PROJECT SUMMARY: Deficits in cognitive control are core features of late-life depression, contributing both to emotion dysregulation and problems with inhibiting irrelevant information, conflict detection, and working memory. Clinically characterized as executive dysfunction, these deficits are associated with poor response to antidepressants and higher levels of disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood and cognitive performance, however no current pharmacotherapy improves CCN deficits in LLD. Supported by our pilot data, we propose that nicotine acetylcholine receptor agonists enhance CCN function and resultantly improve mood and cognitive performance in late-life depression. The objective of this R61 / R33 proposal is to first determine whether transdermal nicotine enhances CCN neural activity in an exposure-dependent fashion during an emotional response inhibition task (the emotional Stroop task). If we meet our Go Criteria by demonstrating exposure-dependent CCN target engagement, we will then conduct the R33 pilot randomized controlled trial to: 1) determine the relationship between target engagement and clinical improvement; 2) examine the specificity of transdermal nicotine’s effects on the CCN; and 3) obtain preliminary evidence of TDN’s clinical effects. The long-term goal of this line of research is to determine whether nicotinic acetylcholine receptor agonists enhance CCN function and provide clinical benefit to individuals with late-life depression. Supported by our pilot data, this project’s rationale is that it will elucidate whether broad nicotinic acetylcholine receptor agonists enhance CCN activity and if so, does that mechanism positively influence clinical symptoms. A negative finding will improve our understanding of the neural effects of broadly active nicotinic receptor agonists and whether targeting the CCN has therapeutic benefit. Our approach for the R61 phase is to examine in 36 older adults with Major Depressive Disorder whether transdermal nicotine patches enhance CCN activity over 12 weeks as measured during fMRI with the emotional Stroop task while measuring nicotine and nicotine metabolite levels. If we meet Go Criteria by demonstrating exposure-dependent target engagement, we will proceed to the R33 pilot clinical augmentation trial. Seventy-two depressed elders on stable SSRI or SNRI monotherapy will be randomized to 13 weeks of active transdermal nicotine or placebo patches, completing MRI and cognitive testing at baseline and at the trial’s end. Dosing will be guided by nicotine blood levels and based on the relationship between exposure and target engagement as observed in the R61 phase. This proposal is significant and innovative as no current pharmacotherapy improves CCN function or improves cognitive deficits in late-life depression. Transdermal nicotine has a mechanism of action that is distinct from current antidepressants, potentially making it an import...