Dataset Information

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 by inducing indoleamine 2,3-dioxygenase (IDO, the rate-limiting enzyme) leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs).

Aims

To systematically review and meta-analyze central and peripheral (free and total) TRP levels, its competing amino-acids (CAAs) and TRYCATs 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 IDO activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD.

Conclusions

Our findings suggest that MDD and 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.

SUBMITTER: Almulla AF

PROVIDER: S-EPMC9630622 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Almulla Abbas F AF Thipakorn Yanin Y Vasupanrajit Asara A Abo Algon Ali Abbas AA Tunvirachaisakul Chavit C Hashim Aljanabi Ashwan Abdulzahra AA Oxenkrug Gregory G Al-Hakeim Hussein K HK Maes Michael M

Brain, behavior, & immunity - health 20221021

<h4>Background</h4>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 by inducing indoleamine 2,3-dioxygenase (IDO, the rate-limiting enzyme) leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs).<h4>Aims</h4>To systematical ...[more]

PMID: 36339964

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Project description:IntroductionThe kynurenine pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of the kynurenine pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD.MethodsPubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies until April 2022 that assessed kynurenine metabolites, namely, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinolinic acid (QA), and 3- hydroxykynurenine (3-HK) in SZ, BD, or MDD subjects compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The random effects model method was selected when comparing the standardized mean differences (SMD) between two groups.ResultsThere were 23 articles that met the inclusion criteria (k=8, k=8, k=11, for SZ, BD, and MDD, respectively). In SZ, KA levels were increased [SMD=2.64, confidence interval (CI) =1.16 to 4.13, p=0.0005, I2=96%, k=6, n=384 subjects]. TRP (k=5) and KYN (k=4) did not differ significantly. In BD, TRP levels (k=7) did not differ significantly. The level of KA was increased in MDD (k=2), but the small number of studies made not possible for statistical significance evaluation. Finally, in MDD, although some studies tended to have an increased level of KYN in those with remission versus decreased levels in those with current depression, no significant difference was found in any of the kynurenine metabolite levels. Similarly, there was an increased level of QA (k=2) but the number of studies (k= 2) was small.ConclusionKA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD. There were no alterations in BD. There may be alterations in this pathway based on population characteristics and mood states. Future studies should explore the utility of these metabolites as biomarkers.

Project description:Real-time fMRI neurofeedback (rtfMRI-nf) left amygdala (LA) training is a promising intervention for major depressive disorder (MDD). We have previously proposed that rtfMRI-nf LA training may reverse depression-associated regional impairments in neuroplasticity and restore information flow within emotion-regulating neural circuits. Inflammatory cytokines as well as the neuroactive metabolites of an immunoregulatory pathway, i.e. the kynurenine pathway (KP), have previously been implicated in neuroplasticity. Therefore, in this proof-of-principle study, we investigated the association between rtfMRI-nf LA training and circulating inflammatory mediators and KP metabolites. Based on our previous work, the primary variable of interest was the ratio of the NMDA-receptor antagonist, kynurenic acid to the NMDA receptor agonist, quinolinic acid (KynA/QA), a putative neuroprotective index. We tested two main hypotheses. i. Whether rtfMRI-nf acutely modulates KynA/QA, and ii. whether baseline KynA/QA predicts response to rtfMRI-nf. Twenty-nine unmedicated participants who met DSM-5 criteria for MDD based on the Mini-International Neuropsychiatric Interview and had current depressive symptoms (Montgomery-Åsberg Depression Rating Scale (MADRS) score > 6) completed two rtfMRI-nf sessions to upregulate LA activity (Visit1 and 2), as well as a follow-up (Visit3) without rtfMRI-nf. All visits occurred at two-week intervals. At all three visits, the MADRS was administered to participants and serum samples for the quantification of inflammatory cytokines and KP metabolites were obtained. First, the longitudinal changes in the MADRS score and immune markers were tested by linear mixed effect model analysis. Further, utilizing a linear regression model, we investigated the relationship between rtfMRI-nf performance and immune markers. After two sessions of rtfMRI-nf, MADRS scores were significantly reduced (t[58] = -4.07, p = 0.009, d = 0.56). Thirteen participants showed a ≥ 25% reduction in the MADRS score (the partial responder group). There was a significant effect of visit (F[2,58] = 3.17, p = 0.05) for the neuroprotective index, KynA to 3-hydroxykynurenine (3-HK), that was driven by a significant increase in KynA/3-HK between Visit1 and Visit3 (t[58] = 2.50, p = 0.03, d = 0.38). A higher baseline level of KynA/QA (β = 5.23, p = 0.06; rho = 0.49, p = 0.02) was associated with greater ability to upregulate the LA. Finally, for exploratory purposes correlation analyses were performed between the partial responder and the non-responder groups as well as in the whole sample including all KP metabolites and cytokines. In the partial responder group, greater ability to upregulate the LA was correlated with an increase in KynA/QA after rtfMRI-nf (rho = 0.75, p = 0.03). The results are consistent with the possibility that rtfMRI-nf decreases metabolism down the so-called neurotoxic branch of the KP. Nevertheless, non-specific effects cannot be ruled out due to the lack of a sham control. Future, controlled studies are needed to determine whether the increase in KynA/3HK and KynA/QA is specific to rtfMRI-nf or whether it is a non-specific correlate of the resolution of depressive symptoms. Similarly, replication studies are needed to determine whether KynA/QA has clinical utility as a treatment response biomarker.

Dataset Information

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

Background

Aims

Methods

Results

Conclusions

Publications

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

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