Depression is the leading cause of disability worldwide.1 Antidepressants are widely used in the treatment of major depressive disorder (MDD), but there is longstanding debate about their efficacy and effectiveness. Clinicians need high-quality evidence to guide the selection of antidepressant medication for individual patients.
Cipriani and colleagues2 performed a systematic review and network meta-analysis of the efficacy and acceptability of antidepressants for adults with acute MDD. The authors searched multiple databases to identify randomized, double-blind controlled trials (RCTs) comparing antidepressants with either placebo or another antidepressant as monotherapy for adults age ≥18 with MDD (DSM-III, DSM-IV, DSM-5, and ICD-10). They included all second-generation antidepressants approved by regulatory agencies in the United States, Europe, or Japan. They also included two tricyclic antidepressants (amitriptyline and clomipramine), trazodone, and nefazodone. Studies were excluded if antidepressants were not in the therapeutic range, were quasi-randomized trials, if ≥20% of subjects had bipolar disorder, psychotic depression, or treatment-resistant depression, or if subjects had serious comorbid physical illness.
The primary outcomes were:
1) efficacy (proportion of subjects with ≥50% reduction of the total score on a standardized observer-rating scale for depression) and
2) acceptability (proportion of subjects who discontinued treatment for any reason)
Secondary outcomes were endpoint depression score, remission rate, and the proportion of early dropouts because of adverse events. Outcomes were recorded as close to 8 weeks as possible for all analysis. The authors estimated summary odds ratios (ORs) for dichotomous outcomes and standardized mean differences (SMD) for continuous outcomes using pairwise and network meta-analysis. Risk of bias was assessed in accordance to the Cochrane Handbook for Systematic Reviews of Interventions. The robustness of findings for primary outcomes was evaluated using subgroup analyses and meta-regression.
The authors identified 522 RCTs (comprising 116,477) patients, done between 1979 and 2019), and comparing 21 different antidepressants or placebo that met study inclusion criteria.
Mean sample study size was 224 participants; mean age was 44; and median duration of treatment was 8 weeks. All antidepressants except milnacipran had at least one placebo-controlled trial, and only levomilnaipran was not directly compared with another active drug.
In terms of efficacy, all antidepressants were more effective than placebo (OR range=1.37 to 2.13). There was a small- to medium-effect size for remission with all antidepressants (SMD=0.30). In terms of acceptability, agomelatine (OR=0.84) and fluoxetine (OR=0.88) were associated with significantly fewer dropouts than placebo; by contrast, clomipramine (OR=1.30) was associated with significantly more dropouts than placebo. All antidepressants were associated with higher dropouts due to adverse events (OR range=1.64 to 4.44). The certainty of evidence was graded as moderate to very low.
Agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (OR range=1.19 to 1.96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were among the least efficacious drugs (OR range=0.51 to 0.84). In terms of acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (OR range=0.43 to 0.77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine were the antidepressants associated with the highest dropout rates (OR range=1.30 to 2.32).
The authors concluded that all antidepressant were more efficacious than placebo in adults with MDD with modes effect size. Escitalopram, mirtazapine, paroxetine, agomelatine, and sertraline had a relatively higher response and lower dropout rate than the other antidepressants. By contrast, reboxetine, trazodone, and fluvoxamine were associated with generally inferior efficacy and acceptability profiles compared with the other antidepressants. Differences between antidepressants were smaller in placebo-controlled trials than in head-to-head studies. Industry funding was not associated with substantial differences in terms of response or dropout rates. The authors also observed that antidepressants tended to show a better efficacy profile when they were novel and used as experimental treatments than when they had become old. An important limitation is that the quality of many comparisons was assessed as low or very low for some antidepressants.
The bottom line
Findings from this network meta-analysis represent the most comprehensive currently available evidence base to guide the initial choice about antidepressant treatment for acute MDD in adults.
Dr Miller is Associate Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Editor for Psychiatric Times.
1. GBD 2015 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1603–1658.
2. Cipriani A, Furukawa TA, Salanti G, et al. 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. Lancet. 2018;391:1357–1366.