During the last decade, several meta-analytic studies employing different methodological approaches have had inconsistent conclusions regarding antidepressant efficacy. Herein, we aim to comment on methodological aspects that may have contributed to disparate findings. We initially discuss methodological inconsistencies and limitations related to the conduct of individual antidepressant randomized controlled trials (RCTs), including differences in allocated samples, limitations of psychometric scales, possible explanations for the heightened placebo response rates in antidepressant RCTs across the past two decades as well as the reporting of conflicts of interest. In the second part of this article, we briefly describe the various meta-analyses techniques (e.g., simple random effects meta-analysis and network meta-analysis) and the application of these methods to synthesize evidence related to antidepressant efficacy. Recently published antidepressant metaanalyses often provide discrepant results and similar results often lead to different interpretations. Finally, we propose strategies to improve methodology considering real-world clinical scenarios.