Introduction: Recent epidemiologic studies have shown that nonmedical use of prescription opioids (NMUPO) and major depression frequently co-occur. Comorbid forms of drug use and mental illness such as NMUPO and depression pose a greater disease burden than either condition alone. However, sociodemographic and substance use differences between individuals with either NMUPO or depression and those with comorbid conditions have not yet been fully investigated. Methods: Data came from the 2011 and 2012 National Survey on Drug Use and Health (NSDUH). Adolescents and adults were examined independently because of differences in screening for major depressive episodes (MDE). Weighted multinomial logistic regression investigated differences between persons with either past-year NMUPO (4.0%) or MDE (5.5%) and those with comorbid NMUPO and MDE (0.6%), compared to persons with neither condition. Results: Females were more likely than males to report either MDE-alone and comorbid NMUPO and MDE, whereas adult men were marginally more likely to report NMUPO-alone (not significant among adolescents). Polydrug use and alcohol use disorders were more pronounced among those with comorbid NMUPO and MDE than persons with either NMUPO-alone or MDE-alone. Persons with independent and comorbid NMUPO and MDE were more likely to report lower income and unemployment versus employment. Conclusions: This study found that independent and comorbid NMUPO and MDE were disproportionately clustered with burdens of lower socioeconomic position, suggesting that a population-based approach to address NMUPO would target these social determinants of health, whereas a high-risk approach to prevention should be tailored to females experiencing MDE symptoms and polydrug users
