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Lucas Spanemberg,1,2 Marco Antonio Caldieraro,1 Edgar Arrua Vares,1 Bianca Wollenhaupt-Aguiar,3,4 Márcia Kauer-Sant’Anna,3,4 Sheila Yuri Kawamoto,1 Emily Galvão,3–5 Gordon Parker,6,7 Marcelo P Fleck1,8 1Mood Disorders Program, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2Department of Psychiatry, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, 3INCT Translational Medicine, Hospital de Clínicas de Porto Alegre, 4Bipolar Disorders Program and Laboratory of Molecular Psychiatry, Universidade Federal do Rio Grande do Sul, 5Centro Universitário Metodista, Porto Alegre, Brazil; 6School of Psychiatry, University of New South Wales, 7Black Dog Institute, Sydney, NSW, Australia; 8Neuromodulation Research Clinic, Douglas Mental Health University Institute, Montréal, ON, Canada Background: The purpose of this study was to compare melancholic patients rated by the CORE measure of observable psychomotor disturbance with nonmelancholic and control subjects across a set of biomarkers.Methods: Depressed patients were classified as melancholic or nonmelancholic by using the CORE measure. Both groups of patients, as well as control subjects, were compared for a set of clinical and laboratory measures. Serum levels of brain-derived neurotrophic factor, of two markers of oxidative stress (protein carbonyl content [PCC] and thiobarbituric acid reactive substances [TBARS]), and of several immunity markers (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-alpha, and interferon-gamma) were analyzed. Results: Thirty-three depressed patients and 54 healthy controls were studied. Depressive patients showed higher IL-4, IL-6, and PCC values than healthy controls. Thirteen (39%) of the depressed patients were assigned as melancholic by the CORE measure. They generated lower interferon-gamma (compared with nonmelancholic depressed patients) and TBARS (compared with both the nonmelancholic subset and controls) and returned higher IL-6 levels than controls. Both depressive groups generated higher PCC scores than controls, with no difference between melancholic and nonmelancholic subsets. Conclusion: A sign-based measure to rate melancholia was able to replicate and extend biological findings discriminating melancholic depression. Signs of psychomotor disturbance may be a useful diagnostic measure of melancholia. Keywords: melancholic depression, oxidative stress, inflammatory cytokines, brain-derived neurotrophic factor