Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression

Maes, Michaël; Meltzer, Herbert Y.; Scharpé, Simon; Bosmans, E.; Suy, E.; Meester, Ingrid De; Calabrese, J. R.; Cosyns, Paul

doi:10.1016/0165-1781(93)90102-m

Cited by 149 publications

(86 citation statements)

References 53 publications

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“…21,22 In another type of investigation, associations between plasma TRP concentrations and immune variables have been observed in psychiatric patients with major depression. 23 Taken together, these data point to the possibility that depressive symptoms in patients treated with cytokine therapy could be related to the actions of cytokines on monoamine metabolism. The aim of the present study was therefore to assess the relationship between the development of depressive symptoms and blood concentrations of the amino acid precursors of serotonin and norepinephrine in cancer patients receiving IL-2 or IFN-␣ therapy.…”

Section: Cytokines and Neurotransmitter Functionsmentioning

confidence: 95%

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

et al. 2002

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Cytokine therapy for cancer or viral diseases is accompanied by the development of depressive symptoms in a significant proportion of patients. Despite the increasing number of studies on the neurotoxic effects of cytokines, the mechanisms by which cytokines induce depressive symptoms remain largely unknown. In view of the relationship between neurotransmitter precursors and mood, the present study aimed at assessing the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depressive symptoms in cancer patients undergoing cytokine therapy. Sixteen cancer patients eligible to receive immunotherapy with interleukin-2 and/or interferon-alpha participated in the study. At baseline and after one week and one month of therapy, depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), and blood samples were collected for the determination of the large neutral amino acids (LNAA) (tryptophan, tyrosine, valine, leucine, isoleucine, phenylalanine) which compete for transport across the blood-brain barrier. Serum concentrations of tryptophan as well as the tryptophan/LNAA ratio significantly decreased between baseline, one week and one month of therapy. The development and severity of depressive symptoms, especially anorexia, pessimistic thoughts, suicidal ideation and loss of concentration were positively correlated with the magnitude of the decreases in tryptophan concentrations during treatment. These findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophan.

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Section: Cytokines and Neurotransmitter Functionsmentioning

confidence: 95%

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

et al. 2002

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“…Moreover, depression is characterized by immune-serotonin interactions, including activation of indoleamine 2,3-dioxygenase (IDO) with increased levels of tryptophan catabolites (TRYCATs) and lowered levels of tryptophan [20][21][22]; immune-endocrine interactions, including cytokine-associated glucocorticoid resistance [6,9]; and immune-metabolic (in particular lipids) interactions, including inverse associations between immune activation and lowered high density cholesterol, 3 polyunsaturated fatty acid (PUFAs) levels and the reverse cholesterol transport [11,23]. Interestingly, animal depression models based on psychosocial stress show that depression-like behaviors are associated with activated immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways [24,25].…”

Section: Inflammation Is Not the Only Drug Target In Depressionmentioning

confidence: 99%

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

et al. 2015

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Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g. C-reactive protein, and pro-inflammatory cytokines, e.g. interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways.Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g. activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, activation of the Toll-like Receptor and neuroprogressive pathways. Thirdly, antiinflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e. path and drug discovery processes, omics-based techniques and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics and microbiomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular 4 networks, pathways and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.

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“…Finally, given the role of hippocampal GR in feedback regulation of neuroendocrine responses, JNKrelated influences on the GR may play a role in the pathophysiology of altered hypothalamic-pituitary-adrenal axis function found in neuropsychiatric disorders including depression. For example, dexamethasone nonsuppression is a reliable finding in patients with major depression (Pariante and Miller, 2001) and has been correlated with increased plasma concentrations of IL-1 (an activator of JNK pathways) (Maes et al, 1993). Moreover, chronic treatment with the JNK activator, lipopolysaccharide, has been shown to lead to dexamethasone nonsuppression in rodents (Weidenfeld and Yirmiya, 1996;Yirmiya, 1996).…”

Section: Inhibition Of Jnk Increases Gr Functionmentioning

confidence: 99%

Inhibition of Jun N-Terminal Kinase (JNK) Enhances Glucocorticoid Receptor-Mediated Function in Mouse Hippocampal HT22 Cells

Wang

Lakdawala

et al. 2004

Neuropsychopharmacol

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Mitogen-activated protein kinases (MAPKs), including Jun N-terminal kinase (JNK), promote inflammatory and proliferative responses to infection and other environmental stimuli including stress. Relevant to negative regulation of inflammatory pathways by glucocorticoids and the development of glucocorticoid resistance (observed in inflammatory disorders as well as certain neuropsychiatric disorders such as major depression), activation of JNK has been reported to inhibit glucocorticoid receptor (GR) function. In this study, the role of JNK pathways in modulating GR function was further investigated. Treatment of mouse hippocampal (HT22) cells with the selective JNK inhibitor, SP-600125 (0.1-10 mM), resulted in dose-dependent induction of GR-mediated MMTV-luciferase activity. SP-600125 also significantly enhanced dexamethasone-induced MMTV-luciferase activity, while increasing GR binding to the glucocorticoid responsive element, both in the presence and absence of Dex. Similar effects were observed in mouse fibroblast cells (LMCAT), and in HT22 cells treated with a JNK specific antisense oligonucleotide. The induction of GR-mediated function by SP-600125 was not due to altered cytosolic GR binding or GR protein expression or enhancement of GR nuclear translocation as determined by Western blot. Taken together, the data indicate that constitutive expression of JNK plays a tonic inhibitory role in GR function, which is consistent with findings that activation of JNK pathways inhibits GR. The data also identify potential pathways involved in the pathogenesis of the glucocorticoid resistance found in certain chronic immune/inflammatory diseases and subgroups of patients with major depression. Moreover, JNK pathways may represent a therapeutic target for normalization of GR function in these disorders.

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Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression

Cited by 149 publications

References 53 publications

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

Inhibition of Jun N-Terminal Kinase (JNK) Enhances Glucocorticoid Receptor-Mediated Function in Mouse Hippocampal HT22 Cells

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