Reduced peripheral availability of tryptophan and increased activation of the kynurenine pathway and cortisol correlate with major depression and suicide

Messaoud, A.; Mensi, R.; Douki, Wahiba; Neffati, Fadoua; Najjar, Mohamed Fadhel; Gobbi, Gabriella; Valtorta, Flavia; Gaha, L.; Comai, Stefano

doi:10.1080/15622975.2018.1468031

Cited by 74 publications

(46 citation statements)

References 57 publications

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“…Although this strategy is also used in other metaanalyses [26,68], however, this limitation may also lead to selection bias. For example, previous studies utilizing highperformance liquid chromatography with fluorescence detection reported decreased or unchanged tryptophan levels in MDD patients compared with controls [69,70]. Fourth, confidence in metabolite annotation and quantification remains a primary challenge for metabolomics studies [71,72]; therefore, plausible metabolite candidates from the included studies may limit the generalization of our findings.…”

Section: Discussionmentioning

confidence: 91%

An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder

et al. 2020

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Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of L-acetylcarnitine, creatinine, L-asparagine, L-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, L-serine, oleic acid, myo-inositol, dodecanoic acid, L-methionine, hypoxanthine, palmitic acid, L-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. L-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of L-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan-kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased L-tryptophan and kynurenic acid levels, and alterations in the tryptophan-kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.

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Section: Discussionmentioning

confidence: 91%

An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder

et al. 2020

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“…The subsequent cortisol and indolamine 2,3-dioxygenase activation affects serotonin metabolism and increases N-methyl-D-aspartate (NMDA) agonist levels [10]. Thus, inflammatory markers could potentially be used to predict and monitor suicide risk in patients with mental disorder [11,12].…”

Section: Introductionmentioning

confidence: 99%

Neutrophil-to-lymphocyte ratio: A potential new peripheral biomarker of suicidal behavior

et al. 2020

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Background. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have emerged as important peripheral inflammatory biomarkers. Recent data suggest a possible role of the immune system in the pathophysiology of suicidal behavior (SB). The aim of this study is to evaluate the association among NLR, MLR, and PLR and SB in patients with major depressive disorder (MDD), and to test its validity as a biomarker for suicidality. Methods. We evaluated 538 patients with MDD (mean age [standard deviation] = 43.87 [14.36] years; females: 68.8%). A logistic regression model was estimated to determine the independent factors associated with suicide risk in patients with and without a history of suicide attempt (SA). Results. Three hundred ninety-three patients (74.7%) had a personal history of SA. Patients with a previous SA were more frequently female (71.9% vs. 59.6%; p = 0.007), significantly younger (41.20 vs. 51.77 years; p < 0.001), had lower depression severity at enrolment (15.58 vs. 18.42; p < 0.000), and significantly higher mean NLR and PLR ratios (2.27 vs. 1.68, p = 0.001; 127.90 vs. 109.97, p = 0.007, respectively). In the final logistic regression model, after controlling for age, sex, and depression severity, NLR was significantly associated with SB (β = 0.489, p = 0.000; odds ratio [95% confidence intervals] = 1.631 [1.266–2.102]). We propose a cut-off value of NLR = 1.30 (sensitivity = 75% and specificity = 35%). Conclusions. Our data suggest that NLR may be a valuable, reproducible, easily accessible, and cost-effective strategy to determine suicide risk in MDD.

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“… 17 – 19 Researchers have found that patients with depression have increased IDO activity in the blood, and depressive patients with suicidal tendencies have higher IDO activity than those without suicidal tendencies. 20 , 21 Moreover, clinical studies have indicated that depressed patients could benefit from anti-inflammatory drugs and IDO inhibitors. 22 – 24 Therefore, we speculated that inhibiting IDO activity is a viable therapeutic target for inflammation-associated depression.…”

Section: Introductionmentioning

confidence: 99%

<p>Electroacupuncture Relieves LPS-Induced Depression-Like Behaviour in Rats Through IDO-Mediated Tryptophan-Degrading Pathway</p>

Zhang¹,

Liu²,

Gao³

et al. 2020

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Background: Neuroinflammation is an important pathological mechanism of depression that leads to an increase in indoleamine-2,3-dioxygenase (IDO) activity and NMDAR activation. This study aimed to observe the effects of electroacupuncture on depressionlike behaviour in lipopolysaccharide (LPS)-treated rats and the underlying mechanism. Methods: Wistar rats were intraperitoneally administered LPS (0.5 mg/kg) for 7 consecutive days to establish a depression model. Electroacupuncture treatment was administered 1 hour after daily LPS injection. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to evaluate the depressive-like behaviours. IL-1β, IL-6, and TNF-α levels were determined by enzyme-linked immunosorbent assay (ELISA); Trp, 5-hydroxytryptamine (5-HT), kynurenine (Kyn) and quinolinic acid (Quin) were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry; and N-methyl-D-aspartate receptor (NMDAR) protein and mRNA were assessed by Western blot and real-time qPCR. Results: The results showed that electroacupuncture treatment successfully corrected LPSinduced depressive-like behaviour, reduced the inflammatory factor (IL-1β, IL-6 and TNF-α) levels in the blood and hippocampus, prevented IDO over-activation and recovered NR2B expression after challenge by LPS. Conclusion: Electroacupuncture treatment provided protection against LPS-induced depressive-like behaviour, and the associated mechanisms may be related to inhibiting the inflammatory response, regulating the IDO-mediated tryptophan-degrading pathway, and inhibiting NR2B activation.

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Reduced peripheral availability of tryptophan and increased activation of the kynurenine pathway and cortisol correlate with major depression and suicide

Abstract: Reduced availability of Trp for 5-HT synthesis and increased activation of the Kyn pathway and cortisol correlate with depression and suicide. Low plasma Trp levels may be a biomarker of MDD and suicide in MDD.

Cited by 74 publications

References 57 publications

An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder

An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder

Neutrophil-to-lymphocyte ratio: A potential new peripheral biomarker of suicidal behavior

<p>Electroacupuncture Relieves LPS-Induced Depression-Like Behaviour in Rats Through IDO-Mediated Tryptophan-Degrading Pathway</p>

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