668. Serotonin, melatonin, and kynurenines: bridging neurochemical pathways in schizophrenia and beyond

Abstract

Abstract Background Cognitive deficits and metabolic syndrome are highly prevalent in schizophrenia (SCZ), suggesting shared underlying biological mechanisms. Emerging evidence points to the dysregulation of tryptophan (Trp) metabolism, specifically the balance between the serotonin/melatonin (MLT) and kynurenine (Kyn) pathways, as a critical factor. Coupled with inflammation and gut microbiome alterations, these neurochemical disruptions may drive the complex pathophysiology of SCZ. Aims & Objectives This research aimed to investigate the interplay between Trp metabolism, inflammation, and gut microbiota in modulating cognitive and metabolic phenotypes in SCZ. We sought to bridge clinical observations with mechanistic insights using a translational approach involving patients with SCZ and complementary SCZ mouse models. Method The clinical study recruited 193 SCZ patients from two centers in Iatly (San Raffaele Hospital and University of Cagliari). Assessments included cognitive domains, metabolic status, inflammatory markers, Trp-MLT/Kyn pathway metabolites, and gut microbiota composition. Two preclinical studies provided mechanistic validation: 1) Melatonin-deficient (C57BL/6) and melatonin-proficient (C3H/HeN) mice were exposed to high-fat diets and MK-801 (to mimic psychosis) to assess genotype-diet interactions; 2) Fecal microbiota transplantation (FMT) from SCZ patients with varying symptom severity was performed into mice to evaluate microbiota-driven neurophysiological changes. Results In patients with SCZ significant associations between Trp metabolites and SCZ phenotypes were found; specifically, the 3-HK/Kyn ratio positively correlated with psychomotor speed, while IDO1 gene expression correlated with executive functioning. Microbiome analysis indicated that Prevotella abundance was associated with obesity, whereas Clostridium sensu stricto was depleted in patients with metabolic syndrome. Preclinical data confirmed that melatonin availability significantly influences vulnerability to psychosis-like behaviors and metabolic stress. Furthermore, FMT from SCZ patients to mice transferred behavioral phenotypes proportional to donor severity and modulated ventral tegmental area dopaminergic firing, alongside shifts in central Trp metabolism and cytokine profiles. Discussion & Conclusions These findings suggest that dysregulated Trp metabolism acts as a translational bridge connecting genetic background, metabolic status, and microbiota-derived signals to SCZ pathophysiology. The integrity of serotonin/melatonin and kynurenine pathways appears essential for maintaining neurocognitive and metabolic homeostasis. Consequently, targeting these interacting pathways and specific biomarkers offers a promising avenue for patient stratification and the development of personalized precision medicine strategies in schizophrenia.