Depression doubles the risk of incident heart failure (Arch Int Med 2001;161:1725). Depression also doubles the risk of death in heart failure (Eur J Heart Failure 2002;4:541). The potential mediators of the relationship between depression and heart failure are largely unknown. The cytokine hypothesis of depression, states that excessive secretion of cytokines (IL1b, IL6 and TNFa) mediate many of the changes observed in depression (Eur Arch Psychiatry Clin Neurosci, 1992;241:317). The purpose of this prospective study was to evaluate the brain body interaction of depression and heart failure via potential mediators that are known or hypothesised to be altered in depression and in heart failure. 139 HF patients referred for transplant evaluation had PRIME-MD, HAM-D, measures of HF severity, Kansas City Quality of Life, cytokines and neurohormones. Age 53, BP 102/61, NYHA 2.7, EF 28, 6 minute walk 371 meters. Major depression/dysthmia was present in 22% and minor depression in 8%. Depression severity (HAM-D) correlated with log TNFR1 (r=0.26, p=0.003), log MCP-1 (r=0.18, 0.043) and log IL6 (r=0.15, p=0.08). There was an interaction between current depression and current antidepressant use. Subjects without current depression but on antidepressants had higher IL6 than non-depressed subjects who were not on antidepressants (Table). This interaction between antidepressant use and current depression was observed for IL6, TNFR1, MCP-1, Creactive protein, Serum amyloid A (SAA), and Norepinephrine. Patients on antidepressants (regardless of current depression) or with current depression had higher levels of CRP, SAA, TNFR1, and IL6 (all p<0.05) than without depression and no current antidepressant use.