IMMUNOMETABOLIC FEATURES MAPPING CLINICAL DOMAINS IN STRESS RELATED PSYCHIATRIC DISORDERS: IMPLICATIONS FOR PERSONALIZED INTERVENTIONS
Authors: Cattaneo *Annamaria , D'Aprile Ilari , Petrillo Giulia , Zonca Valentina , Pariante Carmine Maria , Riva Marco Andrea 
Published: February 2025

Abstract
It is well known that one third of depressed patients do not respond to two or more antidepressant treatments and the majority has a chronic or intermittent disease course, experiencing recurrent relapses, or developing physical comorbidity, such as cardiometabolic disorders. The biological underpinnings are multifaceted, complex, and not yet fully understood and we currently lack biomarkers for a better and earlier diagnosis, and biomarkers that can predict and monitor the efficacy of interventions. I will show from both clinical and preclinical perspectives, the role of inflammation, hormones and metabolism as biological systems that could be involved in different pathological domains and targeted differentially by pharmacological and non pharmacological interventions. At preclinical level I will also show data coming from the Prenatal Stress Model, where we have shown that both adolescent and adult vulnerable (for sociability and anhedonia) but not resilient animals, have a pro inflammatory status both in the brain (hippocampus and cortex) and in the periphery (liver). In particular, we have shown higher levels of pro-inflammatory cytokines and microglia markers in the hippocampus of PNS vulnerable animals as compared to control and resilient ones (+26% for IL-1b, +18% for IL-6, +21% for TNFa, +23% of IBA1 all p&lt;0.05). A similar pattern was also observed in the liver (+24% for IL-1b, +20% for IL-6, +18% for TNFa), where we have also found a dysregulated metabolic profile with leptin and adiponectin among the most significant molecules (+23% for leptin and -18%, p&lt;0.05, for adiponectin in vulnerable vs control and resilient). A similar dysregulated immune-metabolic profile was also observed in adult PNS vulnerable animals, suggesting the persistence of this biological features in association with the vulnerable phenotype. I will also show immune metabolic data from clinical cohorts of controls characterized for childhood trauma, depressed patients and patients suffering from borderline personality disorder. For example, we have demonstrated the presence of altered levels of inflammatory and metabolic mediators depressed patients as compared to controls (e.g. for inflammation: +22% for IL-6, +20% for IL-1b, and +18% of MIF, all p&lt;0.05; e.g. for metabolism +25% of insulin, +32% of leptin), which is more pronounced in those that do not respond to pharmacological interventions. Interestingly, a reduction in inflammatory markers is observed, after 12 weeks of treatment, in those patients that do respond to treatment. Finally, I will show data from a cohort of patients with depression (BIODEP study) and a cohort of patients with borderline personality disorder, where we have also performed a RNAseq analyses to show also how not only immune metabolic biomarkers, but also omics mechanisms could serve as potential biomarkers mapping different pathological domains (e.g anhedonia) and the efficacy of pharmacological and psychotherapy based interventions. Overall, I will present clinically relevant research that combines innovative tools in rodents with findings from human studies to provide transformative frameworks to improve our knowledge in the biological mechanisms associated with diseases, also considering different pathological domains, and also the clinical practice, with interventions prescribed in a personalized perspective.