Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis

A systematic literature review was conducted in accordance with the Population, Intervention, Comparison, Outcome strategy: the population comprised adults in the maintenance phase of MDD, the intervention was monotherapy with antidepressants, the comparator medication was a placebo, and the outcomes were described in the following section. The inclusion criteria were as follows: (1) DBRPCTs with a minimum duration of 12 weeks and (2) DBRPCTs with an enrichment design in which patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or a placebo. The following studies were excluded: (1) studies focusing on specific generations (e.g., children and/or adolescents or older individuals) because the efficacy and safety of antidepressants in children and older individuals differ from those in the general adult population [1]; (2) studies including individuals with a dual diagnosis of MDD and other disorders because these studies could lead to heterogeneity [1]; and (3) continuation studies in which individuals with acute symptoms were randomly assigned to treatment groups (i.e., the target population for a continuation study was individuals with MDD in the acute phase). In the present systematic review and meta-analysis, among adults with MDD who benefited symptomatically from antidepressant treatment (i.e., the target population for our systematic review and meta-analysis was individuals with MDD in the maintenance phase), the differences in relapse rates were compared between those who continued with the same antidepressant and those who discontinued the antidepressant. Information on the literature search is displayed in Fig. S1.

The primary outcome was the 6-month relapse rate (efficacy), and the secondary outcome was all-cause discontinuation (acceptability). Other outcomes included discontinuation due to adverse events (tolerability) and the incidence of individual adverse events (safety). If at least five studies have data sufficient to perform a network meta-analysis for a specific safety outcome, a network meta-analysis was conducted for the safety outcome. In the International Classification of Diseases 11th Revision [13], recurrent depressive disorder is defined by a history of at least two depressive episodes with an interval of several months without substantial mood disturbance. In the present study, the term “relapse” is used for convenience rather than “recurrence” similar to the previous study [7], because few studies in this meta-analysis included cases in which worsening of symptoms during the study period was considered a recurrence. The definitions of relapse for each included study are presented in Table S2, and the data synthesis results are shown in Table S3. To avoid unit-of-analysis errors in studies involving two or more treatment arms of the same drug at different doses, data from the treatment arms were pooled for analysis [9]. The extracted data were analyzed based on intention-to-treat or modified intention-to-treat principles. If necessary data were missing from the studies, we searched for them in published systematic review articles; we also attempted to contact the original investigators in order to obtain previously unpublished data.

Both pairwise [14] and Bayesian network meta-analyses [15] were performed using the random-effects model [16]. Because all of the outcomes in our study were dichotomous, risk ratios (RRs) with 95% credible intervals (CrIs) were calculated as effect sizes. Network heterogeneity was assessed using τ² statistics. In pairwise meta-analyses, heterogeneity was assessed using I² statistics. A statistical evaluation of incoherence was not possible because there was no head-to-head study comparing different antidepressants. The treatments for each outcome were ranked using the surface under the curve cumulative ranking probabilities. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool for randomized trials (ROB2) (https://www.riskofbias.info/welcome/rob-2-0-tool↗). The assumption of transitivity was tested by extracting potential effect modifiers such as sample size, duration of study, and mean age and comparing their distribution across comparisons in the network. We determined whether the distribution differences were large enough to threaten the validity of the analysis by comparing the distribution of these possible effect modifiers across treatments included in the network meta-analysis using the Kruskal–Wallis test (continuous variables), the Pearson chi-squared test or the Fisher exact test (categorical variables) and by assessing their actual impact on the treatment effect through meta-regression analyses [17, 18]. A meta-regression analysis was performed to determine the relationship of potentially confounding factors (e.g., mean age, proportion of females, number of episodes, total number of participants, patient status, publication year, sponsorship, duration of preliminary phase, country, discontinuation methods, risk of bias, antidepressant class, dosage schedule, and antidepressant dose) to the magnitude of the effect on the primary outcome. Funnel plots were created to investigate potential publication bias. Finally, to assess the credibility of the findings of each network meta-analysis, the findings were incorporated into the Confidence in Network Meta-Analysis (CINeMA) application, which is an adaptation of the Grading of Recommendations Assessment, Development, and Evaluation approach [19–21].

The literature search and selection strategy are depicted in Fig. S1. The initial search retrieved 148 articles, 50 of which were excluded as duplicates, 95 were excluded based on a review of the abstract and/or title, and three were included in our study [22–24]. In addition, 31 studies were retrieved [25–55] by manually searching the reference lists of previous review article [7]. There were no additional studies found in the clinical trial registers. Finally, the present review included a total of 34 DBRPCTs comprising 9384 patients with MDD (mean age = 43.80 years and %females = 68.10%). The characteristics of the 34 DBRPCTs included are summarized in Table S4. The average length of the study was 40.94 ± 16.27 weeks. Adults in the maintenance group were administered agomelatine (K = 2), amitriptyline (K = 1), bupropion (K = 1), citalopram (K = 3), desvenlafaxine (K = 2), duloxetine (K = 2), escitalopram (K = 1), fluoxetine (K = 4), fluvoxamine (K = 1), levomilnacipran (K = 2), milnacipran (K = 1), mirtazapine (K = 1), nefazodone (K = 1), paroxetine (K = 2), reboxetine (K = 1), sertraline (K = 2), tianeptine (K = 1), venlafaxine (K = 3), vilazodone (K = 1), and vortioxetine (K = 2). In 32 studies, participants in the acute study were required to have a scale-derived minimum of symptoms at baseline. However, one study lacked such a criterion, while another lacked detailed information on the criterion. Although 20 of the studies included only outpatients, six included both inpatients and outpatients, and the remaining eight did not report the status. All studies employed operationalized criteria such as those found in Diagnostic and Statistical Manual of Mental Disorders [56]. For the placebo group, the drug was discontinued abruptly (7 studies) and gradually (12 studies), and the remaining 15 studies did not report the detailed method of drug discontinuation. In addition, 31 studies were sponsored by the industry. The distribution of potential effect modifiers was similar across the comparisons in the network (Table S5). In at least one domain of the ROB2 tool, no studies were determined to be at high risk of bias (Table S6).

The network meta-analysis results are shown in Appendices–. S1 S13

In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed the placebo (Fig. 1, Appendix S1), with RRs (95% CrIs) ranging from 0.149 (0.018–0.610) for nefazodone to 0.583 (0.410–0.789) for fluoxetine. In addition, citalopram, fluvoxamine, and tianeptine outperformed vilazodone. Moreover, nefazodone outperformed agomelatine, bupropion, and vilazodone. Furthermore, sertraline outperformed agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, levomilnacipran, milnacipran, paroxetine, reboxetine, venlafaxine, vilazodone, and vortioxetine. Global heterogeneity was moderate. A funnel plot for this outcome, although no comparisons included at least 10 studies, is displayed in Appendix S1. On meta-regression analyses, no potentially confounding factors were associated with the RR of the primary outcome (Appendix S1). Heterogeneity was not strongly reduced despite adjustments for any potentially confounding factors in a meta-regression (Appendix S1). Thus, no clear evidence of violations of the transitivity assumption for any of the potential effect modifiers analyzed was found (Table S5 and Appendix S1).

Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation (Fig. 1, Appendix S2), with RRs (95% CrIs) ranging from 0.523 (0.327–0.817) for paroxetine to 0.768 (0.518–0.998) for vortioxetine. Desvenlafaxine, paroxetine, and venlafaxine outperformed levomilnacipran and vilazodone. Sertraline also outperformed levomilnacipran. Global heterogeneity was moderate.

Compared to placebo, sertraline was associated with a higher rate of discontinuation due to adverse events (Fig. 2 and Appendix S3). Compared to placebo, although desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting (Fig. 2 and Appendix S4), venlafaxine was associated with a lower incidence of dizziness (Appendix S5). Compared to placebo, any antidepressants were not associated with an increased incidence of headache, somnolence, insomnia, dry mouth, constipation, sweating, weight gain, or sexual dysfunction (Appendices S6–13).

Global heterogeneity was rated as moderate for all outcomes, except for constipation and sexual dysfunction, for which global heterogeneity was rated as high (Appendices S1–13). A considerable local heterogeneity was observed for the majority of outcomes in specific comparisons. Statistical evaluation of incoherence was impossible due to the absence of a head-to-head study comparing various antidepressants. Between network meta-analysis and pairwise meta-analysis, results showed differences in the following in comparison to placebo: agomelatine and levomilnacipran for the 6-month relapse rates, tianeptine for all-cause discontinuation rate, desvenlafaxine and mirtazapine for discontinuation rates due to adverse events, sertraline for nausea/vomiting, desvenlafaxine for dizziness, duloxetine for dry mouth, citalopram for constipation, and sertraline for sexual dysfunction. The within-study bias was rated as “some concerns” for all comparisons. Because funnel plots with fewer than 10 studies were not meaningful [9], all comparisons for publication bias were rated as “suspected,” and any inconsistency could not be evaluated. Furthermore, the comparison was downgraded one level if it was based only on indirect evidence. Therefore, the confidence in the evidence for all comparisons other than vortioxetine versus placebo (low) in terms of the primary outcome was rated as “very low (Appendix S1).”

The current study data were reported in articles cited in this paper.