Sex and gender differences in co-occurring substance use and depressive disorders: a systematic review

<i>Background:</i> Major depressive disorder (MDD) and substance use disorders (SUDs) frequently co-occur, influenced by sex (biological) and gender (sociocultural) factors. The extent and consistency of these differences across substance types in populations with co-occurring MDD remains unclear. <i>Objectives:</i> This systematic review synthesizes evidence on sex and gender differences in the prevalence, clinical characteristics, and treatment outcomes of individuals with co-occurring MDD and four SUDs: alcohol use disorder (AUD), cannabis use disorder (CUD), opioid use disorder (OUD) and cocaine use disorders (CoUD). <i>Methods:</i> Following PRISMA guidelines, we searched PsycINFO, MEDLINE, and Embase for peer-reviewed studies from inception to present. Eligible studies examined co-occurring MDD and at least one SUD, and disaggregated outcomes by sex or gender. <i>Results:</i> Forty-seven studies were included (<i>N</i> = 648,414), spanning diverse age groups and geographic regions. Women with SUDs were more likely to experience co-occurring MDD, particularly in AUD and OUD; findings were less consistent for CUD and CoUD. Men with MDD were more likely than women to report co-occurring AUD. Co-occurring MDD-SUD conferred increased suicide risk, particularly among women. Treatment-related findings were mixed: some evidence suggested MDD increased relapse risk in men but buffered relapse in women. Common methodological limitations included inconsistent definitions of sex and gender and reliance on cross-sectional designs. <i>Conclusion:</i> Sex and gender shape the risks and treatment trajectories of co-occurring MDD and SUDs, underscoring the need for personalized screening, suicide prevention, and relapse management strategies. Greater conceptual clarity and inclusion of gender-diverse individuals could inform equitable clinical practices and targeted interventions.