Major depressive disorder (MDD) is a leading cause of disability, affecting more than 300 million people worldwide. We first review the well-known sex difference in incidence of MDD, with women being twice as likely to be diagnosed as men, and briefly summarize how the impact of MDD varies between men and women, with sex differences in symptoms, severity, and antidepressant drug response. We then attempt to deconstruct the biological bases for MDD and discuss implications for sex differences research. Next, we review findings from human postmortem studies, both from selected candidate gene studies and from well-powered, unbiased transcriptomics studies, which suggest distinct, and possibly opposite, molecular changes in the brains of depressed men and women. We then discuss inherent challenges of research on the human postmortem brain and suggest paths forward that rely on thoughtful cohort design. Although studies indicate that circulating gonadal hormones might underlie the observed sex differences in MDD, we discuss how additional sex-specific factors, such as genetic sex and developmental exposure to gonadal hormones, may also contribute to altered vulnerability, and we highlight various nuances that we believe should be considered when determining mechanisms underlying observed sex differences. Altogether, this review highlights not only how various sex-specific factors might influence susceptibility or resilience to depression, but also how those sex-specific factors might result in divergent pathology in men and women.

重度抑郁症 (MDD) 是导致残疾的主要原因，影响着全球 3 亿多人。我们首先回顾了众所周知的 MDD 发病率的性别差异，女性被诊断的可能性是男性的两倍，并简要总结了 MDD 对男性和女性的影响如何不同，以及症状、严重程度和抗抑郁药物方面的性别差异药物反应。然后，我们尝试解构 MDD 的生物学基础并讨论对性别差异研究的影响。接下来，我们回顾了人类尸检研究的结果，包括选定的候选基因研究和强有力的、公正的转录组学研究，这些研究表明抑郁男性和女性大脑中存在明显的、可能相反的分子变化。然后，我们讨论人类死后大脑研究的固有挑战，并提出依赖于深思熟虑的队列设计的前进道路。尽管研究表明，循环性腺激素可能是MDD中观察到的性别差异的基础，但我们讨论了其他性别特异性因素，例如遗传性别和性腺激素的发育暴露，也可能导致脆弱性改变，并且我们强调了我们认为的各种细微差别。相信在确定观察到的性别差异背后的机制时应该考虑。总而言之，这篇综述不仅强调了各种性别特异性因素如何影响抑郁症的易感性或恢复力，而且还强调了这些性别特异性因素如何可能导致男性和女性的不同病理学。