Sex-specific differences in peripheral blood metabolites and biological functions in major depressive disorder: A systematic review and meta-analysis

To explore the sex-specific peripheral blood metabolites and biological functions altered in patients with major depressive disorder (MDD). A search was conducted on PubMed, Cochrane, Embase, Web of Science, and other databases published up to 11/2023. To maximize the search, we also reviewed systematic reviews and meta-analyses on the same topic. We included studies that conducted metabolic characterizations during current depressive episodes or after antidepressant treatments, with all data stratified by sex. Fifty-eight studies involving 83 cohorts with 5285 MDD participants were included in this meta-analysis. Random effects meta-analysis was conducted for data from ≥3 cohorts. We identified 5 sex-specific metabolites from 22 candidate peripheral blood metabolites. In males with MDD, we observed lower levels of estradiol and progesterone, alongside higher levels of androstenedione, dihydrotestosterone, and uric acid compared with female MDD patients. In addition, steroid hormone biosynthesis has been identified as a potentially sex-specific pathway. Our findings highlight significant evidence for targeting sex hormones as a broad understanding of MDD, providing potentially objective diagnostic and therapeutic insights.