Discussion
LLD, depression, depressed, executive dysfunction
SECONDARY
In this single-site, two-phase randomized, controlled antidepressant trial in LLD, pre-treatment resting-state functional connectivity in DMN, limbic, and CCN regions significantly predicted clinical outcomes. Beyond primary analyses associating pre-treatment regional resting connectivity measures in these networks with post-treatment depression severity, secondary analyses suggested that resting connectivity within the DMN differentially moderated response to treatment assignment and was associated with change in depression severity over time (These findings are largely concordant with past work in younger adult cohorts associating pre-treatment DMN, sgACC, and hippocampal resting functional connectivity patterns with response to antidepressant medications (Chin Fatt et al., In primary analyses, higher pre-treatment resting connectivity between the sgACC with both anterior and posterior DMN hubs was also associated with lower post-trial depression severity (Just as the hippocampus emerged as a key hub predicting antidepressant response in the EMBARC study (Chin Fatt et al., We previously reported volumetric differences in the OFC in LLD (Taylor et al., Finally, higher resting-state connectivity within the CCN was associated with poorer clinical response, or conversely, lower within-network CCN connectivity was associated with better response. This is surprising given previous findings in LLD demonstrating that lower CCN connectivity is related to persistent depression, executive dysfunction, and poor antidepressant medication response (Alexopoulos et al., Exploratory analyses examining outcomes from the open-label bupropion trial should be viewed cautiously. Sample size and multiple comparisons are an issue with these analyses, as less than half of study participants progressed to that study phase. Moreover, by definition, this approach eliminated individuals with a more ‘favorable’ network connectivity pattern who responded during the blinded trial.A strength of this study included its rigorous clinical design as a blinded, controlled trial. However, limitations include a modest overall sample size, with the allocation resulting in a small placebo arm. The number of subjects excluded because of past surgical history due to concerns for MRI safety may have reduced study generalizability to more medical ill elders. Moreover, while antidepressant trial durations of 8 weeks are common, some individuals may need 12 weeks or longer to exhibit a clinical response. Thus our design may have classified some individuals who needed more time on medication as ‘nonresponders’. Multiple comparisons are an additional limitation in our secondary and exploratory analyses. In order to reduce the number of total comparisons, we tested a set number of In conclusion, pre-treatment resting state functional connectivity patterns across multiple intrinsic networks are associated with the response to pharmacotherapy in older depressed adults. This advances our understanding of the neurobiological profile that characterizes an individual who will likely respond to first-line antidepressant treatment and extends it into older adults. When combined with previous work in this area (Chin Fatt et al., 