Depression is a heterogeneous neuropsychiatric disorder with variable clinical presentation and response to treatment. This variability has motivated interest in neuroimaging biomarkers capable of disease characterization and therapeutic prediction. Positron emission tomography (PET) enables in vivo assessment of cerebral glucose utilization, neurochemical targets, inflammatory markers, and cerebral blood flow. This narrative review synthesizes PET studies conducted predominantly in adults with major depressive disorder diagnosed using DSM-based criteria, with bipolar disorder included only when imaging was performed during a depressive episode. Studies were identified through a structured, non-systematic literature search of major databases. Depression is consistently associated with regionally specific PET alterations within cortico-limbic and cortico-striatal circuits; studies most frequently report reduced glucose-derived PET measures in prefrontal and anterior cingulate regions at baseline, with treatment responders showing relative increases or redistribution of these measures following interventions. Neurochemical PET studies demonstrate altered receptor, transporter, or enzyme-related binding in serotonergic, dopaminergic, and noradrenergic systems, while neuroinflammatory and perfusion studies reveal regionally increased PET signals in subsets of patients. Overall, PET findings indicate convergent, region-specific and neurochemical alterations associated with depressive episodes and treatment response. Interpretation is constrained by methodological and clinical heterogeneity, underscoring the need for harmonized, longitudinal PET studies.

Background/Objectives: The present systematic review analyses the neuroradiological findings in subjects with axis I psychiatric disorders (i.e., bipolar, major depressive, schizophrenic, anxiety, and post-traumatic stress disorders) and comorbid substance use disorder in order to elucidate the organic changes that occur in the brains of people suffering from both conditions. Methods: We analysed and compared the different neuroimaging findings extracted from 93 studies and 10,823 patients; articles were obtained from three databases (Scopus, PubMed [Medline], and the Cochrane Controlled Register of Trials [Central]) and subjected to specific eligibility criteria. We selected articles that assessed patients with axis I psychiatric conditions and a comorbid substance abuse disorder; articles had to report relevant neuroimaging findings and bias was assessed via the Newcastle–Ottawa scale. Results: Significant findings were found on the structure or function of psychiatric patients’ brains with comorbid substance abuse, with certain key areas that were further affected by substance use, especially in areas involved in reward processing, with reductions in volume and connectivity and the augmentation of stimuli-related activity. Conclusions: These results present important implications on the current understanding of psychiatric disorders and comorbid substance use, on the importance of neuroradiological tools in the diagnosis and treatment of these disorders, and on the search for potential new targets for the treatment of psychiatric disease and substance addiction.