The study found that, overall substance use was common among adolescents with treatment-resistant MDD. The subjects who had persistently low substance-related impairment or who showed reduced substance-related impairment had better MDD treatment response, although the direction of this association was uncertain. The study found that 28.1 percent of the 334 adolescents with MDD reported repeated experimentation with substance use at baseline. In addition, substance-related impairment was associated with baseline depression severity, older age, physical/sexual abuse, family conflict, hopelessness, and comorbid oppositional defiant disorder/conduct disorder. Among the adolescents who responded to treatment for MDD, there was significant improvement in substance-related impairment. The treatment response for MDD was best among the adolescents with low 12-week substance-related impairment scores regardless of whether they had high or low baseline substance-related impairments. Baseline suicidal ideation was higher among the youth who progressed to high substance-related impairment compared with those whose substance-related impairment remained low; and parental depressive symptoms predicted the persistence of high substance-related impairment during the study. Treatment types (i.e., pharmacological or cognitive-behavioral therapy) had no significant differential effects on substance use. The 334 participating youth were enrolled in the Treatment of SSRI-Resistant Depression in Adolescents trial. SSRI refers to selective serotonin reuptake inhibitors, which are used in treating adults with comorbid MDD and SUD. Analyses examined substance use with the Drug Use Severity Index and changes in substance use in relation to treatment and depressive symptoms. 4 tables and 43 references