Activation and deactivation steps in the tryptophan breakdown pathway in major depressive disorder: A link to the monocyte inflammatory state of patients

Arteaga-Henríquez, Gara; Burger, Bianka; Weidinger, Elif; Grosse, Laura; Moll, Natalie; Schuetze, G.; Schwarz, Markus J.; Wijkhuijs, Annemarie J.M.; Beeck, Gommaar Op de; Berghmans, Raf; Versnel, Marjan A.; Arolt, Volker; Müller, Norbert; Drexhage, Hemmo A.

doi:10.1016/j.pnpbp.2020.110226

Cited by 15 publications

(5 citation statements)

References 75 publications

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“…For example, the low [Kyn] and [KA] levels in unmedicated patients [ 32 ] could be the result of elevated Kyn monooxygenase (KMO) activity depleting [Kyn], thereby depriving KAT of its substrate. IDO induction, however, does not play a role in MDD symptoms or response to antidepressant therapy [ 33 , 34 ]. Thus, it appears that IDO induction, if it occurs in patients with an inflamed state, is overridden by potential overexpression of KMO by IL-1β and IFN-γ [ 35–38 ].…”

Section: Discussionmentioning

confidence: 99%

Inflammation and serotonin deficiency in major depressive disorder: molecular docking of antidepressant and anti-inflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases

2022

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The roles of the kynurenine pathway (KP) of tryptophan (Trp) degradation in serotonin deficiency in major depressive disorder (MDD) and the associated inflammatory state are considered in the present study. Using molecular docking in silico, we demonstrate binding of antidepressants to the crystal structure of tryptophan 2,3-dioxygenase (TDO), but not to indoleamine 2,3-dioxygenase (IDO). TDO is inhibited by a wide range of antidepressant drugs. The rapidly acting antidepressant ketamine does not dock to either enzyme, but may act by inhibiting kynurenine monooxygenase thereby antagonising glutamatergic activation to normalise serotonin function. Antidepressants with antiinflammatory properties are unlikely to act by direct inhibition of IDO, but may inhibit IDO induction by lowering levels of proinflammatory cytokines in immune-activated patients. Of 6 antiinflammatory drugs tested, only salicylate docks strongly to TDO and apart from celecoxib, the other 5 dock to IDO. TDO inhibition remains the major common property of antidepressants and TDO induction the most likely mechanism of defective serotonin synthesis in MDD. TDO inhibition and increased free Trp availability by salicylate may underpin the antidepressant effect of aspirin and distinguish it from other nonsteroidal antiinflammatory drugs. The controversial findings with IDO in MDD patients with an inflammatory state can be explained by IDO induction being overridden by changes in subsequent KP enzymes influencing glutamatergic function. The pathophysiology of MDD may be underpinned by the interaction of serotonergic and glutamatergic activities.

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Section: Discussionmentioning

confidence: 99%

Inflammation and serotonin deficiency in major depressive disorder: molecular docking of antidepressant and anti-inflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases

2022

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“…LC-MS/MS showed that kynurenine and 3-hydroxycaninuric acid increased significantly along the gut-brain axis of depressive-like rats subjected to chronic restraint stress (CRS) [56]. The tryptophan-kynurenine pathway is also linked to the inflammatory state of patients with MDD [57]. Haroon et al analyzed kynurenine pathway metabolites and inflammatory markers in the plasma and CSF of depressed patients [58].…”

Section: Amino Acidsmentioning

confidence: 99%

Recent Progress in Mass Spectrometry-Based Metabolomics in Major Depressive Disorder Research

Liu,

Ma,

et al. 2023

Molecules

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Major depressive disorder (MDD) is a serious mental illness with a heavy social burden, but its underlying molecular mechanisms remain unclear. Mass spectrometry (MS)-based metabolomics is providing new insights into the heterogeneous pathophysiology, diagnosis, treatment, and prognosis of MDD by revealing multi-parametric biomarker signatures at the metabolite level. In this comprehensive review, recent developments of MS-based metabolomics in MDD research are summarized from the perspective of analytical platforms (liquid chromatography-MS, gas chromatography-MS, supercritical fluid chromatography-MS, etc.), strategies (untargeted, targeted, and pseudotargeted metabolomics), key metabolite changes (monoamine neurotransmitters, amino acids, lipids, etc.), and antidepressant treatments (both western and traditional Chinese medicines). Depression sub-phenotypes, comorbid depression, and multi-omics approaches are also highlighted to stimulate further advances in MS-based metabolomics in the field of MDD research.

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“…13 Neurotoxic kynurenine pathway metabolites are thought to play a role in the pathophysiology of depression, but diverging evidence exists. 13,14 Further, altered lymphocyte apportioning for T regulatory cells, Th2 cells, Th17 cells, T memory cells, and NK cells was found among patients with major depressive disorder. [15][16][17] Last but not least, low-grade inflammation was also present in the monocyte gene expression signature of such patients.…”

Section: Introductionmentioning

confidence: 95%

Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder: A Systematic Review of Meta-Analyses

Simon¹,

Arteaga-Henríquez²,

Algendy³

et al. 2023

NDT

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Immune imbalances in major depressive disorder (MDD) have been targeted by anti-inflammatory treatment approaches in clinical trials to increase responsiveness to therapy. However, even after several meta-analyses, no translation of evidence into clinical practice has taken place. We performed a systematic review to evaluate meta-analytic evidence of randomized controlled trials on the use of anti-inflammatory agents for MDD to summarize efficacy estimates and elucidate shortcomings. Methods: Pooled effect estimates and heterogeneity indices were primary outcomes. Characteristics of the included meta-analyses were extracted. Scientific quality of meta-analyses was assessed using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR). Results: N=20 meta-analyses met the eligibility criteria. Study characteristics like outcome scales, composition of patient populations, and add-on or monotherapy regimen varied very little for celecoxib studies, varied little for minocycline studies, and were rather variable for omega 3 fatty acids studies. R-AMSTAR scores ranged from 26 to 39 out of 44 points indicating variable quality, where a comprehensive literature search was the strongest and the consideration of scientific quality in the conclusions was the weakest domain across all meta-analyses. For minocycline and celecoxib, superiority was demonstrated with medium to large effect size with substantial heterogeneity and with large to very large effect size with negligible heterogeneity, respectively. For omega 3 fatty acids, superiority was also demonstrated with mainly small and medium effect sizes with substantial heterogeneity. However, for minocycline and omega 3 fatty acids, non-significant meta-analyses were found also. Conclusion: Even in our synthesized approach, no clear recommendations could be derived on the use of anti-inflammatory treatment for MDD due to several critical aspects like heterogeneity, diversity of patient populations, treatment regimen, and outcomes, and limited scientific quality. However, we observed clear inter-substance differences with meta-analytic evidence being strongest for celecoxib and weakest for omega 3 fatty acids.

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Activation and deactivation steps in the tryptophan breakdown pathway in major depressive disorder: A link to the monocyte inflammatory state of patients

Cited by 15 publications

References 75 publications

Inflammation and serotonin deficiency in major depressive disorder: molecular docking of antidepressant and anti-inflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases

Inflammation and serotonin deficiency in major depressive disorder: molecular docking of antidepressant and anti-inflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases

Recent Progress in Mass Spectrometry-Based Metabolomics in Major Depressive Disorder Research

Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder: A Systematic Review of Meta-Analyses

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