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Screening, brief intervention, and referral to treatment for adolescents (SBIRT-A) is widely recommended to promote detection and early intervention for alcohol and other drug (AOD) use in pediatric primary care. Existing SBIRT-A procedures rely almost exclusively on adolescents alone, despite recognition of caregivers as critical protective factors in adolescent development and AOD use. Moreover, controlled SBIRT-A studies conducted in primary care have yielded inconsistent findings about implementation feasibility and effects on AOD outcomes and overall developmental functioning. There is urgent need to investigate the value of systematically incorporating caregivers in SBIRT-A procedures. This randomized effectiveness trial compares a standard adolescent-only approach (SBIRT-A-Standard) versus a family-based approach (SBIRT-A-Family) in which caregivers are systematically included in SBIRT-A activities. The study includes N = 2,300 adolescents (age 12 – 17) and their caregivers attending one of three hospital-affiliated pediatric settings serving diverse patient populations in major urban areas. Study recruitment, screening, randomization, and all SBIRT-A activities occur during a single pediatric visit. SBIRT-A procedures are delivered digitally on hand-held tablets using patient-facing and provider-facing programming. Primary outcomes (AOD use, co-occurring behavior problems, parent-youth communication about AOD use) and secondary outcomes (adolescent quality of life, therapy attendance) are assessed at screen/initial and 3, 6, 9, and 12 months follow-up. The study is well powered to conduct all planned main and moderator (age, sex, race/ethnicity, youth AOD risk status) analyses. Trial results will inform the critical health decision of whether and how to include caregivers in SBIRT-A activities conducted in pediatric primary care.