Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

Abstract

Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.

Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.

Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.

Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Figure 1

Study selection process RCTs=randomised controlled trials. *Industry websites, contact with authors, and trial registries. The total number of unpublished records is the total number of results for each drug and on each unpublished database source. †522 RCTs corresponded to 814 treatment groups.

Figure 2

Network meta-analysis of eligible comparisons for efficacy (A) and acceptability (B) Width of the lines is proportional to the number of trials comparing every pair of treatments. Size of every circle is proportional to the number of randomly assigned participants (ie, sample size).

Figure 3

Forest plots of network meta-analysis of all trials for efficacy (A) and acceptability (B) Antidepressants were compared with placebo, which was the reference compound. OR=odds ratio. CrI=credible interval.

Figure 4

Head-to-head comparisons for efficacy and acceptability of the 21 antidepressants Drugs are reported in alphabetical order. Data are ORs (95% CrI) in the column-defining treatment compared with the row-defining treatment. For efficacy, ORs higher than 1 favour the column-defining treatment (ie, the first in alphabetical order). For acceptability, ORs lower than 1 favour the first drug in alphabetical order. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken. Significant results are in bold and underscored. The certainty of the evidence (according to GRADE) was incorporated in this figure (appendix pp 231–65). OR=odds ratio. CrI=credible interval. Agom=agomelatine. Amit=amitriptyline. Bupr=bupropion. Cita=citalopram. Clom=clomipramine. Dulo=duloxetine. Esci=escitalopram. Fluo=fluoxetine. Fluv=fluvoxamine. Miln=milnacipran. Mirt=mirtazapine. Nefa=nefazodone. Paro=paroxetine. Rebo=reboxetine. Sert=sertraline. Traz=trazodone. Venl=venlafaxine. Vort=vortioxetine. *Moderate quality of evidence. †Low quality of evidence. ‡Very low quality of evidence.

Figure 5

Two-dimensional graphs about efficacy and acceptability in all studies (A) and head-to-head (B) studies only Data are reported as ORs in comparison with reboxetine, which is the reference drug. Error bars are 95% CrIs. Individual drugs are represented by different coloured nodes. Desvenlafaxine, levomilnacipran, and vilazodone were not included in the head-to-head analysis because these three antidepressants had only placebo-controlled trials. ORs=odds ratios. 1=agomelatine. 2=amitriptyline. 3=bupropion. 4=citalopram. 5=clomipramine. 6=desvenlafaxine. 7=duloxetine. 8=escitalopram. 9=fluoxetine. 10=fluvoxamine. 11=levomilnacipran. 12=milnacipran. 13=mirtazapine. 14=nefazodone. 15=paroxetine. 16=reboxetine. 17=sertraline. 18=trazodone. 19=venlafaxine. 20=vilazodone. 21=vortioxetine. 22=placebo.