Bipolar disorder (BD) patients have shown increased circulating levels of pro-inflammatory cytokines and cortisol and decreased levels of Brain-Derived-Neurotrophic Factor (BDNF) suggesting that these mediators might be involved in the occurrence of affective episodes disrupting brain plasticity. Aim of the study was to assess variations in peripheral neuroendocrine and inflammatory markers during acute phases of the disease and euthymia as possible predictors of affective episodes and as a reliable signature of the disease. BD patients were enrolled during depressive or manic/hypomanic phases together with age- and sex-matched healthy controls. Complete blood count, cytokines and BDNF were assessed in serum; salivary cortisol was used to evaluate hypothalamic-pituitary-adrenal axis activity. Specific scales were used to evaluate psychiatric symptoms, global functioning and suicidal risk, stress levels and physical comorbidities. All assessments were carried out at the time of enrolment (T0) and after 3 (T1) and 6 (T2) months. Interim results: BD patients show greater BMI; at T0, they are characterised by greater total number of white cells, mean neutrophils number and neutrophil/lymphocyte ratio; no difference was observed among groups with respect to sex and age. Overall, these preliminary results suggest that the BD active phases are associated with a low-grade inflammatory state, potentially related to a different metabolic set-point in BD patients. Further analyses are in progress to evaluate specific fluctuations in the levels of the above-mentioned markers to establish a reliable and predictive BD signature. “Bando Ricerca Indipendente ISS 2021-2023; n.ISS20-9286e4091f8e”