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 Hospit...