C, then the network meta-analysis concludes that A is likely to work better than C, even though A and C have never been directly compared.

The investigators selected 89 trials of 25 drugs studied in over 25,000 patients. The primary outcome was change in the Hamilton Rating Scale for Anxiety (HAM-A). Trial length varied from 4 to 26 weeks.

Surprisingly, quetiapine XR was the most efficacious among the medications with large sample sizes. However, its benefit was modest, with a reduction of 3.6 points on the HAM-A compared to placebo (150–300 mg per night, as monotherapy). Quetiapine XR was poorly tolerated with a high discontinuation rate (odds ratio 1.44). The following drugs were well tolerated and are listed in order of efficacy: duloxetine, pregabalin, venlafaxine XR, and escitalopram.

The 4 benzodiazepines were studied as a class, not as individual drugs. Patients quit benzodiazepines much more often than placebo (odds ratio 1.43), although the reasons for discontinuation were not explored.

Studies were excluded if the patients had psychiatric comorbidities other than depression, which means the subjects might have been significantly less ill than the patients we see in routine practice.

One-third of the trials were not placebo controlled, and a fairly large number of them had limited quality. However, a sensitivity analysis concluded that these deficiencies did not significantly distort the results.

Although the meta-analysis did not analyze the data according to the quality of the studies, dose, or duration of treatment, TCPR has analyzed these issues by drilling down on the appendix and the original studies. The studies of pregabalin were all of lower quality. The studies of duloxetine were of the highest quality, followed by escitalopram and venlafaxine XR. For duloxetine, venlafaxine, and escitalopram, high doses (eg, duloxetine 120 mg) were no more efficacious than medium doses (eg, duloxetine 60 mg). Of these 3 antidepressants, only venlafaxine XR was studied for more than 12 weeks, and those studies demonstrated greater efficacy than shorter studies, suggesting that its benefits may build over time.

TCPR’S TAKE
In GAD, duloxetine stands out for its efficacy, safety, and the quality of its studies. This antidepressant has FDA approval in childhood GAD as well. It may take a few months to see the full effects of antidepressants in GAD, and medium doses are as likely to work as higher ones. Quetiapine XR is one of the more effective medications for GAD, but it has major safety and tolerability issues that caused the FDA to withhold its approval in 2009.