Mental illnesses have a complicated genetic basis, and it is very difficult to explain their biology using only a genetic approach. In collaboration with international partners, we have started to develop a complementary strategy focusing on proteins of the central nervous system. This approach is based on the fact that in chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, the pathology is manifested by the detection of insoluble protein aggregates in the brain. Based on the observed abnormal protein homeostasis in postmitotic neurons in patients with these diseases, we drew the parallel and hypothesised that proteins may similarly accumulate in the form of smaller aggregates and occur in chronic mental illness. Initial studies show that such proteins are present in the brains of patients, but their practical diagnostic value is limited. The proteins observed to date were: DISC1, TRIOBP, NPAS3, CRMP1, and dysbinidin-1. Therefore, we hypothesised that the abnormal proteostasis observed in the brain of patients with chronic mental illness might correspond to abnormal expression of serum proteins. In this study, we focused on five proteins previously identified as potentially aggregating proteins in the brains of patients with mental illness. A total of 150 subjects, 50 subjects with schizophrenia, 50 subjects with major depressive disorder, and 50 healthy controls were enrolled in the study. All subjects were informed of the planned testing method prior to their voluntary consent. Blood samples were collected at the Rijeka Clinical Hospital Centre and subsequently analysed as part of a doctoral thesis at the Department of Biotechnology, University of Rijeka. A new protocol for blood serum was therefore developed, adapted from previously published protocols performed on cells and brain samples. The insoluble protein fraction is purified from each serum sample of the blood. Western blotting was used to determine the presence of the above five proteins. In this study, DISC1, CRMP1, and NPAS3 were not detectable in the insoluble fraction of the blood serum of the studied individuals. TRIOBP-1, TRIOBP-5/6, and dysbindin-1 were detected in a subset of samples, indicating possible abnormal proteostasis in the blood manifested as aggregate formation. Dysbindin-1 was detected in two schizophrenia patients, but neither in a control sample nor in patients with major depressive disorder, whereas the detected TRIOBP isomers were not specific for either mental illness diagnosis. Surprisingly, high NPAS3 concentrations were detected in whole blood serum. Higher than average NPAS3 levels was shown to correlate significantly with a diagnosis of schizophrenia. These patients also had a higher proportion of first-degree relatives with other mental illnesses. Considering all patient samples of those who had proteostasis disorder, 11 patients who had one or more of these pathologies (NPAS3, dysbindin-1, TRIOBP-1, and/or TRIOBP-5/6) showed a slight but significant increase in PANSS total score (p = 0.031), primarily due to higher scores on the general psychopathology scale. Other proteins have also been detected by mass spectrometry in insoluble fractions of blood serum, such as vinculin, ANKRD proteins, including POTEF and PDE4IP in individuals diagnosed with major depressive disorder. In summary, most of the proteins that accumulate in the brains of patients with severe mental disorders are not clearly detectable and do not clearly correspond to a particular diagnosis. Two interesting exceptions are dysbindin-1 and NPAS3, which may be associated with schizophrenia and deserve further investigation. Mass spectrometry revealed additional proteins that may form protein aggregates in the blood, particularly in patients with major depressive disorder, and that have not previously been studied in the brain. Despite a limited number of patients, this study provides preliminary evidence that the severity of schizophrenia symptoms may be associated with impaired protein proteostasis that accumulates in the brain of patients with schizophrenia. These findings warrant further studies with larger groups or specific subject populations to confirm the role of abnormal proteostasis in serum blood in patients with chronic mental disorders. Keywords: blood serum, protein aggregates; schizophrenia; major depressive disorder.