The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: a systematic review and meta-analysis

Abstract

Background: There is now evidence that affective disorders including major depressive disorder (MDD) and bipolar disorder (BD) are mediated by immune-inflammatory and nitro-oxidative pathways. Activation of these pathways may be associated with activation of the tryptophan catabolite (TRYCAT) pathway leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs). Aims: To systematically review and meta-analyze TRP, its competing amino-acids (CAAs) and TRYCAT data in MDD and BD. Methods: This review searched PubMed, Google Scholar and SciFinder and included 121 full-text articles and 15470 individuals, including 8024 MDD/BD patients and 7446 healthy controls. Results: TRP levels (either free and total) and the TRP/CAAs ratio were significantly decreased (p<0.0001) in MDD/BD as compared with controls with a moderate effect size (standardized mean difference for TRP: SMD=-0.513, 95% confidence interval, CI: -0.611; -0.414; and TRP/CAAs: SMD=-0.558, CI: -0.758; -0.358). Kynurenine (KYN) levels were significantly decreased in patients as compared with controls with a small effect size (p<0.0001, SMD= -0.213, 95%CI: -0.295; -0.131). These differences were significant in plasma (p<0.0001, SMD=-0.304, 95%CI: -0.415, -0.194) but not in serum (p=0.054) or the central nervous system (CNS, p=0.771). The KYN/TRP ratio, frequently used as an index of indoleamine-dioxygenase (IDO) activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD. Conclusions: Our findings revealed that MDD/BD are accompanied by TRP depletion without IDO and TRYCAT pathway activation. Lowered TRP availability is probably the consequence of lowered serum albumin during the inflammatory response in affective disorders.

The tryptophan catabolite or kynurenine pathway in a major depressive episode with melancholia, psychotic features and suicidal behaviors; a systematic review and meta-analysis

“…We also found that melancholic MDD patients have normal levels of CAAs and a decreased TRP/CAAs ratio, which is therefore solely determined by diminished TRP levels. These findings are consistent with our recent findings in mild to moderate MDD/BD (Almulla, Thipakorn et al 2022). We could not examine the CAA levels and TRP/CAA ratio in MDD/BD patients with psychotic features and/or suicidal behaviors because there were not sufficient studies.…”

“…The first major finding in the current study is that TRP levels and the TRP/CAA ratio are significantly decreased in patients with MDD/BD with melancholia and psychotic features, and suicidal behaviors as compared with healthy controls and that there was no significant difference between the latter phenotypes in TRP and TRP/CAA levels. The current results align with findings of a recent study conducted on MDD and BD patients with mild to moderate forms of depression (Almulla, Thipakorn et al 2022). Moreover, previous studies revealed a significant TRP reduction in affective disorders with melancholic, psychotic and suicidal features (Maes, Wauters et al 1996, Hoekstra, Fekkes et al 2006, Gabbay, Klein et al 2010, Bradley, Case et al 2015).…”

“…The second major finding of the present study is that patients with severe affective disorders showed unchanged KYN levels compared with healthy controls. However, these results showed high heterogeneity, and, hence, we performed group analysis which revealed that only plasma KYN level was significantly decreased which is consistent with previous results in mild to moderate MDD/ BD (Almulla, Thipakorn et al 2022, Almulla, Vasupanrajit et al 2022). We also found that the KYN/TRP ratio was unaltered in all patients combined although patients with psychotic features showed a trend towards significant increases in the KYN/TRP ratio.…”

“…We recently found, in a large-scale meta-analysis, that affective disorders, including mild to moderate severe MDD and BD, are associated with a reduction in TRP levels but without any signs of an overactivated TRYCAT pathway (Almulla, Thipakorn et al 2022). However, in MDD patients with suicidal, melancholic, and psychotic features, central and peripheral reductions in TRP levels, activation of the TRYCAT pathway, and increased TRYCATs levels were frequently reported in previous studies, which may reveal upregulation of the IDO enzyme is the leading cause for TRP depletion and increased TRYCATs levels (Sublette, Galfalvy et al 2011, Erhardt, Lim et al 2013, Bay-Richter, Linderholm et al 2015).…”

Chronic fatigue, depression and anxiety symptoms in Long COVID are strongly predicted by neuroimmune and neuro-oxidative pathways which are caused by the inflammation during acute infection

“…First, the results would be more interesting if we had assessed biomarkers of chlorinative stress, namely chlorotyrosine and dichlorotyrosine, and activation of the tryptophan catabolite (TRYCAT) pathway which may increase TRYCATs and lower the availability of tryptophan, the precursor of 5-HT (Maes, Leonard et al 2011, Almulla, Thipakorn et al 2022. Moreover, our COVID-19 studies have been conducted on Iraqi patients and, therefore, deserve replication in other countries.…”