Major depressive disorder (MDD) is one of the most prominent psychiatric disorders, as well as one of the most disabling. In some cases, MDD can lead to suicide which is a major global problem. Current antidepressant treatments targeting serotonin and norepinephrine brain signalling pathways are not effective in all cases of depression and they have significant limitations as it can take weeks to develop beneficial mood-enhancing effects. The limited understanding of MDD pathophysiology at a molecular level has been a major setback in the development of more effective treatment targets. Evidence suggests that alterations in the kynurenine pathway contribute to the aetiology of MDD. However, there is limited information on whether the kynurenine pathway is altered specifically in the brain in MDD.
Dr Samara Brown and colleagues recently investigated the gene expression of the kynurenine pathway enzymes and relevant neuroinflammatory markers in addition to the kynurenine pathway metabolites. Overall, the study reported interesting sex- and suicide-specific alterations in the kynurenine pathway. In the MDD cohort overall, there was evidence of increased neuroinflammation. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls, however, there was no change specific to males with MDD. In addition, the study also reported that MDD subjects who died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects who did not die by suicide, while subjects who did not die by suicide had increased KYAT2 mRNA. These findings are consistent with evidence from the CSF implicating reduced KYNA following suicide attempts. However, not all studies have reported reduced CSF KYNA following suicide attempts or MDD. Overall, these findings suggest that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers and might also assist in managing suicidal behaviour.