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

Dahl, Johan; Andreassen, Ole A.; Verkerk, Robert; Malt, Ulrik Fredrik; Sandvik, Leiv; Brundin, Lena; Ormstad, Heidi

doi:10.1016/j.psyneuen.2015.02.011

Cited by 47 publications

(48 citation statements)

References 45 publications

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“…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].…”

Section: Discussionsupporting

confidence: 77%

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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Section: Discussionsupporting

confidence: 77%

Tryptophan and Kynurenine Metabolites: Are They Related to Depression?

et al. 2018

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“…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 .…”

Section: Discussionmentioning

confidence: 45%

“…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)].…”

Section: Discussionmentioning

confidence: 99%

Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects

Coccaro

Lee

Fanning

et al. 2016

Psychoneuroendocrinology

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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.

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“…[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.…”

Section: Discussionmentioning

confidence: 90%

“…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.…”

Section: Discussionmentioning

confidence: 98%