<p>Systemic inflammation has been linked with major depressive episode (MDE) severity and treatment-resistant depression (TRD), but not for all patients. Brain mechanisms underlying these processes are still under investigation. Objectives: based on an integrative approach, we aimed at identifying clinical, inflammatory and perfusion markers predictive of depression outcome at 6 months. We conducted a longitudinal study including 60 patients diagnosed with MDE, focusing on anxiety and anhedonia as main clinical candidates, inflammation (C-Reactive Protein - CRP) and cerebral blood flow (CBF) using pseudo-continuous arterial spin labeling (pcASL) MRI. A bootstrapped elastic net regression analysis was conducted including clinical, CBF and inflammation as predictors with depressive severity at 6 months as the dependent variable. Our findings exhibited positive association of depression outcome with baseline depression intensity, duration of current episode, CRP, right accumbens, as well as left and right orbito-frontal CBF. Negative predictors were age, disease duration, right and left caudate nuclei, left amygdala, left mid frontal gyrus, and right ventromedial prefrontal cortex CBF. Neither anxiety nor anhedonia were significant predictors. Combining clinical, inflammation and brain imaging outperformed other models in diagnosing depression severity change over time, highlighting the interest of integrative approaches. These results suggested that systemic inflammation and cerebral perfusion abnormalities in key regions involved in emotion, reward processing and decision making, may serve as biomarkers for identifying patients at risk for persistence of depression.</p>