The kynurenine pathway in major depressive disorder

Major depressive disorder (MDD) is a serious psychiatric disorder, affecting over 264 million people globally. Despite its devastating and widespread burden, our current understanding of MDD neurobiology is limited. A growing body of evidence, largely obtained from peripheral studies, suggests that alterations in the kynurenine pathway contribute to the aetiology of MDD and disorders involving psychosis. Activation of the kynurenine pathway leads to the formation of neuroactive metabolites via two main branches, including kynurenic acid (primarily in astrocytes) and quinolinic acid (primarily in microglia). Peripheral evidence indicates an increased potential for neurotoxic activity of the kynurenine pathway, however, the impact of kynurenine pathway dysfunction in the brain in MDD is unclear. Furthermore, kynurenine metabolites interact with the glutamatergic system, which is also proposed to be dysfunctional in MDD. Given the ability of the kynurenine metabolites to both activate and inhibit glutamatergic signalling, the interplay between these two systems is important to elucidate. Therefore, the aim of this thesis was to investigate the kynurenine pathway and related glutamatergic alterations in the anterior cingulate cortex (ACC) in MDD, with a focus on identifying subgroup specific alterations, predominately utilising human postmortem brain tissues.