Furukawa TA, et al. - In reducing the burden of depression, the use of second-generation antidepressants as first-line treatment needs to be optimized, so researchers conducted a systematic review and dose-response meta-analysis of double-blind, randomized controlled trials focusing on their dose dependency and their optimal target dose. Searching the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries, they identified 28,554 records; of these, they included 77 studies (19,364 participants; mean age 42.5 years, 7,156 [60·9%] of 11,749 were women). For selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline; 99 treatment groups), a gradual rise in the dose-efficacy curve was observed up to doses between 20 mg and 40 mg fluoxetine equivalents; there was a level to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. They noted increasing dose-efficacy relationship for venlafaxine (16 treatment groups), initially, up to around 75–150 mg, with a more modest increase afterwards. For mirtazapine (11 treatment groups), up to a dose of about 30 mg, they noted an increase in efficacy, which then decreased. Observations suggest optimal acceptability of both venlafaxine and mirtazapine in the lower range of their licensed dose. These findings suggest the achievement of the optimal balance between effectiveness, tolerability, and acceptability in the acute treatment of major depression with the lower range of the licensed dose of the most commonly used second-generation antidepressants.