Antidepressants available in Japan for older people with major depressive disorder: A systematic review and meta‐analysis

Abstract Aim To update the major depressive disorder (MDD) treatment guidelines of the Japanese Society of Mood Disorders, we conducted a systematic review and pairwise meta‐analysis of double‐blind, randomized, placebo‐controlled trials of available antidepressants in Japan for older adults with MDD. Methods Outcome measures included response rate (primary), improvement in depressive symptom scale score, remission rate, all‐cause discontinuation, discontinuation due to adverse events, and at least one adverse event. A random‐effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI). Results Nine double‐blind, randomized, placebo‐controlled trials (n = 2145) were identified. No study has been conducted in Japan. Our meta‐analysis included the following antidepressants: duloxetine, escitalopram, imipramine, sertraline, venlafaxine, and vortioxetine. Antidepressants have significantly higher response rates than placebo (RR [95% CI] = 1.38 [1.04, 1.83], p = 0.02). Antidepressants outperformed placebo in terms of improving depressive symptom scale score (SMD [95% CI] = −0.62 [−0.92, −0.33], p < 0.0001). However, antidepressants were associated with a higher discontinuation rate due to adverse events (RR [95% CI] = 1.94 [1.30, 2.88], p = 0.001) and a higher incidence of at least one adverse event (RR [95% CI] = 1.11 [1.02, 1.21], p = 0.02) compared to placebo. The groups did not differ significantly in terms of remission rate or all‐cause discontinuation. Conclusions Our meta‐analysis concluded that treatment with antidepressants available in Japan is only weakly recommended for moderate to severe MDD in older adults.

Recent treatment guidelines have shed light on the etiology, clinical course, and prognosis of adults with early-and late-onset depression. 1 A network meta-analysis for general adults (approximately <65 years) with major depressive disorder (MDD) found that all antidepressants were associated with higher response rates compared to placebo. 2 However, a network meta-analysis for older adults (approximately ≥65 years) with MDD (O-MDD) revealed that the majority of antidepressants had similar response rates to placebo (only duloxetine was effective). 3A recent pairwise meta-analysis also found that pooled newer antidepressants were not more effective for O-MDD than placebo. 4However, this meta-analysis included antidepressants unavailable in Japan, such as buspirone, citalopram, and fluoxetine.Furthermore, some double-blind, randomized, placebo-controlled trials (DBRPCTs) were published after previous meta-analyses [3][4][5] were completed.To update the MDD treatment guidelines of the Japanese Society of Mood Disorders, 6 we conducted a systematic review and pairwise meta-analysis using DBRPCTs of available antidepressants in Japan for O-MDD.

| ME THODS
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Table S1). 7The detailed methods are provided in the Open Science Framework (https:// osf.io/ vnx2u ).Detailed information about our literature search strategy is shown in Figure S1.4][5] To update the literature search of previous systematic reviews, [3][4][5] we searched the PubMed, Cochrane Library, and Embase databases for relevant studies published between January 1, 2016, and November 23, 2023.
The PICO strategy for our study is as follows: P: O-MDD I: Pooled available antidepressants in Japan C: Placebo O: Response rate (primary), improvement in depressive symptom scale score, remission rate, all-cause discontinuation, discontinuation due to adverse events, and at least one adverse event (data synthesis for efficacy outcomes: Table S2).If the required data was missing from the studies, we looked for it in published systematic review articles.
A random-effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI).Heterogeneity was assessed using I 2 statistics (I 2 ≥ 50% indicating heterogeneity). 8In the event of significant differences in the dichotomous variable between 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, as determined by a single-group summary meta-analysis.Because the primary outcome results showed significant heterogeneity (I 2 = 82%), we conducted sensitivity and meta-regression analyses to look for any confounding factors.Furthermore, because imipramine has been shown to have a higher risk of various adverse events when compared to newer antidepressants, 9,10 another sensitivity analysis was performed for allcause discontinuation, discontinuation due to adverse events, and at least one adverse event, excluding imipramine's DBRPCT. 10Egger's regression was used to identify publication bias in the meta-analysis.These analyses were conducted using Review Manager software (version 5.4) 8 and Comprehensive Meta-Analysis Software Version 3 (Biostat Inc., Englewood, NJ, USA).
The sensitivity analyses (antidepressant class and overall risk of bias) revealed no subgroups with a substantially reduced heterogeneity (Table S4).Our meta-regression analyses also revealed no associations between any of the factors (mean age, percentage of males, antidepressant dose, dosing schedule, study duration, and total participants) and the effect size for response rate (Table S5).
Another sensitivity analysis, which excluded the imipramine study revealed that, while newer antidepressants were still associated with a higher discontinuation rate due to adverse events, there was no significant difference in the incidence of at least one adverse event between newer antidepressants and placebo (Table S6).

| DISCUSS ION
Our meta-analysis revealed that antidepressants available in Japan were more effective in treating moderate to severe O-MDD.However, the efficacy outcome results showed considerable heterogeneity.We were also unable to identify any causes of the heterogeneities.Furthermore, antidepressants were poorly tolerated in patients with O-MDD.Because our recent network meta-analysis revealed that the safety profile of each antidepressant varies greatly, 9 clinicians should exercise extreme caution when treating physical and mental aspects of O-MDD, including prescribing antidepressants.Thus, treatment with antidepressants available in Japan is only weakly recommended for moderate to severe O-MDD.
Our study had several limitations.First, because there were few studies and participants.Second, our study did not cover all antidepressants available in Japan, including fluvoxamine, milnacipran, mirtazapine, and paroxetine.Third, we did not assess the efficacy, acceptability, tolerability, or safety of individual antidepressants in treating O-MDD.Fourth, while our meta-analysis focused on antidepressants available in Japan, it did not include any studies conducted in Japan.As a result, our meta-analysis findings may not be directly applicable to the Japanese population.

AUTH O R CO NTR I B UTI O N S
TK developed the study concept and design, and performed the statistical analyses.TK and SK took full responsibility for the data integrity and the accuracy of the data analysis.All authors interpreted the data and wrote the article.NI supervised the article.