An investigation of kynurenine pathway metabolism, the hypothalamic-pituitary-adrenal axis, and inflammatory markers in Major Depressive Disorder

Abstract

Major Depressive Disorder (MDD) is a debilitating mental health problem with a lifetime prevalence rate of more than 16%. Despite its prevalence, a biological mechanism accounting for all aspects of the disorder has yet to be established. While the monoamine hypothesis of depression was the most widely supported biological theory of the disorder’s causation for several decades, there is a lack of evidence that this is the primary dysfunction in MDD. Moreover, the most commonly prescribed type of antidepressant medication, the selective serotonin reuptake inhibitor, enhances serotonergic transmission yet about half of MDD patients who use this treatment do not experience remission. For this reason, it is essential to investigate other biological systems that have been hypothesised to play a role in depression. Shunting of tryptophan metabolism toward kynurenine pathway (KP) and away from 5-HT synthesis has been suggested as a possible aetiological factor in depression, though this theory has yet to be confirmed. Furthermore, the two systems that may promote activation of the KP, the hypothalamic-pituitary adrenal (HPA) axis and activation of the inflammatory response system are known to play a role in depression pathophysiology. This thesis aims to establish the dysfunction of each of these pathways and their relationship to one other in a cohort of depressed patients. The HPA axis is the endocrine system responsible for stress responses which has frequently been shown to be hyperactive in depressed patients. Significant elevation of cortisol, a glucocorticoid produced by the HPA axis in response to stress, was detected at wakening in the depressed cohort. The depressed group also exhibited a higher cortisol/cortisone ratio at wakening. Cortisone is an inert glucocorticoid, thus increased cortisol/cortisone ratio indicates greater HPA activation. This ratio at wakening was positively correlated to transcriptional expression of the gene encoding for the 11β-HSD1 enzyme which converts cortisone to cortisol, providing further supportive evidence for hypercortisolemia. These findings provide evidence in support of HPA axis dysregulation in depression. Activation of the inflammatory response system was assessed in depressed patients by measurement of circulating concentrations and transcriptional expression of inflammatory cytokines. In addition, a volumetric analysis of brain structures of the limbic system was undertaken to ascertain if there were any associations with inflammatory markers. Gene expression of IL-1β in whole blood was found to be elevated in patients compared to healthy controls however this was the only indicator of potential inflammation in the depression cohort. The hippocampal CA3 and CA4 subfields were found to have reduced volume in depressed patients. Furthermore, significant associations between both inflammatory markers and hippocampal subfield volumes with markers of HPA axis activity were revealed by correlational analyses, suggesting the systems are potentially linked. Activation of the HPA axis and the immune system are known to induce tryptophan metabolism into kynurenine via tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) respectively. Tryptophan, the precursor to 5-HT and kynurenine, was found to be depleted in depressed patients in this study, and relative ratios of downstream kynurenine metabolites were determined to be imbalanced in depressed patients. Specifically, circulating kynurenic acid concentration was decreased while the ratio of circulating quinolinic acid to kynurenine concentrations was increased. These findings assert that the imbalance of kynurenine metabolic products, which result in oxidative stress and potential excitotoxicity in the brain, are apparent in depressed patients. Moreover, several measures of KP activity were found to be correlated to measures of HPA axis and immune activation, suggesting that KP dysregulation exists in conjunction with alterations of these systems. Ultimately, these findings indicate that underlying biological causes and consequences of depression may be accounted for by a network that encompasses all of these pathways. Due to the heterogeneous nature of MDD, an additional goal was to evaluate dysfunction of the HPA axis, immune system, and KP between depression subtypes and varying symptom profiles. The effect of early life adversity, atypical depressive subtype, recurrence of depressive episodes, and medication use on expression of biological measures were assessed to gain greater insight into the variation of dysfunction that exists within the disorder. Increased inflammation was witnessed in patients who had experienced early life adversity and in those with greater anxiety symptoms. Meanwhile, depressed patients with increased suicidality expressed greater KP induction which was associated with HPA axis indicators rather than markers of the inflammation response system. While these findings are preliminary, they emphasise the importance of designing future studies with the intention of dissecting biological differences between depressive symptom profiles. Taken together, this study demonstrates a dysfunctional biological network in depression involving HPA axis, immune system, and KP alterations, and emphasises the importance of assessing the interplay of these systems between depressive subtypes.