Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

Clark, Sarah M.; Pocivavsek, Ana; Nicholson, James D.; Notarangelo, Francesca M.; Langenberg, Patricia; McMahon, Robert P.; Kleinman, Joel E.; Hyde, Thomas M.; Stiller, John W.; Postolache, Teodor T.; Schwarcz, Robert; Tonelli, Leonardo H.

doi:10.1503/jpn.150226

Cited by 81 publications

(59 citation statements)

References 60 publications

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“…Together with reports of altered levels of IFNγ in individuals with depression or ASD 53–57 , these findings could suggest that immune dysfunction may contribute to the pathology of neurological disorders that present with social withdrawal. In a post-mortem study, Clark et al 53 revealed that IFNγ levels were reduced in the ventrolateral PFC of individuals diagnosed with depression compared with controls; by contrast, other studies reported increased circulating levels of IFNγ in people with depression 54 . Whether these differences are due to variability in the cohorts or, more intriguingly, to differential expression of IFNγ in the blood versus the CNS is not known.…”

Section: T Cell Influences On the Brainsupporting

confidence: 57%

How and why do T cells and their derived cytokines affect the injured and healthy brain?

2017

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The evolution of adaptive immunity provides enhanced defence against specific pathogens, as well as homeostatic immune surveillance of all tissues. Despite being ‘immune privileged’, the CNS uses the assistance of the immune system in physiological and pathological states. In this Opinion article, we discuss the influence of adaptive immunity on recovery after CNS injury and on cognitive and social brain function. We further extend a hypothesis that the pro-social effects of interferon-regulated genes were initially exploited by pathogens to increase host–host transmission, and that these genes were later recycled by the host to form part of an immune defence programme. In this way, the evolution of adaptive immunity may reflect a host–pathogen ‘arms race’.

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Section: T Cell Influences On the Brainsupporting

confidence: 57%

How and why do T cells and their derived cytokines affect the injured and healthy brain?

2017

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“…The finding of a markedly higher ratio of plasma TRY/KYN concentrations suggests a less efficient metabolic conversion of TRY to KYN in depressed subjects, rather than an expected lowering of this ratio based on some [4] (but not all [13,14]) previously reported findings. Findings of less circulating TRY and more KYN have been proposed as evidence of the decreased production of serotonin in association with depression [2,7,21,23].…”

Section: Discussionmentioning

confidence: 45%

“…Nevertheless, the findings have not always been consistent [13,14,24] and require replication. Based on the aim of verifying some preceding findings, we tested the relationship of circulating concentrations of KYN-related metabolites to current major depression among hospitalized patients diagnosed with MDD or BD, with or without a lifetime history of suicide attempt, compared with healthy, ambulatory controls of similar age and sex distribution.…”

Section: Introductionmentioning

confidence: 81%

“…These proposed associations are supported by observations of altered concentrations of TRY (decreased) or KYN (increased), with an increased ratio of KYN/TRY (or a lower TRY/KYN ratio), sometimes with reduced kynurenic (KA), and increased quinolinic acid (QA) and xanthurenic acid (XA), as well as reduced concentrations of serotonin (5-hydroytryptamine) and its main metabolic product 5-hydroxyindolacetic acid (5-HIAA) in serum, plasma, or cerebrospinal fluid (CSF) [2][3][4][5][6][7][8][9][10][11][12]. However, such associations have not been reported in all studies [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Tryptophan and Kynurenine Metabolites: Are They Related to Depression?

et al. 2018

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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.

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“…Although much of the attention of the literature has been focused on immunologic parameters in the peripheral blood, it should be noted that although the literature is not entirely consistent (Clark et al, 2016), increased activation of microglial cells as well as increased expression of inflammatory cytokines and Toll-like receptors have been described in postmortem brain samples of presumably depressed suicide victims (Steiner et al, 2008(Steiner et al, , 2011Pandey et al, 2012Pandey et al, , 2014Torres-Platas et al, 2014). Inconsistencies in the literature have been attributed to diagnostic considerations, use of medications, brain regions sampled, and small sample sizes.…”

Section: Foundations For the Hypothesis That The Immune System Plays mentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

118

124

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A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

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Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

Cited by 81 publications

References 60 publications

How and why do T cells and their derived cytokines affect the injured and healthy brain?

How and why do T cells and their derived cytokines affect the injured and healthy brain?

Tryptophan and Kynurenine Metabolites: Are They Related to Depression?

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

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