Comparative Remission Rates and Tolerability of Drugs for Generalised Anxiety Disorder: A Systematic Review and Network Meta-analysis of Double-Blind Randomized Controlled Trials

Abstract

Background: Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders associated with substantial dysfunction and socioeconomic burden. Pharmacotherapy is the first choice for GAD. Remission [Hamilton Anxiety Scale (HAM-A) score ≤7] is regarded as a crucial treatment goal for patients with GAD. There is no up-to-date evidence to compare remission rate and tolerability of all available drugs by using network meta-analysis. Therefore, the goal of our study is to update evidence and determine the best advantageous drugs for GAD in remission rate and tolerability profiles.Method: We performed a systematic review and network meta-analysis of double-blind randomized controlled trials (RCTs). We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, wanfang data, China Biology Medicine and ClinicalTrials.gov from their inception to March 2020 to identify eligible double-blind, RCTs reporting the outcome of remission in adult patients who received any pharmacological treatment for GAD. Two reviewers independently assessed quality of included studies utilizing the Cochrane Collaboration’s risk of bias tool as described in Cochrane Collaboration Handbook and extracted data from all manuscripts. Our outcomes were remission rate (proportion of participants with a final score of seven or less on HAM-A) and tolerability (treatments discontinuations due to adverse events). We calculated summary odds ratios (ORs) and 95% confidence intervals (CIs) of each outcome via pairwise and network meta-analysis with random effects.Results: Overall, 30 studies were included, comprising 32 double-blind RCTs, involving 13,338 participants diagnosed as GAD by DSM-IV criteria. Twenty-eight trials were rated as moderate risk of bias, four trials as low. For remission rate, agomelatine (OR 2.70, 95% CI 1.74–4.19), duloxetine (OR 1.88, 95% CI 1.47–2.40), escitalopram (OR 2.03, 95% CI 1.48–2.78), paroxetine (OR 1.74, 95% CI 1.25–2.42), quetiapine (OR 1.88, 95% CI 1.39–2.55), and venlafaxine (OR 2.28, 95% CI 1.69–3.07) were superior to placebo. For tolerability, sertraline, agomelatine, vortioxetine, and pregabalin were found to be comparable to placebo. However, the others were worse than placebo in terms of tolerability, with ORs ranging between 1.86 (95% CI 1.25–2.75) for tiagabine and 5.98 (95% CI 2.41–14.87) for lorazepam. In head-to-head comparisons, agomelatine, duloxetine, escitalopram, quetiapine, and venlafaxine were more efficacious than tiagabine in terms of remission rate, ORs from 1.66 (95% CI 1.04–2.65) for duloxetine to 2.38 (95% CI 1.32–4.31) for agomelatine. We also found that agomelatine (OR 2.08, 95% CI 1.15–3.75) and venlafaxine (OR 1.76, 95% CI 1.08–2.86) were superior to vortioxetine. Lorazepam and quetiapine were poorly tolerated when compared with other drugs.Conclusions: Of these interventions, only agomelatine manifested better remission with relatively good tolerability but these results were limited by small sample sizes. Duloxetine, escitalopram, venlafaxine, paroxetine, and quetiapine showed better remission but were poorly tolerated.

The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta‐analytic evaluation of recent meta‐analyses

“…One hundred and two meta‐analyses fulfilled the inclusion criteria (see Figure 1 and supplementary information). These encompassed 69 meta‐analytic comparisons of pharmacotherapies with placebo or TAU, 26 comparisons of psychotherapies with placebo or TAU, 11 comparisons of psychotherapies vs. pharmacotherapies head‐to‐head, and 13 comparisons of combined psychotherapy and pharmacotherapy to either monotherapy 6,12,13,34‐134 . The 102 meta‐analyses encompassed 3,782 RCTs (range: 2 to 522) and 650,514 patients (range: 65 to 116,477) (see supplementary information).…”

“…In the largest meta-analyses for anxiety disorders, pharmacotherapies achieved SMDs in comparison to placebo between 0.33 and 0.45 53,56,64 (see Figure 2). Overall, effect sizes for pharmacotherapy were between 0.01 and 0.56, with the majority of effect sizes being small 53,[55][56][57][58][59][60][61][62][63][64]66,67,69,70 (see supplementary information). RR ranged between 1.20 and 4.03, with most values being small, one medium (monoamine oxidase inhibitors), and one large (benzodiazepines, RR=4.03) 69 .…”

Vortioxetine as a new frontier in the treatment of chronic neuropathic pain: a review and update

“…However, in a recent systematic review and network meta-analysis of double-blind RCTs performed by Kong et al , 157 despite the tolerability of VO, its efficacy was comparable with that of placebo while the remission rate of agomelatine, duloxetine, escitalopram, paroxetine, quetiapine and venlafaxine was superior to that of placebo.…”

“…In the systematic review of Pae et al, 155 the authors suggest that VO may have a potential benefit in the treatment of GAD since VO was found to be more effective than placebo, particularly in patients with a severe form of GAD and with higher scores in the Hamilton anxiety rating scale (HAM-A) test. 156 However, in a recent systematic review and network meta-analysis of double-blind RCTs performed by Kong et al, 157 despite the tolerability of VO, its efficacy was comparable with that of placebo while the remission rate of agomelatine, duloxetine, escitalopram, paroxetine, quetiapine and venlafaxine was superior to that of placebo.…”

Analysis of the Underlying Mechanism of the Jiu Wei Zhen Xin Formula for Treating Generalized Anxiety Disorder Based on Network Pharmacology of Traditional Chinese Medicine

“…Among them, escitalopram and paroxetine of SSRIs, and venlafaxine and duloxetine of SNRIs are the most studied, respectively. However, those medicines may not be well tolerated in GAD patients [ 7 ], and both SSRIs and SNRIs are associated with decreased efficacy at higher doses [ 8 ]. Although there are many recommended pharmacological treatments of GAD, they inevitably have some side effects and may even aggravate treatment-resistant patients.…”