Newer antidepressant for Japanese adults with major depressive disorder: A systematic review and meta‐analysis

Abstract Introduction The question remains to be elucidated: “Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?” It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with major depressive disorder (MDD). Therefore, we conducted a systematic review and random‐effects pairwise meta‐analysis including these nine double‐blind, randomized, placebo‐controlled trials. Methods We calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI). Results Pooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = −0.20 (−0.27, −0.12), p < 0.00001], response to treatment [RR (95% CI) = 1.23 (1.13, 1.32), p < 0.00001], and remission rate [RR (95% CI) = 1.30 (1.16, 1.45), p < 0.00001]. Although all‐cause discontinuation was not significantly different between the treatment groups, the pooled antidepressant group showed a higher discontinuation rate due to adverse event [RR (95% CI) = 1.60 (1.13, 2.26), p = 0.007] and a higher incidence of at least one adverse event than the placebo group [RR (95% CI) = 1.13 (1.08, 1.18), p < 0.00001]. Discussion We concluded that newer antidepressants are effective for Japanese adults with MDD although the clinicians must monitor the health conditions of these individuals.

Thus, the question remains to be elucidated: "Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?" It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with MDD.Therefore, we conducted a systematic review and random-effects pairwise meta-analysis 14 including these nine DBRPCTs.

| ME THODS
This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Table S4). 15At least two authors simultaneously and independently conducted the literature search, data extraction, and data entry.
Furthermore, the authors double-checked all data for accuracy.
The detailed methods are presented in the Open Science Framework (https://osf.io/h6c2e).The PICO strategy of our study was as follows: P: Japanese adults with MDD.I: Antidepressant.

C: Placebo.
O: Improvement of depressive symptom scale scores (primary outcome), response to treatment, remission rate, all-cause discontinuation, discontinuation due to adverse event, and at least one adverse event (data synthesis for efficacy outcomes: Table S3).
The following studies were excluded: (1) studies focusing on specific generations (e.g., children and/or adolescents or older individuals), (2) studies including individuals with the following characteristics; MDD with psychotic features, MDD with severe somatic illness, treatment resistant depression, and/or bipolar disorder, and (3) studies that allowed to use an antipsychotic during the study. 16We searched the PubMed, the Cochrane Library, ICHUSHI, and Embase databases for studies published before

World Health Organization International Clinical Trials Registry
Platform [http://www.who.int/ictrp/searc h/en/]) to ensure the RCTs were comprehensive and to minimize the effect of publication bias.Moreover, we also used the drug package insert for each newer antidepressant to determine search criteria. 17 The authors independently extracted data from all the included studies.All analyses were based on the intention-to-treat or modified intention-to-treat principles.When the data required for the meta-analysis were incomplete, we contacted the original study investigators to obtain the unpublished data.We also searched for missing data in published systematic review articles.
We calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI) using a randomeffects model and I 2 statistics (I 2 ≥ 50% indicating heterogeneity). 4e pairwise meta-analysis was conducted using the Review Manager software (version 5.4). 4 In case of significant differences in the dichotomous variable between the treatment groups, the number needed to treat to benefit (NNTB) or harm (NNTH) was estimated using the exact rates and 95%CIs in each outcome in both the antidepressant and placebo groups estimated by a single-group summary metaanalysis.Egger's regression was also conducted to detect publication bias in the meta-analysis.These analyses were conducted using the Comprehensive Meta-Analysis Software Version 3 (Biostat Inc.).

| RE SULTS
The result of the literature search is shown in Figure S1.Nine DBRPCTs were included in our systematic review (Table S1).In all trials, the participants were diagnosed with moderate to severe MDD (Table S2), a newer antidepressant (duloxetine, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine) was used.No studies have a high risk of bias in the analysis using the Risk of Bias 2 tool (Fig- ure S2). 4 Pooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = −0.20 (−0.27, −0.12), p < 0.00001, I 2 = 0%, No publication bias for the primary outcome was detected (Figure S3).Although all-cause discontinuation was not significantly different between the treatment groups (Figure 1), the pooled antidepressant group showed a higher discontinuation rate due to adverse event [RR (95% CI) = 1.60 (1.13, 2.26), p = 0.007, I 2 = 0%, NNTH (95% CI) = 56 (31, 143), Figure S4] and a higher incidence of at least one adverse event than the placebo group [RR (95% CI) = 1.13 (1.08, 1.18), p < 0.00001, Our meta-analysis demonstrated that the pooled newer antidepressants group was superior to the placebo group in terms of all efficacy outcomes without considerable heterogeneity.
However, the pooled newer antidepressants seemed to have worse tolerability than placebo.We concluded that newer antidepressants are effective for Japanese adults with MDD although the clinicians must monitor the health conditions of these individuals.
Although the effect size of improvement in depressive symptom scale scores (continuous variable) was small, that of response to treatment (dichotomous variable) was moderate.Thus, there might be a clear difference between Japanese patients with MDD that substantially responded to an antidepressant and those who did not respond well to the antidepressant.Due to possible differences in the efficacy, acceptability, tolerability, and safety of antidepressants in Japanese patients with MDD similar to other population, 18 a network metaanalysis including only Japanese population should be conducted.Our study has some limitations.First, our meta-analysis did not include newer antidepressants such as fluvoxamine, sertraline, and milnacipran because no DBRPCTs for these were conducted in Japan.Second, some DBRPCTs included both Japanese and other populations (Table S3).However, although we conducted a subgroup meta-analysis excluding the studies for the primary outcome,

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2023, without language restriction.The search terms for PubMed, the Cochrane Library, and ICHUSHI (Japanese) included (fluvoxamine OR paroxetine OR sertraline OR escitalopram OR milnacipran OR duloxetine OR venlafaxine OR mirtazapine OR vortioxetine) AND (placebo) AND (Japan OR Japanese) AND (depressi*).The search terms for Embase included ('randomized controlled trial'/exp OR 'randomized controlled trial') AND ('major depression'/exp OR 'major depression') AND ('placebo'/exp OR 'placebo') AND ('japanese (people)'/exp OR 'japanese (people)').Additionally, reference lists of the included articles were manually searched for additional relevant published and unpublished research, including conference abstracts.We also searched clinical trial registries (Clini calTr ials.gov[http://clini caltr ials.gov/] and the Any discrepancies in the selected articles were resolved by consensus of the authors.If multiple papers or academic conference abstracts were reported despite the same research, the literature was screened by confirming the clinical trial registration number and/or reference to past review articles.
pooled newer antidepressants also outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = −0.19(−0.28, −0.10), p < 0.0001, I 2 = 22%].AUTH O R CO NTR I B UTI O N S TK had full access to all data and took full responsibility for the data integrity and the accuracy of the data analysis.TK developed the study concept and design and performed the statistical analyses.All authors interpreted the data and wrote the manuscript.NI supervised the review.