Supplementary Material for: Comparative efficacy and safety of benzodiazepines in the treatment of patients with generalized anxiety disorder: a systematic review and network meta-analysis

Introduction
Guidelines recommend that benzodiazepines (BZD) might be used as an add-on to antidepressant therapy during the first weeks of treatment of generalized anxiety disorder (GAD) or as a first-line and stand-alone. Our aim is to evaluate the comparative efficacy and safety of individual BZD in the treatment of patients with GAD.
Methods
In this systematic review and network meta-analysis, we included randomized controlled trials including adults (≥18 years) with GAD and comparing BZD against placebo or an active intervention. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. This study is registered with PROSPERO (registration number CRD42022330264).
Results
We included 56 studies (7556 participants). The certainty of the evidence for the primary outcomes, as measured with CINeMA, varied from high to very low (overall; 40 comparisons scored “very low”, 7 scored “low” and 814 scored “high”). Regarding efficacy, all BZD, in general, were significantly better than placebo, but there were no significant differences between the different BZD (high heterogeneity and inconsistency were detected). Regarding treatment discontinuation, with some exceptions, no significant differences were observed in the comparisons against placebo or other BZD (no or low heterogeneity and inconsistency were observed in the different analyses). Regarding treatment tolerability, none of the BZD showed significant differences compared to placebo, except diazepam (RR=1.61; 95%CI=1.32;1.96). Moderate heterogeneity and low inconsistency were observed in the treatment tolerability network meta-analysis.
Conclusion
BZD are overall efficacious for the treatment of GAD and have a favourable safety profile. No distinctive differences were identified when comparing BZD among themselves.