Kynurenines are altered in the brain in depression,in a subgroup dependent manner: Implications for targeted treatment approaches

Abstract

Major depressive disorder (MDD) is a complex and multi-faceted disorder with a high level of heterogeneity at both the clinical and molecular level. Emerging evidence suggests a significant role of the kynurenine pathway in MDD neurobiology that may be associated with specific subgroups. In a recent study, we examined the kynurenine pathway in postmortem anterior cingulate cortex tissue obtained from subjects with and without MDD. We identified significant changes in MDD that were associated with sex and suicide but found minimal changes in the kynurenine pathway when grouping our cohort as a general classification of MDD. Furthermore, we identified significant correlations between age and quinolinic acid that were specific to MDD. In this commentary, we discuss the importance of considering a range of subgroups in the design and analysis of molecular studies in psychiatric disorders. Future studies should examine the extent of subgroup-specific changes to advance our understanding of MDD and explore targeted therapeutic approaches designed to address the specific changes in these subgroups.

Introduction

Major depressive disorder (MDD) is a severe psychiatric disorder that affects the lives of millions of people worldwide. It is well recognised that MDD is a heterogenous disorder, with individuals displaying a wide range of clinical symptoms. This heterogeneity has been one of the major impediments to a clear understanding of the molecular mechanisms potentially driving MDD and therefore in developing targeted, more effective treatments. In this commentary, we discuss the importance of considering various subgroups in the design and analysis of molecular studies in psychiatric disorders, specifically commenting on our recent research investigating the kynurenine pathway in MDD. ¹

The kynurenine pathway is responsible for metabolising tryptophan in mammals. It has primarily gained interest in MDD due to the ability of the downstream neuroactive metabolites, quinolinic acid and kynurenic acid, to modulate glutamatergic signalling, which is implicated in MDD. Given the potential for widespread impacts on signalling in the brain related to local kynurenine pathway changes, it is perhaps surprising how little brain changes have been considered. In our recent study, we investigated the kynurenine pathway in postmortem anterior cingulate cortex (ACC) tissue obtained from individuals with MDD and matched controls. This brain region was the focus of our investigation as neuroimaging and molecular studies consistently identify that this region is associated with depression. In this study, we identified significant changes in MDD that were associated with sex and suicide, but found minimal changes in the kynurenine pathway when grouping our cohort as MDD more broadly. Females with MDD had significantly reduced kynurenic acid compared to female controls. Furthermore, MDD suicide subjects showed decreased kynurenic acid compared to both controls and MDD subjects who died from other causes. While we found no direct evidence of changes to quinolinic acid in MDD compared to controls, we did find a positive correlation between quinolinic acid and age that was present in MDD but not in controls, suggesting potential for age specific changes in quinolinic acid in MDD. These findings are the first molecular evidence in the brain of subgroup-specific changes in the kynurenine pathway in MDD (Figure 1). However, whether these subgroup changes extend to other brain regions implicated in depression, is yet to be determined. Furthermore, while the influence of premortem antidepressant drug treatment on these results is unknown, preclinical rodent work from our study ¹ and others,^2,3 suggest it is unlikely that our findings are driven by premortem antidepressant treatment.

Figure 1.

Summary of key findings from the recent investigation exploring the kynurenine pathway in the anterior cingulate cortex in major depression (MDD) compared to controls (brown et al., 2024). Abbreviations: IL6: interleukin 6; IL1B: interleukin 1 beta; KMO: kynurenine monooxygenase (catalyzes kynurenine towards quinolinic acid production), KYAT: kynurenine aminotransferase (catalyzes kynurenine to kynurenic acid); NMDA: N-methyl-D-aspartate; MDD-S: major depression – suicide; MDD-NS: major depression – non suicide.

Subgroup considerations for MDD

MDD affects both males and females, however, MDD is characterised by strong sex differences. This has long been recognised at a clinical level, whereby females are twice as likely to develop MDD, exhibit higher symptom severity and higher rates of comorbid anxiety. ⁴ However, the driving molecular factors contributing to these clinical differences have largely not been considered. Our findings indicate a dysfunction in the kynurenine pathway in the ACC in MDD that is specific to females. In addition to our diagnostic changes in females, we reported significant sex differences in our control cohort. Collectively, these findings suggested that under physiological conditions, females show greater metabolism of kynurenine in the ACC compared to males. Considering women have a higher prevalence rate of MDD and differences in symptom presentation to males, our changes may be of importance concerning the development or treatment of MDD. There has been some preclinical research into the effectiveness of targeting the kynurenine pathway as an antidepressant treatment, however, to date published work has been restricted to male rodent models. Kynurenine-based drugs have recently moved to clinical trials; despite these preliminary trials not showing antidepressant effects, ⁵ it was identified that the central nervous system concentrations of the active drug were likely insufficient, thus further optimization of drug pharmacokinetics is required. Furthermore, the results outlined in our research, suggest females may be better suited to kynurenine-based treatments. As preclinical and clinical studies into the potential of kynurenine-based therapeutics progress, investigation into each sex independently is essential.

Another important consideration in our understanding of MDD neurobiology is suicide. Overall, suicide is highly complex and multifaceted. There is strong evidence to suggest biological mechanisms underlying suicide exist and have been extensively reviewed elsewhere. ⁶ In the brain, we show decreased kynurenic acid in those with MDD that died by suicide, in line with previous reports of decreased kynurenic acid along with increased quinolinic acid in cerebrospinal fluid following suicide attempt. ⁷ Taken together, these findings suggest that increasing kynurenic acid in the brain (which causes a relative reduction in quinolinic acid) could be beneficial in cases of suicidality. This would, in turn, increase potential NMDA receptor antagonism, similar to ketamine which is approved for MDD with suicidal ideation. Furthermore, given the association between suicide and kynurenine pathway dysfunction in peripheral blood and cerebrospinal fluid measures, ⁸ it is proposed that elements of the kynurenine pathway could be suitable as biomarkers of suicide in neuropsychiatric disorders. However, given the limited number of studies investigating these correlations, in addition to the limited understanding of how peripheral KP correlates with the CNS, further research is required.

There has been some interest in the role of the kynurenine pathway in depression in older age, or late life depression (LLD). LLD has become an increasingly severe global health problem, owing to its high level of morbidity and comorbidity associated with increasing age. LLD is not well characterised, and the diagnosis is made using the criteria for MDD in the DSM-V. However, older patients with MDD may have a greater impact of cognitive impairment, and concurrent medical illness which can further complicate the diagnosis of LLD. As the kynurenine pathway metabolites contribute significantly to numerous key processes related to cell communication and survival, consideration of these metabolites in ageing is important. In our study we saw a positive correlation between age and quinolinic acid in MDD that was not present in control subjects. This could suggest that the kynurenine pathway is differentially regulated in ageing between the diagnoses, where we see an increase in quinolinic acid in ageing in MDD which could be related to the progression of depression in later life. Whilst these results are preliminary, they suggest greater potential for NMDA receptor agonist-induced neurotoxicity in older MDD subjects that may result in greater levels of neurodegeneration and may provide a link between the increased risk of dementia in individuals with a history of depression.

An emerging subgroup phenotype in psychiatric disorders is defined biologically, by inflammatory status. Recent studies have demonstrated clinical utility in stratifying MDD subjects by inflammation in predicting treatment response. ⁹ Stratification by inflammatory markers has also been established in clinical and postmortem schizophrenia cohorts.^10,11 Using these subtypes, the authors have found evidence of increased kynurenic acid production in the frontal cortex of schizophrenia subjects with the higher inflammatory phenotype. ¹² It is possible that this method of stratification may be beneficial in the investigation of MDD neurobiology also, particularly with respect to the kynurenine pathway which can be activated by inflammation. ¹³ In our recent study we measured the gene expression of the proinflammatory cytokines IL6 and IL1B. Overall, MDD subjects exhibited increased gene expression of IL6 and IL1B, suggesting the observed subgroup changes in the kynurenine pathway might not be associated with inflammation, although measurement of a greater number of inflammatory markers, would be required to draw firm conclusions. While we know inflammation is a catalyst for kynurenine pathway activation (in both microglia and astrocytes), it is important to consider that glucocorticoids (commonly activated by stress) also trigger activation of the kynurenine pathway (predominantly in astrocytes via activation of TDO2). ¹⁴ Considering the subgroup changes we observed were restricted to the kynurenic acid arm, which is mostly produced in astrocytes, it is possible that glucocorticoid activation is also altered in these subgroups, however further research is needed.

Conclusion

Overall, exploring subgroup-specific changes in the brain in MDD contributes to advancing our understanding of this heterogenous disorder. The next crucial steps are to examine not only how widespread in the brain these subgroup specific changes are, but also using preclinical and clinical designs to assess the therapeutic implications of emerging (and existing) therapeutics in subgroups, including sex, ageing and suicide, in MDD. By exploring molecular changes and treatment interventions in specific subgroups we open opportunities for more effective and personalised treatments for those impacted by MDD.