Targeting the Kynurenine Pathway to Improve Mood Disorders

Major depressive disorder (MDD) and bipolar disorder (BD) are prevalent mood disorders. They are among the most debilitating psychiatric conditions, with substantial rates of treatment resistance and suicide risk. Traditional pharmacological interventions involve monoaminergic modulation, but they often fail to achieve full remission. Growing evidence indicates that the kynurenine pathway (KP) may play a pivotal role in the pathophysiology of mood disorders and could represent a promising therapeutic target. MDD and BD are characterized by a shift away from the neuroprotective metabolites of the kynurenine pathway rather than by an increase in neurotoxic metabolites. These alterations are often associated with other pathological hallmarks of mood disorders, such as elevated inflammatory cytokines and changes in brain structure, particularly in striatal and hippocampal volumes. In this narrative review, we searched the PubMed and Embase databases. We discuss how the KP is modulated by currently prescribed therapies, including antidepressants, neuromodulation, and NMDAR antagonists. Finally, we present evidence from preclinical and clinical studies on diverse potential therapeutic targets related to the KP, such as indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase (TDO), and kynurenine 3-monooxygenase (KMO) inhibitors, as well as KYNA mimetics and indirect modulators of the kynurenine pathway (mainly anti-inflammatory drugs and probiotics). We also highlight knowledge gaps, including the need to better understand the role of less-studied molecules such as anthranilic acid and xanthurenic acid, the limited number of preclinical studies and clinical trials on drugs targeting the KP, and the lack of studies addressing mania in both animals and humans.