The kynurenine pathway: a finger in every pie

Savitz, Jonathan

doi:10.1038/s41380-019-0414-4

Cited by 438 publications

(451 citation statements)

References 188 publications

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“…Tryptophan‐2,3‐dioxygenase (TDO) converts tryptophan into kynurenine in liver whereas in the brain the conversion depends on indoleamine 2,3‐dioxygenase. However, kynurenine can cross the brain–blood barrier . Second, quinolinic acid, a metabolite with potentially deleterious neuronal excitotoxicity, was not available in the metabolites quantification panel.…”

Section: Discussionmentioning

confidence: 99%

“…However, kynurenine can cross the brain-blood barrier. 49 Second, quinolinic acid, a metabolite with potentially deleterious neuronal excitotoxicity, 17,50 was not available in the metabolites quantification panel. Third, potential confounders, such as glucocorticoid levels, immunity, inflammation, glucocorticoid treatments, vitamin, and mineral levels were not assessed in this study.…”

Section: Discussionmentioning

confidence: 99%

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Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case–control study

Colle

Masson

Verstuyft

et al. 2019

Psychiatry Clin Neurosci

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Aim Tryptophan is the sole precursor of both peripherally and centrally produced serotonin and kynurenine. In depressed patients, tryptophan, serotonin, kynurenine, and their metabolite levels remain unclear. Therefore, peripheral tryptophan and metabolites of serotonin and kynurenine were investigated extensively in 173 patients suffering from a current major depressive episode (MDE) and compared to 214 healthy controls (HC). Methods Fasting plasma levels of 11 peripheral metabolites were quantified: tryptophan, serotonin pathway (serotonin, its precursor 5‐hydroxytryptophan and its metabolite 5‐hydroxyindoleacetic acid), and kynurenine pathway (kynurenine and six of its metabolites: anthranilic acid, kynurenic acid, nicotinamide, picolinic acid, xanthurenic acid, and 3‐hydroxyanthranilic acid). Results Sixty (34.7%) patients were antidepressant‐drug free. Tryptophan levels did not differ between MDE patients and HC. Serotonin and its precursor (5‐hydroxytryptophan) levels were lower in MDE patients than in HC, whereas, its metabolite (5‐hydroxyindoleacetic acid) levels were within the standard range. Kynurenine and four of its metabolites (kynurenic acid, nicotinamide, picolinic acid, and xanthurenic acid) were lower in MDE patients. Conclusion Whilst the results of this study demonstrate an association between the metabolites studied and depression, conclusions about causality cannot be made. This study uses the largest ever sample of MDE patients, with an extensive assessment of peripheral tryptophan metabolism in plasma. These findings provide new insights into the peripheral signature of MDE. The reasons for these changes should be further investigated. These results might suggest new antidepressant therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case–control study

Colle

Masson

Verstuyft

et al. 2019

Psychiatry Clin Neurosci

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“…Nevertheless, a recent pre-clinical study has shown that the blockade of KYN transport across the blood-brain barrier by leucine effectively abrogates inflammationinduced depression-like behavior in mice. (Walker et al, 2018) KYN metabolism is increasingly recognized as a key neurochemical pathway in the link between inflammation and depression (Reus et al, 2015;Savitz, 2019). Inflammatory mediators activate IDO, an enzyme that converts Trp to KYN.…”

Section: Discussionmentioning

confidence: 99%

Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study

Kruse

Cho

Olmstead

et al. 2019

Psychoneuroendocrinology

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Inflammation has an important physiological influence on mood and behavior. Kynurenine metabolism is hypothesized to be a pathway linking inflammation and depressed mood, in part through the impact of kynurenine metabolites on glutamate neurotransmission in the central nervous system. This study evaluated whether the circulating concentrations of kynurenine and related compounds change acutely in response to an inflammatory challenge (endotoxin administration) in a human model of inflammation-induced depressed mood, and whether such metabolite changes relate to mood change. Adults (n = 115) were randomized to receive endotoxin or placebo. Mood (Profile of Mood States), plasma cytokine (interleukin-6, tumor necrosis factor-α) and metabolite (kynurenine, tryptophan, kynurenic acid, quinolinic acid) concentrations were repeatedly measured before the intervention, and at 2 and 6 h post-intervention. Linear mixed models were used to evaluate relationships between mood, kynurenine and related compounds, and cytokines. Kynurenine, kynurenic acid, and tryptophan (but not quinolinic acid) concentrations changed acutely (p's all < 0.001) in response to endotoxin as compared to placebo. Neither kynurenine, kynurenic acid nor tryptophan concentrations were correlated at baseline with cytokine concentrations, but all three were significantly correlated with cytokine concentrations over time in response to endotoxin. Quinolinic acid concentrations were not correlated with cytokine concentrations either before or following endotoxin treatment. In those who received endotoxin, kynurenine (p = 0.049) and quinolinic acid (p = 0.03) positively correlated with depressed mood, although these findings would not survive correction for multiple testing. Changes in tryptophan and kynurenine pathway metabolites did not mediate the relationship between cytokines and depressed mood. Further work is necessary to clarify the pathways leading from inflammation to depressed mood in humans.

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“…How these putative mechanisms alter known dopaminergic and glutamatergic abnormalities in patients with schizophrenia is an important question that must be addressed. Furthermore, understanding the interplay of the immune system with metabolism (180,183,184) or the kynurenine pathway (185,186) may offer an approach to understand the complexities of how the immune system may impact the brain in patients with schizophrenia to lead to negative symptoms. Strategies such as challenges with drugs that target inflammation and/or these neurotransmitter systems, neuroimaging approaches such as positron emission tomography (PET) or magnetic resonance spectroscopy (MRS) or perhaps using novel approaches such as induced pluripotent stem cells (iPSC) from patients with schizophrenia may help elucidate these mechanisms.…”

Section: Inflammation and Negative Symptoms: Future Directionsmentioning

confidence: 99%

Inflammation and Negative Symptoms of Schizophrenia: Implications for Reward Processing and Motivational Deficits

Goldsmith

Rapaport

2020

Front. Psychiatry

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Negative symptoms of schizophrenia are debilitating and chronic in nature, are difficult to treat, and contribute to poor functional outcomes. Motivational deficits are a core negative symptom and may involve alterations in reward processing, which involve subcortical regions such as the basal ganglia. More specifically, dopamine-rich regions like the ventral striatum, have been implicated in these reward-processing deficits. Inflammation is one mechanism that may underlie negative symptoms, and specifically motivational deficits, via the effects of inflammatory cytokines on the basal ganglia. Previous work has demonstrated that inflammatory stimuli decrease neural activity in the ventral striatum and decrease connectivity in reward-relevant neural circuitry. The immune system has been shown to be involved in the pathophysiology of schizophrenia, and inflammatory cytokines have been shown to be altered in patients with the disorder. This paper reviews the literature on associations between inflammatory markers and negative symptoms of schizophrenia as well as the role of anti-inflammatory drugs to target negative symptoms. We also review the literature on the role of inflammation and reward processing deficits in both healthy controls and individuals with depression. We use the literature on inflammation and depression as a basis for a model that explores potential mechanisms responsible for inflammation modulating certain aspects of negative symptoms in patients with schizophrenia. This approach may offer novel targets to treat these symptoms of the disorder that are significant barriers to functional recovery and do not respond well to available antipsychotic medications.

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The kynurenine pathway: a finger in every pie

Cited by 438 publications

References 188 publications

Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case–control study

Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case–control study

Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study

Inflammation and Negative Symptoms of Schizophrenia: Implications for Reward Processing and Motivational Deficits

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