Proposed by the EPA Section on Neuroimaging -Converging evidence suggests that patients with major psychoses such as schizophrenia, bipolar disorder or major depression suffer from deficits in brain anatomy and neurocognitive functioning. Also, enhancing neuroprotective mechanisms and anti-inflammation mediators has recently been shown to be beneficial in these disorders. In this context we will present findings from proof of concept studies with aspirin and N-acetyl aspartate in the treatment of depression in bipolar disorder patients. The potential neuroprotective role of long-term antipsychotic therapy on brain anatomy and myelination in psychotic patients will also be debated. Moreover, we will show distinct and shared contributions of diagnosis and symptoms to neurocognition in severe mental illness in the Paisa population in Colombia. In particular, Bipolar-I and schizophrenia displayed nearly identical impairments in accuracy and speed, across cognitive domains, whereas bipolar-II and major depressive disorder performed similarly to controls, with subtle deficits in executive and social cognition. Finally, we will describe the impact of specific hippocampal subfields on negative symptoms and verbal learning in first-episode and drug-naïve schizophrenia patients. This symposium will be extremely innovative, trying to disentangle the complex inter-relationships between treatment, neuroanatomy, psychopathology and cognition in major psychoses, with the long-term goal of improving response in this patient group along with their quality of life. Finally, the data presented in this symposium we will also be crucial for testing novel interventions in this important area of drug development for the treatment of schizophrenia bipolar disorders, and major depression.