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Depression is one of the significant problems in adults that accounts for up to five percent of cases worldwide. Volunteers were divided into eight groups, and their serum samples were tested for FBG, carbonyl contents, IFN-γ and TNF-α. Reactive oxygen species (ROS) modified human serum albumin (HSA)(ROSHSA) was used as an antigen and levels of serum autoantibodies were estimated by direct binding and inhibition ELISA in all subjects. Significant biophysical structural modifications were observed in ROS-HSA with increased carbonyl contents compared to native-HSA (N-HSA). Significantly high levels of carbonyl content (2.68±0.33 nmol/mg protein; p> 0.001) and pro-inflammatory cytokines IFN-γ (7.4±0.61 pg/ml; p> 0.001) and TNF-α (1.47±0.23 pg/ml; p> 0.001) were detected in serum samples from FDS. Similarly, a high level of autoantibodies against ROS-HSA was observed in females who were depressed and smokers (FDS) group (0.89±0.07; p> 0.001) compared to males who were both depressed and smokers (MDS)(0.66±0.049). Furthermore, inhibition ELISA results exhibited high recognition of serum autoantibodies from FDS subjects (78.6±5.7 mean maximum percentage inhibition MMPI) compared to MDS (58.8±5.2 MMPI) subjects. Incoherence, long term unchecked chronic psychological stress may cause oxidation of blood proteins, which subsequently result in structural alterations of biomolecules, thus generating new-epitopes, capable of inducing autoantibodies specific for ROS-modified proteins. These autoantibodies may be a potential marker for subjects suffering from …