Default mode network connectivity and treatment response in geriatric depression

Introduction Depression is associated with decreased default mode network (DMN) connectivity. Memantine is a non-competitive N-methyl-D-aspartate receptor antagonist that is currently FDA-approved for the treatment of cognitive symptoms in dementia. We evaluated the relationship between changes in DMN connectivity and improvement in depression in a subsample of our parent clinical trial comparing escitalopram/memantine (ESC/MEM) to escitalopram/placebo (ESC/PBO) in older depressed adults (NCT01902004). Methods Twenty-six participants with major depression (age >60 years) and subjective memory complaints underwent treatment with ESC/MEM (n=13) or ESC/PBO (n=13), and completed baseline and 3-month follow-up resting state magnetic resonance imaging scans. DMN maps were estimated using group independent analysis and dual regression; a single DMN component, comprising both anterior and posterior DMN key nodes (precuneus and medial prefrontal cortices), was identified. The 3-month change in DMN connectivity was calculated by subtracting the baseline DMN map from the 3-month DMN map. Multi-block partial least squares correlation analysis was used to evaluate the impact of treatment on DMN connectivity changes and their relationship with symptom improvement (as assessed by the MADRAS) at 3 months (controlling for age and sex). Results A significant latent variable was identified, reflecting DMN connectivity related to symptom improvement (p=0.01). Although there were no significant overall group differences in DMN connectivity changes, greater improvement in depressive symptoms was more strongly correlated with DMN connectivity increases in posterior and lateral DMN regions, as well as both increases and decreases in portions of the anterior DMN, in the ESC/MEM group (r=0.97, 95% confidence interval: 0.85-0.98) than in the ESC/PBO group (r=0.36, 95% confidence interval: 0.14-0.71). Figure 1 shows the DMN connectivity changes associated with symptom improvement (Red areas: increased DMN connectivity following treatment was more positively associated with symptom improvement in the ESC/MEM group than in the ESC/PBO group. Blue areas: decreased DMN connectivity following treatment was more positively associated with symptom improvement in the ESC/MEM group than in the ESC/PBO group). Conclusions Increased DMN connectivity in posterior and lateral nodes of the DMN following 3 months of treatment with ESC was associated with greater improvement in depression severity as assessed by the MADRS; however, this relationship was further enhanced with the addition of MEM than with placebo. This stronger relationship at 3 months from treatment initiation may be related to greater longer-term clinical and cognitive outcomes with ESC/MEM than with ESC/PBO. The present study adds to the limited literature on the role of the DMN in treatment-related effects in geriatric depression, and supports an improved engagement of brain circuitry beneficial to the amelioration of depressive symptoms with combined ESC/MEM treatment in older adults with depression and subjective memory complaints. Funding Sponsored by NIH grants R01MH097892 and AT009198, and National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881.