A collection of postings on a range of issues is available on our website (www.mjacksongroup.ca).  This month’s post is again from Ken Pope’s listserv, where he kindly provides daily summaries of current articles in the field.

The article is as follows:
Molecular Psychiatry includes a study: “Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis.”

The authors are Taro Kishi, Toshikazu Ikuta, Kenji Sakuma, Makoto Okuya, Masakazu Hatano, Yuki Matsuda, & Nakao Iwata.

Here’s how it opens:
Major depressive disorder (MDD) is a common mental illness [1], with a 12-month prevalence of 4.4% worldwide [2]. Individuals with MDD in the acute phase undergo pharmacotherapy (e.g., antidepressant therapy) [3] or non-pharmacotherapy (e.g., psychotherapy [4] and electroconvulsive therapy) [5]. Relapse/recurrence rate of these patients is >85% within a decade of an index depressive episode and an average of ≥50% within 6 months of apparent clinical remission if the initially effective treatment is not continued [6]. Therefore, maintenance therapy is necessary to avoid relapse/recurrence [1].

Kato and colleagues recently conducted an important pairwise meta-analysis that included only double-blind, randomized placebo-controlled trials (DBRPCTs) with an enrichment design in which individuals with MDD were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or a placebo (40 studies, n = 8890) [7]. According to this meta-analysis, the antidepressant maintenance group had a significantly lower relapse rate than the antidepressant discontinuation group (odds ratio = 0.38, 95% confidence interval = 0.33–0.43, p < 0.00001). As the relapse rate remained unchanged in both the maintenance and discontinuation groups from 6 months to 1 year, Kato et al. concluded that antidepressant maintenance treatment for at least 6 months after remission is recommended to prevent relapse, with special attention to relapses and treatment failure during this 6-month period. 

Thanks to this excellent study, we conceived the new clinical question of which antidepressants were better in terms of efficacy, acceptability, tolerability, and safety for adult individuals with MDD as a maintenance treatment. A network meta-analysis on individuals with MDD in the acute phase demonstrated although some antidepressants (e.g., agomelatine, escitalopram, mirtazapine, paroxetine, and sertraline) have a relatively higher response rate and lower dropout rate than the others, fluvoxamine, reboxetine, and trazodone have been reported to have generally inferior efficacy and acceptability profiles compared with the other antidepressants [8]. This suggests that not all antidepressants have similar efficacies and acceptability in individuals with MDD in the acute phase. A network meta-analysis is a technique to compare three or more interventions simultaneously in a single analysis by combining both direct and indirect evidence across a network of studies [9]. A network meta-analysis also produces estimates of the relative effects between any pair of interventions in the network and usually yields more precise estimates than a single direct or indirect estimate, thereby allowing estimation of the ranking and hierarchy of interventions [9]. Results from a network meta-analysis cannot be obtained by a pairwise meta-analysis. Moreover, the previous pairwise meta-analyses for individuals with MDD in the maintenance phase did not evaluate the risk of individual adverse events of antidepressants [7, 10, 11]. To answer our clinical question, we conducted a systematic review and network meta-analysis on the 13 outcomes related to the efficacy, acceptability, tolerability, and safety of 20 antidepressants for the treatment of adults in the maintenance phase of MDD.

Here’s how the Discussion opens:
To the best of our knowledge, this is the first systematic review and network meta-analysis to investigate which antidepressant has the best balance of efficacy and acceptability for the treatment of adult individuals with MDD in the maintenance phase. Although desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had the best balance, sertraline was not well tolerated due to its association with nausea/vomiting. Therefore, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine may be beneficial to individuals with MDD in the maintenance phase. However, desvenlafaxine and vortioxetine were associated with a risk of nausea/vomiting in adults with MDD in the maintenance phase as well as in the acute phase [57]. The efficacy, acceptability, tolerability, and safety of the treatment of MDD in the maintenance phase should be carefully considered as treatments prescribed for an acute depressive episode are typically continued into maintenance. Results of a network meta-analysis of adults with acute MDD also revealed that desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had good efficacy and acceptability [8].

In contrast, the findings of the present network meta-analysis suggest that agomelatine, bupropion, escitalopram, levomilnacipran, milnacipran, and vilazodone did not outperform the placebo in terms of 6-month relapse rate. The original DBRPCTs reported that although vilazodone did not differ from placebo in terms of relapse rate at the study-endpoint [23], escitalopram and bupropion were superior to placebo [43, 55]. Two DBRPCTs on agomelatine had inconsistent results [32, 33]. One DBRPCT reported that levomilnacipran outperformed placebo in terms of relapse rate at the study-endpoint [22], while another DBRPCT did not report the statistical result of the outcome [49]; one trial investigating milnacipran also did not report the statistical results [47]. Our pairwise meta-analysis showed that agomelatine and levomilnacipran outperformed the placebo (Appendix S1). Due to the small number of individuals in these antidepressant trials, the 95% CrIs for the primary outcome in the network meta-analysis might be wider. As a result, our network meta-analysis might not be able to detect the significant differences between these antidepressants and placebo.

Here’s how the article ends:
In conclusion, antidepressants such as desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had balanced efficacy, acceptability, and tolerability in the treatment of adults with MDD in the maintenance phase. However, desvenlafaxine and vortioxetine had a risk of nausea/vomiting in adults with MDD in both the maintenance and acute phases.

REPRINTS & OTHER CORRESPONDENCE:
Ken Pope
Hector Y. Adames, Nayeli Y. Chavez-Dueñas, Melba J.T. Vasquez, & Ken Pope:Succeeding as a Therapist: How to Create a Thriving Practice in a Changing World (APA, September, 2022)
Ken Pope, Melba J.T. Vasquez, Nayeli Y. Chavez-Dueñas, & Hector Y. Adames:
Ethics in Psychotherapy & Counseling: A Practical Guide, 6th Edition (Wiley, 2021)

Ken Pope:
Five Steps to Strengthen Ethics in Organizations and Individuals: Effective Strategies Informed by Research and History   (Routledge, 2019)
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