Mediating Effects of Neural Targets on Depression, Weight and Anxiety Outcomes of an Integrated Collaborative Care Intervention: The ENGAGE-2 Mechanistic Pilot RCT

Integrated treatments for comorbid depression (often with anxiety) and obesity are lacking; mechanisms are poorly investigated. In a mechanistic pilot trial, adults with BMI ≥30 and Patient Health Questionnaire-9 scores ≥10 were randomized to usual care (n=35) or an integrated behavioral intervention (n=71). Outcomes were changes at 6 months in BMI and Depression Symptom Checklist 20-item (SCL-20) as co-primary, and Generalized Anxiety Disorder Scale (GAD-7) as secondary. Neural targets were changes at 2 months in the activation and functional connectivity of regions of interest in the negative affect circuit as primary, and in the cognitive control, default mode, and positive affect circuits as secondary. Participants were 47.0 (SD 11.9) years, 76% women, 55% Black, and 20% Latino. SCL-20 (between-group difference, -0.3 [95% CI: -0.6, -0.1]) and GAD-7 (-2.9 [-4.7, -1.1]), but not BMI, decreased significantly at 6 months in the intervention vs. usual care. Only GAD-7 changes at 6 months significantly correlated with neural target changes at 2 months in the negative affect (anterior insula, subgenual/pregenual ACC, amygdala) and cognitive control circuits (dlPFC, dACC). Effects were medium-to-large (0.41ꟷ1.18 SDs). Neural target changes at 2 months in the cognitive control circuit only differed by treatment group. Effects were medium (0.58ꟷ0.79 SDs). Compared with usual care, the study intervention led to significantly improved depression but not weight loss, and the results on neural targets were null for both outcomes. The significant intervention effect on anxiety might be mediated through changes the cognitive control circuit, but this warrants replication.