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Ongoing episode of major depressive disorder is not associated with elevated plasma levels of kynurenine pathway markers

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... 1 In major depressive disorder (MDD), an upregulation of the microglial branch leading to increased 3-HK and QA levels along with decreased KYNA levels and decreased neuroprotective ratios (KYNA/3-HK, KYNA/QA) have been described. 1,4 However, unchanged plasma levels 6 and even a downregulation of both branches in postmortem brain have been shown. 7 In schizophrenia, studies in CSF and postmortem brain showed increased activation of astrocytes and elevated KYNA levels. ...
... 12 In depressive populations such a link between inflammation, kynurenine metabolism, and depressive symptoms has not yet been shown. 6,30 The aim of this study was to further explore the relation between inflammation, kynurenine metabolism, and mood symptoms F I G U R E 1 The kynurenine pathway. Cytokines as interferon-y (IFN-y) and tumor necrosis factor-alfa (TNF-α) activate indoleamine 2,3-deoxygenase (IDO-1) to metabolize tryptophan (TRP) into kynurenine (KYN) at the expense of serotonin (5-HT) formation. ...
... 1,10,19,39 We are the first, however, to document a strong relation between inflammatory cytokines (mainly IFN-y), IDO-1 activation and neurotoxic kynurenine metabolites in a depressive patient population. 6 The course of mood symptoms in our study population is typical for patients with BD. Depressive episodes can be severe with often long-term subsyndromal residual symptoms. ...
Article
Objectives: Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause neurotoxicity. We measured inflammatory markers in patients with BD and studied their relation to kynurenine metabolites and mood. Methods: Patients with BD suffering from an acute mood episode were assigned to the depressive (n=35) or (hypo)manic (n=32) subgroup. Plasma levels of inflammatory markers [cytokines, C-reactive protein] and kynurenine metabolites [tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KYNA)] were measured on 6 time points during 8 months follow-up. Biological marker levels in patients were compared to controls (n=35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis. Results: Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor-α and KYN, KYN/TRP, 3-HK and QA (rho>0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3-HK, p=0.0004) and a strong association between interferon-y and kynurenine pathway activation (p<0.0001). KYNA was low in both patient groups versus controls throughout the whole follow-up (p=0.0008). Conclusions: Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism. This article is protected by copyright. All rights reserved.
... Our main results are mostly consistent with previous studies as follows. Specifically, out of the 17 studies on KYNA, 4 studies noted lower KYNA levels in patients with depression in comparison with HCs (Erhardt et al., 2013;Nikkheslat et al., 2015;Schwieler et al., 2016;Young et al., 2016), while no differences were found in KYNA levels between the groups in the remaining studies (Cho et al., 2017;Clark et al., 2016;Dahl et al., 2015;Erhardt et al., 2013;Hu et al., 2017;Krause et al., 2017;Krause et al., 2012;Maes, 2011;Meier et al., 2016;Savitz et al., 2015a,b,c;Veen et al., 2016). Lower ratios of KYNA/QUIN and KYNA/3-HK were found in patients with depression in all of the five studies that measured these ratios (Cho et al., 2017;Meier et al., 2016;Savitz et al., 2015a,c;Young et al., 2016). ...
... Lower ratios of KYNA/QUIN and KYNA/3-HK were found in patients with depression in all of the five studies that measured these ratios (Cho et al., 2017;Meier et al., 2016;Savitz et al., 2015a,c;Young et al., 2016). Moreover, out of the 18 studies on KYN, 6 studies noted lower KYN levels in depression (Hennings et al., 2013;Hu et al., 2017;Krause et al., 2017;Nikkheslat et al., 2015;Quak et al., 2014;Veen et al., 2016) while no differences were found in KYN levels between the groups in the remaining studies (Cho et al., 2017;Clark et al., 2016;Dahl et al., 2015;Maes, 2011;Meier et al., 2016;Moller, 1982;Myint et al., 2007;Savitz et al., 2015a,b,c;Sublette et al., 2011;Young et al., 2016). In addition, no differences were found in 3-HK levels between the groups in all of the nine studies (Cho et al., 2017;Clark et al., 2016;Krause et al., 2012;Meier et al., 2016;Nikkheslat et al., 2015;Savitz et al., 2015a,b,c;Veen et al., 2016;Young et al., 2016). ...
... 95% CI = −0.016 to −0.0001, p = 0.046). noted higher QUIN levels in patients with depression (Erhardt et al., 2013;Savitz et al., 2015c;Young et al., 2016) and 2 studies showed lower QUIN levels in patients with depression (Clark et al., 2016;Zheng et al., 2013), while no differences were found in the QUIN levels between the groups in the remaining studies (Cho et al., 2017;Dahl et al., 2015;Meier et al., 2016;Savitz et al., 2015a,b). Thus, our null finding on QUIN levels may be attributable to these mixed findings from the included studies. ...
Article
Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.
... While most studies reported significantly lower TRP and TRP/CAA ratio in MDD patients, some studies also found negative results (Myint et al., 2007;Pinto et al., 2012). In our recent study of involvement of the KYN pathway in MDD (Dahl et al., 2015), the levels of TRP and TRP/CAA ratio were not significantly different between depressed MDD patients and controls. Some data has indicated that a lowered TRP/CAA ratio is associated with treatment resistance in MDD (Maes et al., 1997). ...
... The study population (n=50) was recruited from patients with an ongoing depression who were referred to a psychiatric outpatient clinic serving one catchment area in Ringerike Psychiatric Center, Norway (Dahl et al., 2014(Dahl et al., , 2015. The study was approved by the local Ethical Committee, and the patients provided written consent to participate after receiving verbal and written information regarding the study. ...
... The HPLC analyses were carried out at the Laboratory of Medical Bio-chemistry, University of Antwerp, Belgium. The procedure has been described in detail previously (Dahl et al., 2015). ...
Article
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Lowered plasma tryptophan (TRP) and TRP/competing amino acid (CAA) ratio may be involved in the pathophysiology of major depression (MDD). Increased cortisol and immune-inflammatory mediators in MDD may affect the availability of TRP to the brain. We investigated whether baseline or post-treatment TRP, CAAs and TRP/CAA ratio are associated with a treatment response in MDD and whether these effects may be mediated by cortisol or immune biomarkers. We included 50 medication-free MDD patients with a depressive episode (DSM diagnosis) and assessed symptom severity with the Inventory of Depressive Symptomatology (IDS) before and after treatment as usual for 12 weeks (endpoint). Plasma levels of TRP, CAAs, the ratio, cortisol, CRP and 6 selected cytokines were assayed. The primary outcome was a 50% reduction in the IDS, while the secondary was a remission of the depressive episode. In IDS non-responders, CAAs increased and the TRP/CAA ratio decreased, while in IDS responders CAAs decreased and the TRP/CAA ratio increased from baseline to endpoint. In patients who were still depressed at endpoint TRP and CAAs levels had increased from baseline, while in remitted patients no such effects were found. Increases in CAAs were inversely correlated with changes in interleukin-1 receptor antagonist levels. The results show that increased CAA levels from baseline to endpoint are associated with a non-response to treatment in MDD patients. This suggests that the mechanism underpinning the CAA-related treatment resistance may be related to changes in immune pathways. CAA levels and amino acid metabolism may be new drug targets in depression.
... Overall, our observations regarding circulating levels of TRP and KYN pathway metabolites suggest that the low levels of inflammation observed in IED subjects may not be associated with the kind of changes in the TRP and in the KYN pathway as reported in some (Kegel et al., 2014;Linderholm et al., 2012;Raison et al., 2010;Sublette et al., 2011), though not all (Dahl et al., 2015), studies of psychiatric, and related, patients. This may be due to fundamental differences in the subjects studied [e.g., Depressed Suicide Attempters (Sublette et al., 2011); Schizophrenia; (Kegel et al., 2014;Linderholm et al., 2012); Hepatitis C patients treated with IFN-α (Raison et al., 2010)] or in the body compartment examined [e.g., plasma (Dahl et al., 2015;Sublette et al., 2011) vs. cerebrospinal fluid [CSF (Kegel et al., 2014;Linderholm et al., 2012;Raison et al., 2010)]. ...
... Overall, our observations regarding circulating levels of TRP and KYN pathway metabolites suggest that the low levels of inflammation observed in IED subjects may not be associated with the kind of changes in the TRP and in the KYN pathway as reported in some (Kegel et al., 2014;Linderholm et al., 2012;Raison et al., 2010;Sublette et al., 2011), though not all (Dahl et al., 2015), studies of psychiatric, and related, patients. This may be due to fundamental differences in the subjects studied [e.g., Depressed Suicide Attempters (Sublette et al., 2011); Schizophrenia; (Kegel et al., 2014;Linderholm et al., 2012); Hepatitis C patients treated with IFN-α (Raison et al., 2010)] or in the body compartment examined [e.g., plasma (Dahl et al., 2015;Sublette et al., 2011) vs. cerebrospinal fluid [CSF (Kegel et al., 2014;Linderholm et al., 2012;Raison et al., 2010)]. For example, patients with major depression and a recent suicide attempt, had reduced plasma levels of TRP, and elevated levels of KYN, compared with healthy controls, in one study (Sublette et al., 2011), but not in another study focusing on patients with major depression where no TRP/KYN pathway metabolite differed from healthy controls (Dahl et al., 2015). ...
... This may be due to fundamental differences in the subjects studied [e.g., Depressed Suicide Attempters (Sublette et al., 2011); Schizophrenia; (Kegel et al., 2014;Linderholm et al., 2012); Hepatitis C patients treated with IFN-α (Raison et al., 2010)] or in the body compartment examined [e.g., plasma (Dahl et al., 2015;Sublette et al., 2011) vs. cerebrospinal fluid [CSF (Kegel et al., 2014;Linderholm et al., 2012;Raison et al., 2010)]. For example, patients with major depression and a recent suicide attempt, had reduced plasma levels of TRP, and elevated levels of KYN, compared with healthy controls, in one study (Sublette et al., 2011), but not in another study focusing on patients with major depression where no TRP/KYN pathway metabolite differed from healthy controls (Dahl et al., 2015). Patients with schizophrenia had elevations of CSF KYN/KA, but not CSF QA, compared with healthy volunteers, in one study (Kegel et al., 2014), as well as elevations of CSF KYN/KA, but not TRP, in another study (Linderholm et al., 2012). ...
Article
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Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects.
... Chez les rongeurs Effets potentiels de la kétamine dans le stress chronique chez les rongeurs [67] De faibles taux de 5-HIAA dans le LCR et la dérégulation du système 5-HT sont associés à l'agressivité et à l'impulsivité chez l'homme [68] L-Trp et kynurenine, acide quinolinique Les taux plasmatiques et cérébraux de kynurénine sont augmentés par des chocs au pied chez le rat [69] Effet anti-inflammatoire de la kétamine via l'inhibition de la voie de la kynurénine serait associé à son effet antidépresseur [70] Les taux plasmatiques de kynurénine sont plus élevés dans le LCR des personnes qui tentent de se suicider que chez les personnes en bonne santé [71,72]. L'acide quinolinique serait un marqueur de la réponse à la kétamine chez les patients TDC [70,73] BDNF Les souris hétérozygotes BDNF+/-, les souris knock-out BDNF conditionnelles et les souris mutantes présentant une perturbation spécifique du promoteur Bdnf I présentent une agressivité inter-mâle accrue [15,46] Augmentation des concentrations sériques de BDNF lors d'un stress chronique [74] Les taux de BDNF dans le cortex préfrontal, l'hippocampe et l'amygdale sont plus faibles dans le cerveau post-mortem des individus décédés par suicide [75]. ...
... Les taux plasmatiques de kynurénine sont élevés chez les suicidés présentant une dépression par rapport aux patients dépressifs non suicidaires ou aux témoins sans antécédent de dépression [71] (Tableau 1). Cependant, d'autres études ont contesté ces résultats [72]. Peu de données comparables existent dans des modèles animaux de stress. ...
... From post-mortem studies it has been found that the brains of depressed patients demonstrate an increased expression of IL-1β, IL-6, TNFα and Toll-like receptors 3 and 4 (TLR3 and TLR4) (Maes, 1999;Miller et al., 2009;Miller & Raison, 2016). Raised peripheral levels of proinflammatory cytokines, IL-1, IL-6, TNFα and elevated CRP levels, which mediate systemic inflammation are most frequently and consistently reported in association with depression (Dahl et al., 2015;Danner, Kasl, Abramson, & Vaccarino, 2003;Dowlati et al., 2010;Elovainio et al., 2009;Karlović, Serretti, Vrkić, Martinac, & Marčinko, 2012;Köhler et al., 2017;Liu et al., 2012;Liukkonen et al., 2006;Maes et al., 2009;Miller et al., 2009;Osimo et al., 2019;Raison et al., 2006;Stewart, Rand, Muldoon, & Kamarck, 2009;Valkanova, Ebmeier, & Allan, 2013; Wium-Andersen, Ørsted, Nielsen, & Nordestgaard, 2013) (see Osimo et al. (2019) for a metaanalysis), although elevated serum or plasma concentrations of IL-10, IL-12, IL-13, IL-18, sIL-2, IL-1RA, soluble TNF receptor (sTNFR)2 and the C\ \C chemokine ligand (CCL)2 have also been found, in comparison to healthy controls (Himmerich, Patsalos, Lichtblau, Ibrahim, & Dalton, 2019;Köhler, Freitas, Maes, et al., 2017). There is considerable variability in the strength of these associations however, and some studies have failed to replicate these findings (Duivis et al., 2011;Stewart et al., 2009) or noticed that they disappeared when adjustments were made for body mass index (BMI) (Shelton & Miller, 2010;Shelton & Miller, 2011) or when participants were categorized and compared by gender. ...
... Equally, neurotoxic effects leading to degeneration of the hippocampus are thought to be involved in the evolution of major depression (Doolin et al., 2018). Even so, these results should be treated with caution, as some studies have found no evidence of changes in kynurenine pathway biomarkers in relation to mood, despite an elevation in cytokine levels (Dahl et al., 2015;Kruse et al., 2019). ...
Article
Patients with cancer are at greater risk of developing depression in comparison to the general population and this is associated with serious adverse effects, such as poorer quality of life, worse prognosis and higher mortality. Although the relationship between depression and cancer is now well established, a common underlying patho-physiological mechanism between the two conditions is yet to be elucidated. Existing theories of depression, based on monoamine neurotransmitter system dysfunction, are insufficient as explanations of the disorder. Recent advances have implicated neuroinflammatory mechanisms in the etiology of depression and it has been demonstrated that inflammation at a peripheral level may be mirrored centrally in astrocytes and microglia serving to promote chronic levels of inflammation in the brain. Three major routes to depression in cancer, in which proinflammatory mediators are implicated, seem likely. Activation of the kynurenine pathway, involving cytokines, increased tryptophan catabolism, resulting in diminished levels of serotonin, which is widely acknowledged as being the hallmark of depression. It also results in neurotoxic effects on brain regions thought to be involved in the evolution of major depression. Proinflammatory mediators also play a crucial role in impairing regulatory glucocorticoid mediated feedback of the hypothalamic-pituitary-adrenal axis, which is activated by stress and considered to be involved in both depression and cancer. The third route is via the glutamatergic pathway, whereby glutamate excitotoxicity may lead to depression associated with cancer. A better understanding of the mechanisms underlying these dysregulated and newly emerging pathways may provide a rationale for therapeutic targeting, serving to improve the care of cancer patients.
... Furthermore, the changes can be implicated in the inflammation process in depression (Kolodziej et al., 2011;Ogyu et al., 2018). Recent research studies indicate that kynurenine pathways can be useful biomarkers, as indicated by results obtained on subjects with depression, in comparison with HCs, indicating that the kynurenine contribution was expected to decrease (Gabbay et al., 2010;Raison et al., 2010;Sublette et al., 2011;Myint et al., 2013;Dahl et al., 2015;Savitz et al., 2015). Relatively few studies on gardening intervention in conjunction with biomarker approaches were reported (Park et al., 2020) and have indicated changes in depression-related urinary tryptophan metabolites among nongardening (control group) and gardening subjects. ...
... In the open scientific literature, higher levels of KYN biomarker is often associated with higher levels of depression (Myint et al., 2013;Dahl et al., 2015;Savitz et al., 2015), which may indicate that therapeutic horticulture intervention had a benefic effect on the subjects. ...
... A number of human studies have also investigated the relationship between metabolites of the KYN pathway and depressive features and/or SB by measuring these metabolites in the blood or CSF. Eleven studies of the KYN pathway metabolite, KYN, provided no convincing evidence of differences in blood KYN levels between depressed patients without SB relative to healthy controls (91,(98)(99)(100)(101)(102)(103)(104)(105)(106)(107). On the other hand, seven studies reported lower blood KYN concentrations in the depressed group (108)(109)(110)(111)(112)(113)(114). ...
... Several studies have also measured levels of the KYN pathway metabolite, QUIN, in the blood or CSF in patients with depression. Among these investigations, six studies identified no group differences in blood QUIN concentrations between depressed patients and HC (99,100,102,105,106,115), while three found elevated levels of QUIN in patients with depression, with two reporting the finding after measuring QUIN levels in blood (91,98) and another from measuring QUIN levels in CSF (120). A metaanalysis, which also reviewed the above studies, additionally revealed that blood QUIN levels were higher in the depressed group, although the effect size was small (115). ...
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According to the stress-diathesis model of suicidal behavior, completed suicide depends on the interaction between psychosocial stressors and a trait-like susceptibility. While there are likely multiple biological processes at play in suicidal behavior, recent findings point to over-activation of microglia, the resident macrophages of the central nervous system, as implicated in stress-induced suicidal behavior. However, it remains unclear how microglial dysregulation can be integrated into a clinical model of suicidal behavior. Therefore, this narrative review aims to (1) examine the findings from human post-mortem and neuroimaging studies that report a relationship between microglial activation and suicidal behavior, and (2) update the clinical model of suicidal behavior to integrate the role of microglia. A systematic search of SCOPUS, PubMed, PsycINFO, and Embase databases revealed evidence of morphological alterations in microglia and increased translocator protein density in the brains of individuals with suicidality, pointing to a positive relationship between microglial dysregulation and suicidal behavior. The studies also suggested several pathological mechanisms leading to suicidal behavior that may involve microglial dysregulation, namely (1) enhanced metabolism of tryptophan to quinolinic acid through the kynurenine pathway and associated serotonin depletion; (2) increased quinolinic acid leading to excessive N-methyl-D-aspartate-signaling, resulting in potential disruption of the blood brain barrier; (3) increased quinolinic acid resulting in higher neurotoxicity, and; (4) elevated interleukin 6 contributing to loss of inhibition of glutamatergic neurons, causing heightened glutamate release and excitotoxicity. Based on these pathways, we reconceptualized the stress-diathesis theory of suicidal behavior to incorporate the role of microglial activity.
... Increased formation of kynurenine and downstream KP metabolites has been repeatedly described in the blood and CSF of individuals suffering from depressive disorders and suicide attempters. [21][22][23]45 Nevertheless, this has not been con sistently reported in the literature, 25,26,46,47 and changes in KP metabolites and their corresponding enzymes in human se rum and CSF do not necessarily parallel events in the brain. 14 Furthermore, to our knowledge only 2 groups had examined the KP in postmortem brains of individuals with depressive illnesses prior to the present study. ...
... For example, a recent study reported that depressive episodes were not as sociated with increased KP metabolites in medicationfree patients with major depressive disorder (MDD). 46 At the same time, a functional imaging study reported increased microglial activation in the PFC and ACC in patients with MDD after a depressive episode. 55 An interpretation of these apparently contradictory results is that the absence of KP ac tivation may indicate an alternative microglial activation pro cess, which likely reflects dysfunction and dystrophy in de pression, as shown in studies of rats and mice that developed depressivelike behaviour. ...
Article
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Background: Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology. Methods: We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls (n = 36) and individuals with depressive disorder not otherwise specified (DD-NOS, n = 45) who died of natural causes, homicide, accident, or suicide. Results: We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls. Limitations: Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons. Conclusion: Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.
... Future research should explore inflammatory status in AMDD. It is important to acknowledge that studies examining IDO1 activity have yielded conflicting results [7,8,34,[48][49][50][51], possibly due to variations in race, age, sample size, sample types, and measurement techniques [52,53]. Furthermore, inclusion criteria and considerations like antidepressant use and first-episode depression contribute to observed discrepancies. ...
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Metabolites disruptions in tryptophan (TRP) and kynurenine pathway (KP) are believed to disturb neurotransmitter homeostasis and contribute to depressive symptoms. This study aims to investigate serum levels of KP metabolites in adolescent major depressive disorder (AMDD), and examine their relationship with depression severities. Liquid chromatography-tandem mass spectrometry (LC–MS/MS) was used to analyze serum levels of TRP, kynurenic acid (KYNA), kynurenine (KYN), and 3-hydroxy-kynurenine (3-HK) in 143 AMDD participants and 98 healthy controls (HC). Clinical data, including Children’s Depression Inventory (CDI) scores, were collected and analyzed using statistical methods, such as ANOVA, logistic regression, Receiver operating characteristic curve analysis and a significance level of p < 0.05 was used for all analyses. AMDD showed significantly decreased serum levels of KYNA (−25.5%), KYN (−14.2%), TRP (−11.0%) and the KYNA/KYN ratio (−11.9%) compared to HC (p < 0.01). Conversely, significant increases were observed in 3-HK levels (+50.4%), the 3-HK/KYNA ratio (+104.3%) and the 3-HK/KYN ratio (+93.0%) (p < 0.01). Logistic regression analysis identified increased level of 3-HK as a contributing factor to AMDD, while increased level of KYNA acted as a protective factor against AMDD. The 3-HK/KYNA ratio demonstrated an area under the curve (AUC) of 0.952. This study didn’t explore AMDD’s inflammatory status and its metabolites relationship explicitly. These findings indicate that metabolites of TRP and KP may play a crucial role in the pathogenesis of AMDD, emphasizing the potential of the 3-HK/KYNA ratio as a laboratory biomarker for early detection and diagnosis of AMDD. Graphical abstract HC healthy controls, AMDD adolescent major depressive disorder, LC-MS/MS Liquid chromatography-tandem mass spectrometry, CDI Children's Depression Inventory, which provides a measure of the severity of depressive symptoms. The CDI scores were categorized into three ranges: mild depression (CDI-I), moderate depression (CDI-II), and severe depression (CDI-III)
... Some studies support this connection and have shown higher levels of metabolites of kynurenine pathway among patients with depression [24,25]. However, other studies do not reinforce this thesis as other authors, such as Dahl et al., have noticed a significant negative correlation [26]. It is believed that quinolinic acid, which is formed as a result of the immune processes that activate macrophages and microglia in the brain, can be responsible for development of not only depression but also diseases such as Parkinson's disease, Alzheimer's disease, neurodegenerative diseases or amyotrophic lateral sclerosis [16]. ...
Article
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Psoriasis is a common dermatosis which affects the patient's skin and general well-being because of its link to diseases such as depression, kidney disease and metabolic syndrome. Pathogenesis remains unknown; however, genetic, environmental and immunological factors seem to play a role in the development of the disease. Due to a lack of complete understanding of the psoriasis pathology, effective treatment is yet to be developed. The kynurenine pathway is one of the ways amino acid tryptophan is metabolised. In comorbidities typical for psoriasis such as chronic kidney disease, depression and atherosclerotic alterations in the activation of the kynurenine pathway were observed, which were mainly characterised by higher activity compared to that in healthy individuals. However, the kynurenine pathway has not been thoroughly studied among patients with psoriasis even though increased levels of L-kynurenine, one of the enzymes in the kynurenine pathway, were found in psoriatic skin lesions. Given the unknown pathogenesis of the disease, this finding seems to be a potential new field of study and shows a possible link between psoriasis and its comorbidities that could also lead to novel effective treatment for this chronic condition.
... Plasma kynurenine levels were found to be elevated in suicide attempters with major depressive disorders when compared with either non-suicidal depressive patients or controls with no history of depression [69] (Table 1). However, these results have since been challenged by others [70]. In animal models of stress (foot shocks), kynurenine levels were found to be increased in the plasma and brain [71]; however, this 20-year-old data will need to be replicated. ...
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Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive–aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive–aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility.
... Due to exclusion criteria mentioned in ESF, table 4, three out of these 124 studies were excluded. Hence, the current meta-analysis involved 121 studies (Aarsland et al., 2019;Achtyes et al., 2020;Anderson et al., 1990;Baranyi et al., 2017;Bay-Richter et al., 2015;Birner et al., 2017;Bradley et al., 2015;Brundin et al., 2016;Busse et al., 2015;Carrillo--Mora et al., 2020;Castillo et al., 2019;Cathomas et al., 2021;Chiaroni et al., 1990;Chiu et al., 2021;Cho et al., 2017;Clark et al., 2016;Colle et al., 2020;Coppen et al., 1972;Coppen et al., 1973;Cowen et al., 1989;Czermak et al., 2008;Dahl et al., 2015;DeMyer et al., 1981;DeWitt et al., 2018;Doolin et al., 2018;Ebesunun et al., 2012;Erabi et al., 2020;Erhardt et al., 2013;Gabbay et al., 2010;Georgin-Lavialle et al., 2016;Gerner et al., 1984;Guicheney et al., 1988;Hayward et al., 2005;Healy et al., 1982;Heilman et al., 2019;Hennings et al., 2013;Hoekstra et al., 2006;Hoekstra et al., 2001;Hu et al., 2017;Hüfner et al., 2015;Hughes et al., 2012;Joseph et al., 1984;Karege et al., 1994;Krause et al., 2019;Krause et al., 2017;Kuwano et al., 2018;Liu et al., 2018;Lucca et al., 1992;Maes et al., 2011b;Maes et al., 1990;Maes et al., 1993;Maes and Rief, 2012;Maes et al., 1997b;Maes et al., 1996;Manjarrez-Gutierrez et al., 2009;Mauri et al., 2001;Mauri et al., 1998;Meier et al., 2016;Menna-Perper et al., 1983;Milaneschi et al., 2021;Miller et al., 2006;Moaddel et al., 2018;Møller, 1993;Moller et al., 1976;Møller et al., 1982;Moreno et al., 1999;Moreno et al., 2013;Mukherjee et al., 2018;Murata et al., 2020;Myint et al., 2007a;Myint et al., 2007b;Nikkheslat et al., 2015;Ogawa et al., 2018;Olsson et al., 2010;Ortiz et al., 1993;Ö ztürk et al., 2021;Pan et al., 2018;Paul et al., 2022;Pinto et al., 2012;Platzer et al., 2017;Poletti et al., 2019;Poletti et al., 2018;Pompili et al., 2019;Porter et al., 2003;Price et al., 1991;Quak et al., 2014;Quintana, 1992;Reininghaus et al., 2014;Rief et al., 2004;Roiser et al., 2009;Russ et al., 1990;Ryan et al., 2020;Sakurai et al., 2020;Savitz et al., 2015a;Savitz et al., 2015b;Savitz et al., 2015c;Savitz et al., 2015d;Schwieler et al., 2016;Sellgren et al., 2019;Shaw et al., 1980;Song et al., 1998;Sorgdrager et al., 2017;Steen et al., 2020;Steiner et al., 2011;Sublette et al., 2011;Sun et al., 2020;Teraishi et al., 2015;Trepci et al., 2021;Umehara et al., 2017;van den Ameele et al., 2020;Veen et al., 2016;Wood et al., 1978;Wu et al., 2018a;Wu et al., 2018b;Wurfel et al., 2017;Xu et al., 2012;Yoshimi et al., 2016;Young et al., 2016;Zhou et al., 2018;Zhou et al., 2019). Ten of the eligible articles examined TRP and TRYCATs in MDD and BD within the same study. ...
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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.
... The current results align with findings of a recent study conducted on MDD and BD patients with mild to moderate forms of depression [40]. Moreover, previous studies revealed a significant TRP reduction in affective disorders with melancholic, psychotic and suicidal features [55,61,62,66]. 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. ...
Article
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Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways, which may stimulate indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs). The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino acids (CAAs) and TRYCATs in patients with severe affective disorders. Methods: PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4647 participants including 2332 unipolar (MDD) and bipolar (BD) depressed patients and 2315 healthy controls. Severe patients showed significant lower (p < 0.0001) TRP (standardized mean difference, SMD = −0.517, 95% confidence interval, CI: −0.735; −0.299) and TRP/CAAs (SMD= −0.617, CI: −0.957; −0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD= 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD= 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD= −0.260, CI: −0.487; −0.034) in severe MDD/BD. Patients with affective disorders with melancholic and psychotic features and suicidal behaviors showed normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels.
... Some polymorphisms of the IDO1, 2 and KMO encoded genes are identified in patients with depression [81]. On the other hand, data on increased levels of KP metabolites in blood serum and CSF in individuals with depressive disorders have been inconsistent [82][83][84][85]. It has been also proposed that changes in enzymes and metabolites of the KP are not necessarily parallel to events in the brain [86]. ...
Article
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Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.
... There is evidence that tryptophan, kynurenine and kynurenic acid are decreased specifically in late-life depression (Wu et al., 2018b(Wu et al., , 2018a, while in contrast kynurenic acid and 3-hydroxykynurenine are increased in post-stroke depression (Carrillo-Mora et al., 2020). Furthermore, increased quinolinic acid has been reported in depression subjects free of antidepressant drugs (Ogyu et al., 2018), however, it has also been shown that twelve weeks of treatment does not result in a change in kynurenine metabolites, despite a decrease in depression severity (Dahl et al., 2015). In regard to the course of depression, those with recurrent major depression have higher levels of quinolinic acid compared to first presentation and controls, suggesting an accumulative effect of the kynurenine pathway metabolites in depression (Doolin et al., 2018). ...
Article
Major depression is a serious psychiatric disorder, occurring in up to 20% of the population. Despite its devastating burden, the neurobiological changes associated with depression are not fully understood. A growing body of evidence suggests the kynurenine pathway is implicated in the pathophysiology of depression. In this review, we bring together the literature examining elements of the kynurenine pathway in depression and explore the implications for the pathophysiology and treatment of depression, while highlighting the gaps in the current knowledge. Current research indicates an increased potential for neurotoxic activity of the kynurenine pathway in peripheral blood samples but an increased activation of the putative neuroprotective arm in some brain regions in depression. The disconnect between these findings requires further investigation, with a greater research effort on elucidating the central effects of the kynurenine pathway in driving depression symptomology. Research investigating the benefits of targeting the kynurenine pathway centred on human brain findings and the heterogenous subtypes of depression will help guide the identification of effective drug targets in depression.
... It has been suggested that the development of depressive symptoms as a result of cytokine therapy is attributable to cytokine-induced elevated activity of the KP (Myint and Kim, 2014). Nevertheless, studies of KP in patients with MDD have, however, produced varying results (Dahl et al., 2015;Elovainio et al., 2012;Gabbay et al., 2010;Hughes et al., 2012;Myint et al., 2013Myint et al., , 2007Quak et al., 2014). The inconsistencies seen could be due to low sample size, different recruitment procedures and patient characteristics, or patients not being drug-naive at the start of treatment. ...
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S U M M A R Y Chronic fatigue and major depression (MDD)-like symptoms are common manifestations of multiple sclerosis (MS), both with huge impact on quality of life. Depression can manifest itself as fatigue, and depressive symptoms are often mistaken for fatigue, and vice versa. The two conditions are sometimes difficult to differentiate, and their relationship is unclear. Whether chronic fatigue and depression occur primarily, secondarily or coincidentally with activated immune-inflammatory pathways in MS is still under debate. We have carried out a descriptive review aiming to gain a deeper understanding of the relationship between chronic fatigue and depression in MS, and the shared pathways that underpin both conditions. This review focuses on immune-inflammatory pathways, the ky-nurenine pathway and the gut-brain axis. It seems likely that proinflammatory cytokines, tryptophan catabolites (the KYN pathway) and the gut-brain axis are involved in the mechanisms causing chronic fatigue and MDD-like symptoms in MS. However, the evidence base is weak, and more research is needed. In order to advance our understanding of the underlying pathological mechanisms, MS-related fatigue and depression should be examined using a longitudinal design and both immune-inflammatory and KYN pathway biomarkers should be measured, relevant clinical characteristics judiciously registered, and self-report instruments for both fatigue and depression should be used.
... Comparing patients with healthy controls, these studies have shown higher levels of neurotoxic kynurenines [37,38], lower levels of neuroprotective kynurenines [6,17,30,38] and altered kynurenine ratios with lower KA/Kyn [6,17] and KA/QA [14e16]. However, one study found normal levels of kynurenines in depressed patients compared to healthy controls [39]. ...
Article
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Background: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. Objective: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. Methods: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5'-phosphat (PLP), riboflavin, neopterin and cotinine were measured. Results: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. Conclusion: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway.
... Indeed, some studies showed no correlation or even a negative correlation between kynurenine pathway activity and depression. Dahl and colleagues (Dahl et al. 2015) found no increase in kynurenine pathway plasma markers in patients with a depressive episode, assessed with DSM-IV criteria and the Montgomery-Åsberg Depression Rating Scale (MADRS, total score ≥ 20), compared with healthy controls. The kynurenine pathway was unaltered after a 12-week antidepressant treatment, which significantly reduced symptoms scores. ...
Article
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Depression is a common comorbidity in cancer cases, but this is not only due to the emotional distress of having a life-threatening disease. A common biological mechanism, involving a dysregulated immune system, seems to underpin this comorbidity. In particular, the activation of the kynurenine pathway of tryptophan degradation due to inflammation may play a key role in the development and persistence of both diseases. As a consequence, targeting enzymes involved in this pathway offers a unique opportunity to develop new strategies to treat cancer and depression at once. In this work, we provide a systematic review of the evidence up to date on the kynurenine pathway role in linking depression and cancer and on clinical implications of this evidence. In particular, complications due to chemotherapy are discussed, as well as the potential antidepressant efficacy of novel immunotherapies for cancer.
... Moreover, we found no relation between KYN-related metabolites and a lifetime history of suicidal behavior, unlike previous findings regarding recent suicide attempts [4,22]. Plasma concentrations of other KYN-related analytes (AA, XA, and 5-HIAA) did not differ between depressed subjects and controls (Table 1), in accord with previous reports [32,33]. ...
Article
Background: Some previous studies found decreased concentrations of L-tryptophan (TRY) and increased L-kynurenine (KYN), or its metabolites, in the body fluids of subjects with major depressive disorder (MDD), sometimes in association with suicidal behavior. Such changes might indicate a shift of TRY away from serotonin production, possibly via the effects of inflammatory peptides which activate indoleamine-2,3-dioxygenase. However, these findings have been inconsistent and require replication. Methods: We used sensitive liquid-chromatography mass spectrometry methods to assay plasma concentrations of TRY, 5-hydroxyindoleacetic acid (5-HIAA), and KYN and its metabolites (anthranilic acid and xanthurenic acid). We compared 49 hospitalized, depressed subjects diagnosed with MDD (n = 37) or bipolar disorder (BD, n = 12), with (n = 22) or without (n = 27) previous suicide attempts, to 78 healthy, ambulatory controls of similar age and sex (total n = 127). Findings: Contrary to expectation, TRY plasma concentrations were higher, KYN plasma concentrations were lower, and their ratio much higher in depressed subjects, with no relationship to suicidal history. Concentrations of 5-HIAA and the kynurenine metabolites did not differ between depressed and healthy subjects. Conclusions: These findings are opposite to expectations and not consistent with a hypothesized increased conversion from TRY to KYN in depressed subjects. In addition, we found no evidence of altered production of serotonin as 5-HIAA concentration was unchanged. None of the observed changes was associated with a history of suicide attempt.
... Interestingly, 23 patients treated with electroconvulsive therapy showed an increase in the Kyn/Trp-ratio over the treatment period (Guloksuz et al., 2015). Another study by Dahl et al. (2015) found no changes in kynurenine and metabolites in medication free depressive individuals after 12 weeks of treatment as usual. Importantly, treatment response was not included as an outcome variable in these studies. ...
Article
There exists a critical link between immunological processes and metabolic changes. Furthermore, it becomes more and more evident that changes in immunometabolic pathways are highly interconnected with psychological processes and the nervous system. Depressive disorders are a major contributor to the overall burden of disease worldwide. Despite extensive research, therapeutic interventions are often not satisfying. This may be due to the yet only partially elucidated pathobiochemistry underlying the development of depression which may be influenced by multiple factors including genetics, environment, lifestyle, and importantly by the immunological status. In this review article the roles and consequences of the interferon gamma dependent pathways of tryptophan breakdown and neopterin formation are discussed, as well as phenylalanine metabolism, trying to provide a rational link between immunology, metabolism and mental status. Besides underlining the complexity of the mechanism involved in the development of depression, the knowledge on relevant biomarkers may be useful in orchestrating personalized therapy regimes.
... These discrepancies between studies may primarily result from whether their respective patient populations received medications, as we found elevated plasma KYN levels and a trend towards elevated KYN/TRP ratio after the patients in our study had been treated with antidepressants. Previous studies have reported elevated serum KYN levels and KYN/TRP ratio during the course of antidepressant treatment in MDD patients 31,32 . ...
Article
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Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS) is a comprehensive, quantitative, and high throughput tool used to analyze metabolite profiles. In the present study, we used CE-TOFMS to profile metabolites found in the blood plasma of 33 medication-free patients with major depressive disorder (MDD) and 33 non-psychiatric control subjects. We then investigated changes which occurred in the metabolite levels during an 8-week treatment period. The medication-free MDD patients and control subjects showed significant differences in their mean levels of 33 metabolites, including kynurenine (KYN), glutamate (Glu), glutamine (Gln), methionine sulfoxide, and methionine (Met). In particular, the ratios of KYN to tryptophan (TRP), Gln to Glu, and Met to methionine sulfoxide were all significantly different between the two groups. Among the 33 metabolites with altered levels in MDD patients, the levels of KYN and Gln, as well as the ratio of Gln to Glu, were significantly normalized after treatment. Our findings suggest that imbalances in specific metabolite levels may be involved in the pathogenesis of MDD, and provide insight into the mechanisms by which antidepressant agents work in MDD patients.
... However, it should be noted that there have also been more nuanced or negative findings regarding the role of the kynurenine pathway in depression pathophysiology. For example, in one study, somatization but not depression was characterized by disorders in the kynurenine pathway [48]; and in another study, kynurenine pathway markers were not significantly different between patients with major depressive disorder and healthy controls [49]. ...
Article
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Objective Although the interrelationships between sleep disturbance, inflammation, and depression have been found, molecular mechanisms that link these conditions are largely unknown. Kynurenine metabolism is hypothesized to be a key mechanism that links inflammation and depression. Inflammation activates the kynurenine pathway, leading to increases in 3-hydroxykynurenine (3HK) and quinolinic acid (QA), potentially neurotoxic metabolites, and decreases in kynurenic acid (KynA), a potentially neuroprotective compound. This relative neurotoxic shift in the balance of kynurenine metabolites has been associated with depression, but never been examined regarding sleep disturbance. We tested the association between sleep disturbance and this relative neurotoxic shift in 68 currently depressed, 26 previously depressed, and 66 never depressed subjects. Methods Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index. Serum concentrations of kynurenine metabolites were measured using high performance liquid chromatography. Putative neuroprotective indices reflecting the relative activity of neuroprotective and neurotoxic kynurenine metabolites were calculated as KynA/QA and KynA/3HK (primary outcomes). Results Sleep disturbance was associated with reduced KynA/QA in the currently depressed group only (unadjusted beta −0.43, p < 0.001). This association remained significant even after controlling for age, sex, analysis batch, body-mass index, and depressive symptoms in currently depressed subjects (adjusted beta −0.30, p = 0.02). There was no significant association between sleep disturbance and KynA/3HK in any of the groups. Sleep disturbance was associated with increased C-reactive protein in currently depressed subjects only (unadjusted beta 0.38, p = 0.007; adjusted beta 0.33, p = 0.02). Conclusion These data support the hypothesis that altered kynurenine metabolism may molecularly link sleep disturbance and depression.
... 130 There is no apparent activation of the kynurenine pathway, at least in the peripheral blood, of depressed patients without current suicidal thoughts. 131 Consistent with these observations, Steiner et al. 132 showed increased expression of QUIN-reactive microglia cells in the brains of depressed patients who died by suicide. ...
Article
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Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic–pituitary–adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio.
... 130 There is no apparent activation of the kynurenine pathway, at least in the peripheral blood, of depressed patients without current suicidal thoughts. 131 Consistent with these observations, Steiner et al. 132 showed increased expression of QUIN-reactive microglia cells in the brains of depressed patients who died by suicide. ...
Article
Full-text available
Worldwide, suicide is a leading cause of death. While a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. While nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic-pituitary-adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity, and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development, and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (e.g. childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated, and ultimately impactful suicide research portfolio.
... However, it should be noted that there have also been more nuanced or negative findings regarding the role of the kynurenine pathway in depression pathophysiology. For example, in one study, somatization but not depression was characterized by disorders in the kynurenine pathway [48]; and in another study, kynurenine pathway markers were not significantly different between patients with major depressive disorder and healthy controls [49]. ...
Article
Sleep disturbance is known to increase inflammation. Inflammation may activate the kynurenine metabolic pathway and increase the synthesis of potentially neurotoxic metabolites such as 3-hydroxykynurenine (3HK) and quinolinic acid (QA), relative to kynurenic acid (KynA). However, the associations between sleep disturbance and kynurenine metabolism have not been examined. This study examined such associations in a group of 68 currently depressed, 26 previously depressed, and 66 never depressed subjects (total N = 160). All subjects were unmedicated and interviewed with the Structured Clinical Interview for DSM-IV-TR. Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index. Serum concentrations of kynurenine metabolites were measured using high performance liquid chromatography. Neuroprotective indices of kynurenine metabolites, the primary outcome variables, were calculated as KynA/3HK and KynA/QA. Sleep disturbance was inversely correlated with KynA/3HK (r = −0.24, p = 0.002) and KynA/QA (r = −0.22, p = 0.005). The association between sleep disturbance and KynA/QA remained significant even after adjusting for age, sex, body-mass index, diagnosis, and depressive symptoms (adjusted beta −0.31, p = 0.02). This study is the first to demonstrate an association between sleep disturbance and a neurotoxic profile of kynurenine metabolism. Sleep disturbance is a well-known risk factor for depression, and inflammation has been suggested as a potential mechanism of this association. Thus, kynurenine metabolism, increasingly recognized as a potential pathway linking inflammation to depression, may be an underlying mechanism of the connection among sleep disturbance, inflammation, and depression.
... Sublette et al (2011) were the first to demonstrate that blood kynurenine levels are elevated in suicide attempters compared with a depressed-only control group. Interestingly, Dahl et al (2015) also reported that depressive episodes in MDD patients are not associated with an increase in plasma kynurenine metabolite levels, despite the presence of elevated cytokine levels in these individuals. In addition, it should be noted that certain metabolites do not freely cross the BBB, and it might, therefore, be of importance to study the CSF levels of metabolites when determining their correlation to neuropsychiatric symptoms (Schwarcz et al, 2012). ...
Article
Suicidal behavior is complex and manifests because of a confluence of diverse factors. One such factor involves dysregulation of the immune system, which has been linked to the pathophysiology of suicidal behavior. This review will provide a brief description of suicidality and discuss the contribution of upstream and downstream factors in the etiology of suicidal behavior, within the contextual framework of inflammation. The contribution of inflammatory conditions such as traumatic brain injury, autoimmune disorders, and infections to neuropsychiatric symptoms and suicidality is only beginning to be explored. We will summarize studies of inflammation in the etiology of suicide, and provide a neurobiological basis for different mechanisms by which inflammation might contribute to the pathophysiology. Finally, we will review treatments that affect upstream and downstream pathways related to inflammation in suicidality.Neuropsychopharmacology accepted article preview online, 05 July 2016. doi:10.1038/npp.2016.116.
... Many risk factors for depression, such as stress, inflammation, and low levels of exercise, may activate IDO/TDO [37]. In line with our finding that low levels of melatonin are not specific to the diagnosis of current depressive episode but are instead true for a subgroup of patients, elevated activity in the kynurenine pathway is not seen for all patients with depression [38]. ...
Article
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Reduced levels of melatonin have been associated with severe depression. The aim was to investigate the correlation between salivary melatonin and dimensional measures of depressive symptom severity in young adult psychiatric patients. Levels of melatonin were analyzed in six saliva samples during waking hours from 119 young adult patients under outpatient psychiatric care. Melatonin levels were tested for association with the severity of depressive symptoms using the self-rating version of the Montgomery Åsberg Depression Rating Scale (MADRS-S). Where possible, depressive symptoms were assessed again after 6±2 months of treatment. Response was defined as decrease in MADRS-S by ≥50% between baseline and follow-up. Patients with levels of melatonin in the lowest quartile at bedtime had an increased probability of a high MADRS-S score compared to those with the highest levels of melatonin (odds ratio 1.39, 95% CI 1.15-1.69, p<0.01). A post hoc regression analysis found that bedtime melatonin levels predicted response (odds ratio 4.4, 95% CI 1.06-18.43, p<0.05). A negative relationship between salivary melatonin and dimensional measures of depressive symptom severity was found in young patients under outpatient psychiatric care. Bedtime salivary melatonin levels may have prognostic implications.
... Adding further evidence to a role for IDO and quinolinic acid in depression, the metabolites of kynurenine are elevated in depressed patients in the CSF, without any corresponding change in CSF tryptophan (Raison et al., 2010). Other papers have failed to show alterations in kynurenine or its metabolites in the plasma of M a n u s c r i p t 13 depressed patients (Dahl et al., 2015; Meier et al., 2015) and one reported a decrease in plasma kynurenine levels (Hennings et al., 2013). While Meier et al (2015) does not see changes in kynurenine, he does report that depressed patients have altered kynurenic acid/quinolinic acid and kynurenic acid/3-hydroxykynurenine ratios. ...
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Inflammation and depression are closely inter-related to each other, inflammation inducing symptoms of depression and conversely depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission.
... One study does report an elevated serum concentration of kynurenine and depleted tryptophan and 5HIAA availability in a mixed cohort of bipolar and depressed patients relative to healthy controls (Myint et al., 2013). However, recent reports by Dahl and colleagues suggest that despite the presence of a dysregulated inflammatory profile in a cohort of unmediated depressed patients at baseline, there was no difference in kynurenine metabolite plasma markers or tryptophan concentrations relative to healthy controls at baseline (Dahl et al., 2014, Dahl et al., 2015). Furthermore, in accordance with findings by , reporting decreased tryptophan availability in the absence of kynurenine pathway activation, in a cohort of depressed patients relative to matched controls, Maes and colleagues report that while depression and somatic disorders are both characterised by decreased tryptophan concentrations, they did not find any evidence in support of increased IDO activity in depression ( Rief, 2012). ...
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Major depression is a serious psychiatric disorder; however, the precise biological basis of depression still remains elusive. A large body of evidence implicates a sregulated endocrine and inflammatory response system in the pathogenesis of depression. Despite this, given the heterogeneity of depression, not all depressed patients exhibit dysregulation of the inflammatory and endocrine systems. Evidence suggests that inflammation is associated with depression in certain subgroups of patients and that those who have experienced stressful life events such as childhood trauma or bereavement may be at greater risk of developing depression. nsequently, prolonged exposure to stress is thought to be a key trigger for the onset of a depressive episode. This review assesses the relationship between stress and the immune system, with a particular interest in the mechanisms by which stress impacts immune function, and how altered immune functioning, in turn, may lead to a feed forward cascade of multiple systems dysregulation and the subsequent manifestation of depressive symptomology. The identification of stress-related immune markers and potential avenues for advances in therapeutic intervention is vital. Changes in specific biological markers may be used to characterize or differentiate epressive subtypes or specific symptoms and may predict treatment response, in turn facilitating a more effective, targeted, and fast-acting approach to treatment.
... Many features of what is commonly referred to as 'sickness behaviour' may be linked to metabolism of kynurenine, including anxiety and anhedonia or apathy that seems to be induced by IDO activation [93]. Quak et al. [94] and Dahl et al. [95] do not agree with the presented relationship. During experiments, they did not confirm an elevated level of kynurenine metabolites in patients with diagnosed depression as compared to a control group of healthy subjects. ...
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Separating emotions from cognition seems impossible in everyday experiences of a human being. Emotional processes have an impact on the ability of planning and solving problems, or decision-making skills. They are a valuable source of information about ourselves, our partners in interactions and the surrounding world. Recent years have shown that axial symptoms of depression are caused by emotion regulation disorders, dysfunctions in the reward system and deficits of cognitive processes. There is a few studies concerning a link between emotional and inflammatory processes in depression. The aim of this article is to present results of contemporary research studies over mutual connections between social cognition, cognitive processes and inflammatory factors significant for the aetiology of recurrent depressive disorders, with particular reference to the role of kynurenine pathways.
... The IDO-induced activation of the KYN pathway has been studied in MDD for several years, but there have been inconsistent reports regarding the KYN pathway activity in MDD. One recent study found that IDO activation was not associated with depressive symptoms, which does not support the hypothesis that MDD depressive episodes are associated with elevated activity in the KYN pathway [84]. This suggests that the pathophysiology underlying depressive episodes in common MDD differs from that of interferon-induced depression. ...
Article
Poststroke fatigue (PSF) and poststroke depression (PSD) are both common and difficult sequelae following acute ischemic stroke (AIS). Two main perspectives to explain these sequelae are the biomedical perspective and the psychosocial perspective. Research has shown that PSF and PSD are undoubtedly associated with each other, although each can occur in the absence of the other. However, the nature of the relationship is unclear. For example, do stroke patients become fatigued because of being depressed, or do they become depressed because they are fatigued? Alternatively, is there a bidirectional relationship between these two sequelae, with each influencing the other? We propose a biopsychosocial model of PSF and PSD that supports the AIS-induced immune response and kynurenine pathway activation being related to fatigue but not (directly) to depression. We hypothesize that the risk of developing depression may be reduced if the experience of fatigue is acknowledged, and then addressed accordingly.
... Studies describing kynurenine metabolism in patients with depression report increases in CSF QA and decreases in plasma KA and the KA/QA ratio (Table 1) (103,104,108). Despite these data, other studies report no difference in kynurenine metabolism between patients with depression and controls ( Table 1) (106,107). Analysis of kynurenine metabolites in patients with depression who had also attempted suicide revealed an elevation in CSF QA and a decrease in KA (Table 1) (104, 105). These results suggest a role for altered kynurenine metabolism in the pathogenesis of depression, and additional studies have demonstrated that inflammation can induce both depression symptoms and metabolic changes. ...
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Mounting evidence demonstrates that kynurenine metabolism may play an important pathogenic role in the development of multiple neurological and neuropsychiatric disorders. The kynurenine pathway consists of two functionally distinct branches that generate both neuroactive and oxidatively reactive metabolites. In the brain, the rate-limiting enzyme for one of these branches, kynurenine 3-monooxygenase (KMO), is predominantly expressed in microglia and has emerged as a pivotal point of metabolic regulation. KMO substrate and expression levels are upregulated by pro-inflammatory cytokines and altered by functional genetic mutations. Increased KMO metabolism results in the formation of metabolites that activate glutamate receptors and elevate oxidative stress, while recent evidence has revealed neurodevelopmental consequences of reduced KMO activity. Together, the evidence suggests that KMO is positioned at a critical metabolic junction to influence the development or trajectory of a myriad of neurological diseases. Understanding the mechanism(s) by which alterations in KMO activity are able to impair neuronal function, and viability will enhance our knowledge of related disease pathology and provide insight into novel therapeutic opportunities. This review will discuss the influence of KMO on brain kynurenine metabolism and the current understanding of molecular mechanisms by which altered KMO activity may contribute to neurodevelopment, neurodegenerative, and neuropsychiatric diseases.
... The magnitude of their depressive and suicidal symptoms fluctuated with increasing cytokine levels and decreasing KYNA levels. In line with this, decreased plasma KYNA levels in depressed patients have previously been observed (74), although recent studies indicate that patients with depression without suicidality may not have any significant changes in the peripheral kynurenine pathway (75). ...
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Over the past decade, clinical data have accumulated showing that inflammation might contribute to the pathophysiology of suicide. To evaluate the associations and to identify the support for pathways linking inflammatory processes with suicidal behaviour, a comprehensive review of the literature was undertaken. The search terms 'cytokine', 'risk factors', 'kynurenine', 'asthma', 'allergy', 'autoimmunity', 'traumatic brain injury', 'infection' along with the terms 'inflammation' and 'suicide' were entered into PubMed, and a thorough analysis of the publications and their reference lists was performed. The effects of inflammation on mood and behaviour could partially be mediated by kynurenine pathway metabolites, modulating neuroinflammation and glutamate neurotransmission. At the same time, the triggers of the inflammatory changes documented in suicidal patients may be attributed to diverse mechanisms such as autoimmunity, neurotropic pathogens, stress or traumatic brain injury. Targeting the inflammatory system might provide novel therapeutic approaches as well as potential biomarkers to identify patients at increased risk. For the goal of improved detection and treatment of suicidal individuals to be achieved, we need to develop a detailed understanding of the origin, mechanisms and outcomes of inflammation in suicidal behaviour. © 2015 The Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.
Chapter
Tryptophan (Trp) is an essential amino acid that serves as a precursor for the synthesis of many neuroactive compounds, particularly serotonin, and its significance has recently been highlighted (Marx, Wolfgang 2021). Its daily dietary intake, as well as local turnover by the GIT and the extent use of Trp by the gut microbiota, can have far-reaching consequences for the development and proper functioning of both the enteric and central nervous systems (Cervenka, Igor 2017). Trp metabolism can be divided into two main branches: first one produces chemical messengers such as the indolamines serotonin (5-HT), N-acetyl serotonin (NAS) and melatonin (MLT) and trace amine tryptamine and its derivatives, and others limited to about 3-10% of Trp biotransformation’s, the other common (about 90% or more) is the kynurenine pathway, which produces kynurenines, nicotinic acid, and nicotinamide adenine dinucleotide (NAD+) synthesis (Jon P Ruddick, 2006). Serotonin is synthesized in the body from about 1% tryptophan. The majority of serotonin synthesis occurs in enterochromaffin cells in the gut, with the remaining 10-20% occurring in the 5-HTergic neurons of mesencephalic raphe nuclei; pinealocytes in the pineal gland in the brain from tryptophan, which crosses the blood-brain barrier (Jon P Ruddick, 2006). The rate-limiting enzymes tryptophan 2,3-dioxygenase (TDO, stress sensitive) and indoleamine 2,3-dioxygenase (IDO, immune response) convert the remaining 99% of tryptophan to kynurenine (IDO1, immune response), the first one is in the liver and the latter in the immune system and mucosal tissues such as the gut (Kanai, Masaaki, 2009, Pallotta, Maria T., 2011). IDO can be activated by proinflammatory cytokines such as TNF- α, IL-6, and its most potent activator, IFN- γ (Zhang, Peifen, 2021). Furthermore, Th1 cytokines activate microglial IDO, increasing QA production, whereas Th2 cytokines deactivate microglial IDO, shifting KYN metabolism to astroglial KYNA production (Najjar, Souhel, 2013). Kyn in the CNS, 60% of which is supplied from the periphery by crossing the blood-brain barrier (BBB), is converted to 3-hydroxyanthranilic acid via anthranilic acid or converted by Kynurenine 3-monooxygenase (KMO) to 3-hydroxyquinurenin and then to quinolinic acid in microglia (Boado, Ruben J. 1999). This latter pathway has been linked to neurotoxicity via free radical generation, which contributes to oxidative stress, and the excitotoxic effects of quinolinic acid as an NMDA receptor agonist (Stone, Trevor W. 2012). The KMO transcript is increased via IL-1β stimulation and KMO expression is enhanced after lipopolysaccharide (LPS) administration (Zunszain, Patricia A. 2012, Connor, Thomas J. 2008). Furthermore, the activated immune state contributes to the impairment of BBB integrity (Pollak, Thomas A. 2018), facilitating the transportation of TRP and KYN into the brain to provide original materials for the KYN pathway (Savitz, Jonathan, 2019). In contrast, kynurenine is converted by kynurenine aminotransferases (KAT) to kynurenic acid in astrocytes, which has neuroprotective potential via NMDA and 7 nicotinic acetylcholine receptor antagonism, as well as anti-inflammatory and immunosuppressive functions (Lovelace, Michael D. 2017). The modulatory effect of KynA on the immune response is through its agonistic effects on the aryl hydrocarbon receptor (AhR), a transcription factor involved in xenobiotic metabolism (Gutiérrez-Vázquez, Cristina, 2018). In many cell types, including macrophages, AhR signaling appears to be important in the termination of cytokine release (Gutiérrez-Vázquez, Cristina, 2018).
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Background: A disruption of the kynurenine (KYN) pathway may exist in major depressive disorder (MDD). However, the changing pattern of the KYN pathway across the different disease states in MDD is unclear. Herein, we performed a meta-analysis to examine the differences in KYN metabolites between patients in the current episode of MDD (cMDD) and patients in remission (rMDD), as well as the changes after treatments. Methods: Literature was systematically searched from electronic databases, from inception up to September 2022. Random-effect models were used to quantify the differences in KYN metabolites between patients with MDD across acute depressive episode and remission phases, as well as the changes after treatments. Results: Fifty-one studies involving 7056 participants were included. Tryptophan (TRP), KYN, kynurenic acid (KYNA), KYNA/quinolinic acid (QA), KYNA/3-hydroxykynurenine (3-HK), and KYNA/KYN were significantly lower, while KYN/TRP was significantly higher in patients with cMDD. Moreover, these effect sizes were generally larger in medication-free patients. No significant differences were found between patients with rMDD and HCs. Additionally, KYNA was found negatively correlated with depression severity and significantly increased after treatments, while the alteration was not found in QA. Limitations: The number of included studies of patients with rMDD and longitudinal studies investigating the change of the KYN metabolites after treatment with antidepressants was limited. In addition, the heterogeneity across included studies was relatively high. Conclusions: These findings showed a comprehensive image of the unique dysfunction pattern of the KYN pathway across different MDD states and highlighted KYNA as a potentially sensitive biomarker of MDD.
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Tryptophan is an essential amino acid absorbed by the gut depending on a homoeostatic microbiome. Up to 95% of unbound tryptophan is converted into tryptophan catabolites (TRYCATs) through the kynurenine system. Recent studies identified conflicting associations between altered levels of TRYCATs and genetic polymorphisms in major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). This meta-analysis aimed to understand how tryptophan catabolic pathways are altered in MDD, SCZ, and BD. When compared to healthy controls, participants with MDD had moderately lower levels of tryptophan associated with a moderate increase of kynurenine/tryptophan ratios and no differences in kynurenine. While significant differences were found in SCZ for any of the TRYCATs, studies on kynurenic acid found opposing directions of effect sizes depending on the sample source. Unique changes in levels of TRYCATs were also observed in BD. Dynamic changes in levels of cytokines and other immune/inflammatory elements modulate the transcription and activity of kynurenine system enzymes, which lastly seems to be impacting glutamatergic neurotransmission via N-methyl-D-aspartate and α-7 nicotine receptors.
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Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of ‘tonic’ kynurenine pathway affecting baseline activity and the superimposed ‘phasic’ cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.
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The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges’ g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.
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Background The biological mechanisms underlying major depressive disorder (MDD) are not yet sufficiently understood. The kynurenine pathway has been proposed to play a key role between peripheral inflammation and alterations in the central nervous system. This is because of reduced usability of tryptophan (TRP) and production of oxygen radicals and highly potent neurotoxic agents in this pathway. Objective In this study, we aimed to compare the metabolites of the serum kynurenine pathway (tryptophan, kynurenine, quinolinic acid and kynurenic acid) and IFN‐γ, IL‐6, IL‐1β and high‐sensitivity C‐reactive protein (hsCRP) levels in patients with major depressive disorder and in healthy controls and to evaluate the relationship between cytokine levels and the functioning of the kynurenine pathway. Methods Clinical and biochemical data from the patients were obtained and assessed in a cross‐sectional design. Serum samples were analysed for IL‐6, IL‐1β, interferon (IFN)‐γ, tryptophan (TRP), quinolinic acid (QUIN), kynurenic acid (KYNA) and kynurenine (Kyn) levels by the enzyme‐linked immunosorbent assay. hsCRP test was analysed by the immunoturbidimetric method. Results In total, 48 adolescent patients with major depressive disorder (no drug use) and 31 healthy controls were included in the study. TRP levels were observed to be significantly lower in patients with MDD than in healthy controls (P = .046); the Kyn/TRP ratio was significantly higher in patients with MDD than in healthy controls (P = .032); the levels of QUIN were significantly higher in patients with MDD than in healthy controls (P = .003). No significant difference was found between the groups in terms of other kynurenine metabolites and cytokines levels. Conclusion These results suggest that the Kyn and related molecular pathways may play a role in the pathophysiology of MDD. The most important finding was the increased level of QUIN, which has a neurotoxic effect, in the kynurenine pathway.
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Significance: Approximately 6.5 million people in the United States suffer from chronic wounds. The chronic wound population is typically older and is characterized by a number of comorbidities associated with inflammation. In addition to experiencing wound-related pain, individuals with chronic wounds commonly experience multiple concurrent psychoneurological symptoms such as fatigue and depression, which delay wound healing. However, these distressing symptoms have been relatively overlooked in this population, although their adverse effects on morbidity are well-established in other chronic disease populations. Recent Advances: Inflammation is involved in multiple pathways which activate brain endothelial and innate immune cells that release pro-inflammatory cytokines, which have been produce multiple symptoms known as sickness behaviors. Inflammation-based activation of the kynurenine pathway and its metabolites is a mechanism associated with chronic illnesses. Critical issues: Although putative humoral and neuronal routes have been identified, the specific metabolic variations involved in sickness behaviors in chronic wound patients remains unclear. To improve health outcomes in the chronic wound population, clinicians need to have better understanding of the mechanisms underlying sickness behaviors to provide appropriate treatments. Future directions: This paper presents a synthesis of studies investigating associations between inflammation, metabolic pathways, and sickness behaviors in multiple chronic diseases. The presentation of a theoretical framework proposes a mechanism underlying sickness behaviors in the chronic wound population. By mediating the immune system response, dysregulated metabolites in the kynurenine pathway may play an important role in sickness behaviors in chronic inflammatory conditions. This framework may guide researchers in developing new treatments to reduce the disease burden in the chronic wound population.
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Objective: Repetitive transcranial magnetic stimulation (rTMS) improves depressive symptoms and motor function in stroke patients. While metabolic derangement of the kynurenine pathway has been reported in stroke patients, the effect of rTMS on this pathway remains unknown. This study was performed to investigate the effect of rTMS on serum levels of kynurenine and tryptophan in stroke patients. Methods: Sixty-two stroke patients received rTMS in addition to intensive rehabilitation and 33 stroke patients received intensive rehabilitation alone for 14 days. The rTMS involved low-frequency stimulation (at 1 Hz) of the primary motor cortex on the unaffected side of the cerebrum. The depressive state of the patients was evaluated with the Beck Depression Inventory (BDI) before and after treatment. Motor function of the patients was evaluated with Fugl-Meyer Assessment (FMA). Serum levels of kynurenine and tryptophan levels were also measured before and after treatment. Results: The serum tryptophan level decreased in the group receiving rTMS to the right brain and increased in the group receiving rTMS to the left brain. The serum kynurenine/tryptophan ratio was elevated in the group receiving rTMS to the right brain. The BDI indicated improvement of depressive symptoms in the rehabilitation alone group and the group receiving rTMS to the right brain plus rehabilitation. The FMA improved in all groups. Conclusions: The effect of low-frequency rTMS on the kynurenine pathway may differ depending on whether it is applied to the right or left cerebral hemisphere.
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Introduction La fatigue post-AVC (FP-AVC) est une complication fréquente qui est associée à une moins bonne récupération fonctionnelle des patients à moyen terme et à une augmentation de la mortalité à long terme. Quelques pistes thérapeutiques sont actuellement explorées, mais nous avons encore besoin de mieux comprendre les mécanismes sous-jacents à la FP-AVC pour améliorer ces traitements. Certaines études ont retrouvé un lien entre la localisation de l’AVC, notamment des noyaux gris centraux, et la présence d’une fatigue. L’objectif principal de notre travail était de rechercher une éventuelle corrélation entre l’intensité de la FP-AVC et les anomalies perfusionnelles cérébrales évaluées par tomoscintigraphie couplée à la tomodensitométrie. Méthode Les patients étaient recrutés durant leur hospitalisation initiale en unité neurovasculaire. À 3, 6 et 12 mois (M3, M6 et M12), l’intensité de la FP-AVC était mesurée grâce à la Fatigue Assessment Scale (FAS), un score élevé signifiant un haut niveau de fatigue. De même, chaque patient réalisait une scintigraphie cérébrale à M3, M6 et M12. Les corrélations entre la FAS et l’intensité de fixation du traceur de perfusion observée en scintigraphie ont été calculées en utilisant SPM. Résultats Vingt-huit patients ont été inclus, pour un total de 59 examens (26 à M3, 18 à M6 et 15 à M12). Nous avons retrouvé une corrélation négative entre le score FAS et l’intensité de perfusion des noyaux gris centraux et du pôle temporal ipsilatéraux à l’AVC. Il est intéressant de noter que seulement 5 patients, correspondant à 11 scintigraphies, ont présenté un infarctus des ganglions de la base. Conclusion L’hypoperfusion des noyaux gris centraux et du pôle temporal ipsilatéraux semble impliquée dans le développement de la FP-AVC. De plus, cette hypoperfusion des noyaux gris centraux est due pour certains patients à un infarctus de cette région mais pour d’autre probablement à un diaschisis. L’utilisation de la dopamine dans le traitement de la FP-AVC pourrait donc être une voie à explorer pour améliorer la qualité de vie de ces patients.
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Introduction: Despite the knowledge of sex differences concerning neurobiological parameters as well as clinical course of illness in individuals with mood disorders, the literature concerning tryptophan (Trp) breakdown, specific for women and men, is sparse to date. The current study aimed to evaluate sex differences in Trp, kynurenine (Kyn) and Kyn/Trp concentrations in general, as well as differences in changes of those concentrations over the course of a 6-week rehabilitation program in individuals with life-time unipolar affective disorder. For this purpose changes in Trp and Kyn as well as the Kyn/Trp concentrations between the time of admission (t1) and discharge (t2) were analyzed in dependence of sex. Furthermore, correlations between Trp and Kyn levels and clinical parameters were performed separately for male and female participants. Material and Methods: Results: For the current analysis 426 individuals with lifetime affective disorder completing a 6-week rehabilitation program were included. In both sexes, psychiatric symptoms decreased significantly over time. There was a significant difference between women (n = 242) and men (n = 184) regarding the changes in Trp, Kyn, and Kyn/Trp over time even if controlled for relevant covariates [multivariate: F(3, 380) = 2.663, η² = 0.021, p = 0.048]. Kyn as well as Kyn/Trp concentrations increased significantly in men over time (Kyn F = 4.809, η² = 0.012, p = 0.029; Kyn/Trp F = 7.923, η² = 0.020, p = 0.005). Results remained the same when controlled for psychiatric symptoms. Discussion: The main finding of the present study is the significant difference between women and men regarding the change in Trp, Kyn, and Kyn/Trp over a 6-week psychiatric treatment period, while the depression severity scores as well as general psychiatric symptoms decreased. Sex specific changes in Trp-Kyn pathways have only been explored to a very small extent to date in the literature but are of high clinical relevance in the context of personalized medicine.
Chapter
The kidneys are critical for the secretion of cytokines and hormones, the excretion of waste metabolites, and the homeostasis of electrolytes. Chronic kidney disease (CKD) is a major epidemiologic problem and a risk factor for cardiovascular events and cerebrovascular accidents. At present, renal function is generally evaluated by measuring estimated glomerular filtration rate (eGFR). However, this method has low sensitivity during the early stages of CKD. A new biomarker that can detect CKD during its early stages is eagerly awaited: mass spectrometry (MS), an effective technology for the discovery of biomarkers due to its high sensitivity to detect many compounds, seems to fit these conditions. Metabolomics using mass spectrometry is a powerful strategy for profiling metabolites and can be used to effectively explore unknown compounds that change in abundance with respect to disease condition. Recently, many researchers have endeavored to apply metabolomics techniques to diagnose various diseases, including CKD. Some metabolites that can serve as biomarkers for CKD severity have been discovered, thanks to their efforts. This chapter reviews metabolomics techniques and their potential to be applied to CKD diagnosis.
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Activation of the kynurenine pathway is one of the described mechanisms by which inflammation can induce depression. It involves multiple pathways including interference with the bioavailability of tryptophan central to the synthesis of the neurotransmitter serotonin. In this systematic review, we examine the relationship between kynurenine metabolites (kynurenine, kynurenic acid, tryptophan, quinolinic acid, the ratio of kynurenine and tryptophan) and mood disorders by conducting a meta-analysis. Fifty-six studies were identified, 21 met inclusion criteria and 14 were deemed suitable (9 investigating unipolar depression and 5 bipolar disorder). We found decreased levels of kynurenine in unipolar major depression vs. healthy controls but studies were significantly heterogeneous in nature. No significant differences were found in tryptophan levels or kynurenine/tryptophan ratios. Kynurenine metabolites are likely to play a role in major depression but an exact etiological role in mood disorder seem complex and requires further research.
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In spite of the extensive application of electroconvulsive therapy (ECT), how it works remains unclear. So far, researchers have made great efforts in figuring out the mechanisms underlying the effect of ECT treatment via determining the levels of neurotransmitters and cytokines and using genetic and epigenetic tools, as well as structural and functional neuroimaging. To help address this question and provide implications for future research, relevant clinical trials and animal experiments are reviewed.
Chapter
The kidneys are critical for the secretion of cytokines and hormones, the excretion of waste metabolites, and the homeostasis of electrolytes. Chronic kidney disease (CKD) is a major epidemiologic problem and a risk factor for cardiovascular events and cerebrovascular accidents. At present, renal function is generally evaluated by measuring estimated glomerular filtration rate (eGFR). However, this method has low sensitivity during the early stages of CKD. A new biomarker that can detect CKD during its early stages is eagerly awaited: mass spectrometry (MS), an effective technology for the discovery of biomarkers due to its high sensitivity to detect many compounds, seems to fit these conditions. Metabolomics using mass spectrometry is a powerful strategy for profiling metabolites and can be used to effectively explore unknown compounds that change in abundance with respect to disease condition. Recently, many researchers have endeavored to apply metabolomics techniques to diagnose various diseases, including CKD. Some metabolites that can serve as biomarkers for CKD severity have been discovered, thanks to their efforts. This chapter reviews metabolomics techniques and their potential to be applied to CKD diagnosis.
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Many stroke survivors suffer from poststroke fatigue (PSF) and poststroke depression (PSD), indicating the importance of increasing the base of knowledge about the mechanisms underlying these sequelae. The primary aim of this study was to determine whether activation of the kynurenine (KYN) pathway predicts subsequent fatigue or depression in acute ischemic stroke (AIS) patients. Acute serum levels of 5-hydroxytryptamine (5-HT), tryptophan (TRP) catabolites (TRYCATs), and competing amino acids, as well as subsequent fatigue and depression, were measured in 45 stroke patients. TRP index [=100 × TRP / (tyrosine + valine + phenylalanine + leucine + isoleucine)] was significantly lower in patients with a Fatigue Severity Scale (FSS) score of ≥4 at 12 months than in those with an FSS score of <4 (p = 0.039). Furthermore, the serum level of kynurenic acid in the acute stroke phase was significantly higher in patients with an FSS of score ≥4 at 18 months than in those with an FSS score of <4 (p = 0.026). These findings indicate that stroke patients with PSF have a lower bioavailability of TRP for 5-HT synthesis in the brain in the acute stroke phase. However, they also appear to have greater neuroprotective potential in that phase. In contrast to PSF, no predictors of PSD were found. These findings together with those of previous studies suggest that the immune response and indoleamine 2,3-dioxygenase activation that follows AIS can predict PSF but not PSD.
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Whether the inflammatory response that accompanies acute ischemic stroke induces the kynurenine pathway is currently a matter of conjecture. Activation of this pathway may disturb active metabolites. The aim of this study was thus to characterize the catabolism of tryptophan and tyrosine in acute ischemic stroke (AIS) patients, and its association with cytokines, C-reactive protein, and glucose. Serum levels of 5-hydroxytryptamine, tryptophan catabolites, and competing amino acids and significant ratios of these were measured in 45 AIS patients and compared to those of 40 control subjects. Furthermore, associations between the serum levels of these biomarkers and serum levels of cytokines, C-reactive protein, and glucose were determined. Significantly lower levels of tryptophan and tyrosine in the stroke group indicate increased tryptophan and tyrosine oxidation in acute ischemic stroke, while significantly lowered tryptophan index and tyrosine index indicate a reduced capacity for the synthesis of 5-hydroxytryptamine and catecholamines in the brain, respectively. Furthermore, our findings indicate that the proinflammatory response in acute ischemic stroke may be responsible for a reduced capacity for the biosynthesis of brain catecholamines and mediate neurotoxic effects. Meanwhile, the anti-inflammatory IL-10 may exert a neuroprotective effect and prevent the putative reduced capacity for 5-hydroxytryptamine synthesis in the brain. These mechanisms may be involved in several sequelae following stroke, such as cognitive impairment, depression, and fatigue.
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Studies show that administration of interferon (IFN)-α causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-α-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-α treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood–brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-α treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-α-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.
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Background Patients with depression and suicidality suffer from low-grade neuroinflammation. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). Methods We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over two years (total patient samples n=143, individuals n=30) and healthy controls (n=36). The association between the markers and psychiatric symptoms were assessed using the Montgomery Åsberg Depression Rating Scale and the Suicide Assessment Scale. Results Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. Conclusions We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression.
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Background Several studies have suggested that induced tryptophan (TRP) degradation through the kynurenine (KYN) pathway by the enzyme indoleamine 2,3-dioxygenase (IDO) is implicated in the relation between depression and inflammation. We investigated the role of tryptophan degradation in the relationship between inflammatory markers and depressive symptoms in the Netherlands Study of Depression and Anxiety (NESDA) and hypothesized that tryptophan degradation would mediate (part of) this association. Methods 2812 participants of NESDA were included in this study including 1042 persons with current major depressive disorder (MDD). Assessments of C-reactive protein (CRP), interleukin (IL)-6, tumor-necrosis factor (TNF)-α, KYN and TRP were obtained from fasting blood samples at the baseline assessment. Tryptophan degradation was estimated by calculating the ratio [KYN/TRP]. Depressive symptoms were measured with the Inventory of Depressive Symptomatology. Results Significant associations between inflammation and depressive symptoms were found for CRP and IL-6, for the total group and the subgroup of patients with current MDD. Adjustment for KYN/TRP did not attenuate these associations. There were no significant indirect effects for CRP on depressive symptoms mediated by KYN/TRP for the whole group (B = -0.032; 95% CI: -0.103-0.028) and for the subgroup of patients with current MDD (B = 0.059; 95% CI: -0.037-0.165). Also IL-6 did not indirectly affect depressive symptoms through KYN/TRP in the total group (B= -0.023; 95% CI: -0.093-0.045) and in the MDD subgroup B= 0.052; 95% CI: -0.019-0.144). Finally, no significant relation between depressive symptoms and KYN/TRP was found in the whole group (β=-0.019, p = 0.311) nor in the subgroup with MDD (β=0.025, p = 0.424). Conclusions We did not find indications for tryptophan degradation, measured by KYN/TRP, to mediate the relationship between inflammation and depressive symptoms.
Article
BACKGROUND Cytokines are implicated in the pathophysiology of major depressive disorder (MDD). However, the pattern of alterations in cytokine levels is still unclear. The current study investigated the plasma levels of a range of cytokines in a follow-up design, with the aim of determining their involvement in depression. METHODS Fifty medication-free MDD patients with a depressive episode and 34 healthy controls were included at baseline; the patients were followed up after 12 weeks. Before initiating treatment, the patients were diagnosed and assessed for depressive symptoms and blood for cytokine analysis was obtained. The same clinical assessments and cytokine measurements were performed after 12 weeks of “treatment as usual.” RESULTS The cytokines interleukin (IL)-1β, IL-1 receptor antagonist (IL-1Ra), IL-5, IL-6, IL-7, IL-8, IL-10, granulocyte colony-stimulating factor (G-CSF), and interferon gamma (IFNγ) were significantly elevated (p = 0.01-0.047) in depressed patients at baseline compared to healthy controls. After 12 weeks of treatment, the plasma levels of seven of these nine cytokines (IL-1Ra, IL-6, IL-7, IL-8, IL-10, G-CSF, and IFNγ had decreased significantly compared to baseline and did not differ from those in the healthy controls. The depressive symptoms were simultaneously significantly reduced. In addition, the reduction to normal cytokines levels occurred only in those who met the recovery criteria. CONCLUSION A more general pattern of elevated cytokine levels is described herein relative to what has been described previously shown in MDD. Furthermore, recovery from depression was associated with reduction to normal levels of the majority of the measured cytokines. These results strongly support the notion that a complex network of cytokines is involved in the pathophysiology of MDD.
Article
Alterations in the rate of cellular tryptophan metabolism are involved in mediating important biological activities associated with cytokines and growth factors. Indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase are enzymes of tryptophan metabolism whose expression in a variety of cells and tissues is highly inducible by interferon-γ (IFN-γ). Transforming growth factor-β (TGF-β) antagonizes many cellular responses to IFN-γ. The interaction of these two cytokines plays an important role in maintaining homeostasis during inflammation and repair. In human skin and synovial fibroblasts in vitro, TGF-β caused time- and dose-dependent abrogation of IFN-γ-stimulated expression of IDO and tryptophanyl-tRNA synthetase mRNAs. The inhibition was selective and did not appear to be due to down-regulation of IFN-γ signaling by TGF-β. In parallel with its effect on IDO mRNA expression, TGF-β caused a marked reduction in intracellular IDO protein levels and abrogated IDO activity and tryptophan catabolism in these cells induced by IFN-γ. IFN-γ caused a rapid and striking increase in the amount of IDO heterogeneous nuclear pre-mRNA and induced transcription of the IDO gene, as demonstrated by transient transfection assays. TGF-β partially reversed this stimulation. IFN regulatory factor (IRF)-1 and stat1 are cellular intermediates in IFN signaling. Both are implicated in activation of IDO transcription in response to IFN-γ. The stimulation by IFN-γ of IRF-1 protein and mRNA expression was not prevented by treatment of fibroblasts with TGF-β. Furthermore, gel mobility shift assays indicated that TGF-β did not inhibit the induction of stat1 and IRF-1 binding activity to their cognate DNA recognition sites in the IDO gene promoter. In contrast, the stability of IDO mRNA transcripts was reduced in fibroblasts treated with TGF-β, as shown by determination of mRNA half-lives following blockade of transcription with 5,6-dichlorobenzimidazole riboside. The findings indicate that TGF-β prevents the induction of IDO and tryptophanyl-tRNA synthetase gene expression in fibroblasts. The repression of IDO expression by TGF-β is mediated at both transcriptional and posttranscriptional levels. These results implicate TGF-β in the negative regulation of tryptophan metabolism, provide evidence for the molecular basis of this regulation, and indicate that cellular tryptophan metabolism is under tight immunological control. J. Cell. Physiol. 177:174–186, 1998.
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Background Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-α therapy.
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: 3-Hydroxykynurenine (3-HK) is a potential endogenous neurotoxin whose increased levels have been described in several neurodegenerative disorders. Here, we characterized in vitro neurotoxicity of 3-HK. Of the tested kynurenine pathway metabolites, only 3-HK, and to a lesser extent 3-hydroxyanthranilic acid, were toxic to primary cultured striatal neurons. 3-HK toxicity was inhibited by various antioxidants, indicating that the generation of reactive oxygen species is essential to the toxicity. 3-HK-induced neuronal cell death showed several features of apoptosis, as determined by the blockade by macromolecule synthesis inhibitors, and by the observation of cell body shrinkage with nuclear chromatin condensation and fragmentation. In addition, 3-HK toxicity was dependent on its cellular uptake via transporters for large neutral amino acids, because uptake inhibition blocked the toxicity. Cortical and striatal neurons were much more vulnerable to 3-HK toxicity than cerebellar neurons, which may be attributable to the differences in transporter activities of these neurons. These results indicate that 3-HK, depending on transporter-mediated cellular uptake and on intracellular generation of oxidative stress, induces neuronal cell death with brain region selectivity and with apoptotic features, which may be relevant to pathology of neurodegenerative disorders.