Dear Editors


I read with great interest the article titled ‘The Efficacy of Zuranolone versus Placebo in Postpartum Depression and Major Depressive Disorder: A Systematic Review and Meta-Analysis’ by Winslow et al. (2024) [1]. The authors suggest that in patients with major depressive disorder (MDD) or postpartum depression (PPD), a 14-days course of once-daily zuranolone causes a statistically significant reduction in Hamilton Depression Rating Scale, however, these outcomes are considered clinically significant only for PPD. I have two concerns regarding the presentation of this conclusion.

First, the protocol registered by the authors (registration number INPLASY2023100007; available at doi.org/https://doi.org/10.37766/inplasy2023.10.0007) specifies that both MDD and PPD patients will be included, but no subgroup analysis was planned. Nevertheless, the results of the meta-analysis including MDD and PPD patients were not reported, only MDD and PPD respectively. In addition, even though the Hamilton Anxiety Rating Scale and Montgomery–Asberg Depression Rating Scale were reported in several studies, the results of the meta-analysis were not presented. In other words, the authors likely conducted a meta-analysis and then specifically selected results for PPD patients with significant results, which can cause a selection bias and reporting bias.

Second, the conclusions are based solely on scale-based evaluations. The authors discuss that zuranolone does not provide clinically significant improvement in the treatment of MDD patients, as the mean difference in Hamilton Depression Rating Scale scores compared to placebo is − 2.40. If the authors support this discussion, I should evaluate response and remission rates, which are commonly used indicators of clinical depression [2]. This evaluation is important to clinically demonstrate the efficacy of zuranolone in patients with MDD. In addition, safety outcome should also be incorporated because of the potential for adverse events when doses of zuranolone greater than 30 mg/day are used [3].

Based on the two concerns, not only the long-term use of zuranolone, but also the short-term use of zuranolone may need to be validated in patients with MDD and PPD.