Cognitive dysfunction is a highly prevalent feature of depression that is resistant to anti-depressant treatments
and associated with a worse course and outcome. Although a broad range of cognitive deficits are observed in
depression, it is psychomotor speed and executive function that are most severely impacted during a
depressive episode. A mechanistic understanding of why cognitive deficits emerge in depression is needed to
identify treatment targets. Activated inflammatory physiology - a process in which TNF signaling is critical -
plays a causal role in a substantial proportion of depressed cases based on genetic, clinical, experimental and
observational research. In contrast, evidence that inflammation causes cognitive dysfunction, particularly in the
context of depression, is less clearly established. Both theory and observational data, however, indicate that
inflammation may account for deficits in psychomotor speed and executive function during a depressive
episode. Determining how inflammation relates to cognitive dysfunction in depression is complicated by
notable methodological limitations. First, the nature of the associations between inflammation, depression, and
cognition is difficult to characterize because multiple, overlapping confounds exist (e.g., stress). Second,
cognition is typically assessed intermittently (months/years apart) due to a reliance on in-person, lengthy
cognitive measures that lack (“real-time”) temporal sensitivity. To overcome these limitations, this K23
application proposes using an intensive sampling methodology within a randomized controlled trial (RCT) to
determine whether administration of an anti-inflammatory agent that inhibits tumor necrosis factor (TNF)
signaling improves psychomotor speed and executive function in depressed individuals exhibiting an
inflammatory phenotype over two weeks; exploratory analyses will examine whether decreases in inflammatory
biomarkers are associated with improvements in cognition. Advances in cognitive neuroscience will be
leveraged to assess cognition daily and generate sophisticated estimates of cognitive performance that
address known limitations in conventional indices. A TNF antagonist was selected because of its critical role in
inflammation, known association with psychomotor speed and executive function and because clinical trials
have shown that a TNF antagonist (infliximab) can reduce depressive symptoms and increase effortful
motivation after two weeks in depressed individuals exhibiting an inflammatory phenotype. The applicant
proposes training in the: conduct of experiment research that is well-equipped to determine causality (i.e.
RCT); use of intensive sampling methodologies in clinical samples; use of remote cognitive assessment tools
and sophisticated analytic approaches; and further training in immunology. An interdisciplinary team of
scientists will provide expert mentorship within the highly resourced environment of the Massachusetts General
Hospital. The proposed study will advance the candidate’s long-term career goal of developing a mechanistic
understanding of cognitive dysfunction in depression and accelerate the transition to research independence.
