Dorsolateral prefrontal cortex and subcallosal cingulate connectivity show preferential antidepressant response in major depression

Abstract Background Major depressive disorder (MDD) is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory re-analysis of archival data from a clinical trial to identify moderators of treatment outcome to sertraline over placebo. Methods Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care study participants completed MRI prior to randomization to either sertraline or placebo for 8-weeks (n=279). Seed-based functional connectivity was computed using four bilateral seeds (two spheres defined bilaterally): amygdala (AMY), dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex (SCC), and ventral striatum (VS). Functional connectivity maps were generated, principal component analysis performed, linear mixed effects models used to determine moderators of treatment outcome, and post hoc analyses used to determine level of connectivity (low and high, -1/+1 SD from the mean) that were most sensitive to improved depression severity (baseline to week-8) based on treatment. Results Greater mean reduction in HAMD17 by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p=0.05). Conditional on low connectivity in the DLPFC and SCC and high connectivity in the VS and AMY, there was on average 4.8 points greater reduction in HAMD17 with sertraline relative to placebo (p = 0.003). Conclusion In sum, the level of functional connectivity seeded in both the DLPFC and SCC networks may play an important role in identifying a favorable response to sertraline over placebo.