Metabolic Syndrome and Schizophrenia: Adding a Piece to the Interplay Between the Kynurenine Pathway and Inflammation

The biology of schizophrenia is highly complex and multifaceted. Numerous efforts have been made over the years to disentangle the heterogeneity of the disease, gradually leading to a more detailed understanding of its underlying pathogenic mechanisms. Two cardinal elements in the pathophysiology of schizophrenia are neuroinflammation and alterations of neurotransmission. The kynurenine (KYN) pathway (KP) is of particular importance because it is inducted by systemic low-grade inflammation in peripheral tissues, producing metabolites that are neuroactive (i.e., modulating glutamatergic and cholinergic neurotransmission), neuroprotective, or neurotoxic. Consequently, the KP is at the crossroads between two primary systems involved in the pathogenesis of schizophrenia. It bridges the central nervous system (CNS) and the periphery, as KP metabolites can cross the blood-brain barrier and modulate neuronal activity. Metabolic syndrome plays a crucial role in this context, as it frequently co-occurs with schizophrenia, contributing to a sub-inflammatory state able to activate the KP. This narrative review provides valuable insights into these complex interactions, offering a framework for developing targeted therapeutic interventions or precision psychiatry approaches of the disorder.