The Tryptophan Catabolite or Kynurenine Pathway in a Major Depressive Episode with Melancholia, Psychotic Features and Suicidal Behaviors: A Systematic Review and Meta-Analysis

Background: Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways which may stimulate indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs). Objective: The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino-acids (CAAs) and TRYCATs in patients with severe affective disorders. Methods: PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4,647 participants including 2,332 unipolar (MDD) and bipolar (BD) depressed patients and 2,315 healthy controls. Results: Severe patients showed significant lower (p<0.0001) TRP (standardized mean difference, SMD=-0.517, 95% confidence interval, CI: -0.735; -0.299) and TRP/CAA (SMD= -0.617, CI: -0.957; -0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD= 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD= 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD= -0.260, CI: -0.487; -0.034) in severe MDD/BD. Conclusion: Patients with affective disorders with melancholic and psychotic features and suicidal behaviors show normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels

[1]  G. Oxenkrug,et al.  The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: A systematic review and meta-analysis , 2022, medRxiv.

[2]  Michael Maes,et al.  The tryptophan catabolite or kynurenine pathway in Alzheimer's disease: a systematic review and meta-analysis. , 2022, medRxiv.

[3]  Michael Maes.  Precision Nomothetic Medicine in Depression Research: A New Depression Model, and New Endophenotype Classes and Pathway Phenotypes, and A Digital Self , 2022, Journal of personalized medicine.

[4]  P. Gałecki,et al.  The Immune Profile of Major Dysmood Disorder: Proof of Concept and Mechanism Using the Precision Nomothetic Psychiatry Approach , 2022, medRxiv.

[5]  Michael Maes,et al.  The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis , 2022, BMC Infectious Diseases.

[6]  P. Dalal,et al.  Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study , 2022, Brain sciences.

[7]  Michael Maes,et al.  The Tryptophan Catabolite or Kynurenine Pathway's Role in Major Depression. , 2022, Current topics in medicinal chemistry.

[8]  M. Solmi,et al.  The tryptophan catabolite or kynurenine pathway in schizophrenia: meta-analysis reveals dissociations between central, serum, and plasma compartments , 2021, Molecular Psychiatry.

[9]  M. Maes,et al.  Inflammation and nitro-oxidative stress in current suicidal attempts and current suicidal ideation: a systematic review and meta-analysis , 2021, Molecular Psychiatry.

[10]  S. Trifu,et al.  Neuroplasticity and depression: Rewiring the brain's networks through pharmacological therapy (Review) , 2021, Experimental and therapeutic medicine.

[11]  C. Pariante,et al.  Peripheral levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability , 2021, Brain, Behavior, and Immunity.

[12]  A. Beekman,et al.  The association between plasma tryptophan catabolites and depression: The role of symptom profiles and inflammation , 2021, Brain, Behavior, and Immunity.

[13]  D. Fuchs,et al.  Plasma Anthranilic Acid and Leptin Levels Predict HAM-D Scores in Depressed Women , 2021, International journal of tryptophan research : IJTR.

[14]  Michael Maes,et al.  Suicide attempts are associated with activated immune-inflammatory, nitro-oxidative, and neurotoxic pathways: A systematic review and meta-analysis. , 2021, Journal of affective disorders.

[15]  M. Landén,et al.  Central levels of tryptophan metabolites in subjects with bipolar disorder , 2020, European Neuropsychopharmacology.

[16]  M. Maes,et al.  Towards a new model and classification of mood disorders based on risk resilience, neuro-affective toxicity, staging, and phenome features using the nomothetic network psychiatry approach , 2020, Metabolic Brain Disease.

[17]  E. Mayo-Wilson,et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews , 2020, BMJ.

[18]  A. Carvalho,et al.  Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: a Nomothetic Network Psychiatry Approach , 2020, Molecular Neurobiology.

[19]  D. McLoughlin,et al.  Blood plasma B vitamins in depression and the therapeutic response to electroconvulsive therapy , 2020, Brain, behavior, & immunity - health.

[20]  L. Vécsei,et al.  Antidepressant-like effects of kynurenic acid in a modified forced swim test , 2020, Pharmacological Reports.

[21]  E. Fransen,et al.  A mood state‐specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder , 2020, Bipolar disorders.

[22]  D. McLoughlin,et al.  Tryptophan metabolite concentrations in depressed patients before and after electroconvulsive therapy , 2020, Brain, Behavior, and Immunity.

[23]  J. Luciano,et al.  Peripheral immune aberrations in fibromyalgia: A systematic review, meta-analysis and meta-regression , 2019, Brain, Behavior, and Immunity.

[24]  P. Dobrowolski,et al.  Chronic dietary supplementation with kynurenic acid, a neuroactive metabolite of tryptophan, decreased body weight without negative influence on densitometry and mandibular bone biomechanical endurance in young rats , 2019, PloS one.

[25]  C. Lim,et al.  Inflammation and kynurenine pathway dysregulation in post-partum women with severe and suicidal depression , 2019, Brain, Behavior, and Immunity.

[26]  F. Valtorta,et al.  Reduced peripheral availability of tryptophan and increased activation of the kynurenine pathway and cortisol correlate with major depression and suicide , 2019, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[27]  K. Oedegaard,et al.  The effect of electroconvulsive therapy (ECT) on serum tryptophan metabolites , 2019, Brain Stimulation.

[28]  Livia Ambrus,et al.  Inverse association between serum albumin and depressive symptoms among drug-free individuals with a recent suicide attempt , 2019, Nordic journal of psychiatry.

[29]  M. Maes,et al.  Upregulation of the Nitrosylome in Bipolar Disorder Type 1 (BP1), but not BP2, and Major Depression: Increased IgM Antibodies to Nitrosylated Conjugates are Associated with Indicants of Leaky Gut , 2019 .

[30]  R. Perlis,et al.  Peripheral and central levels of kynurenic acid in bipolar disorder subjects and healthy controls , 2019, Translational Psychiatry.

[31]  Y. Ning,et al.  Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression , 2018, Brain, Behavior, and Immunity.

[32]  M. Maes,et al.  The Role of Aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: the IRS-CIRS Theory of Schizophrenia , 2018, Molecular Neurobiology.

[33]  R. Baldessarini,et al.  Tryptophan and Kynurenine Metabolites: Are They Related to Depression? , 2018, Neuropsychobiology.

[34]  Gang Liu,et al.  The Tryptophan Pathway Targeting Antioxidant Capacity in the Placenta , 2018, Oxidative medicine and cellular longevity.

[35]  M. Maes,et al.  Major Differences in Neurooxidative and Neuronitrosative Stress Pathways Between Major Depressive Disorder and Types I and II Bipolar Disorder , 2018, Molecular Neurobiology.

[36]  M. Maes,et al.  The Compensatory Immune-Regulatory Reflex System (CIRS) in Depression and Bipolar Disorder , 2018, Molecular Neurobiology.

[37]  Micah T. Nelp,et al.  Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form , 2018, Proceedings of the National Academy of Sciences.

[38]  Marcin Siwek,et al.  Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts , 2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[39]  S. Hemrungrojn,et al.  Changes in Tryptophan Catabolite (TRYCAT) Pathway Patterning Are Associated with Mild Impairments in Declarative Memory in Schizophrenia and Deficits in Semantic and Episodic Memory Coupled with Increased False-Memory Creation in Deficit Schizophrenia , 2017, Molecular Neurobiology.

[40]  V. Apostolopoulos,et al.  The effects of vitamin B on the immune/cytokine network and their involvement in depression. , 2017, Maturitas.

[41]  D. Fuchs,et al.  An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation , 2016, Translational psychiatry.

[42]  J. Kleinman,et al.  Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals. , 2016, Journal of psychiatry & neuroscience : JPN.

[43]  M. Maes,et al.  The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders. , 2016, Current pharmaceutical design.

[44]  Michael Lee,et al.  Substrate Oxidation by Indoleamine 2,3-Dioxygenase , 2015, The Journal of Biological Chemistry.

[45]  M. Maes,et al.  Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways , 2015, CNS Spectrums.

[46]  V. Gabbay,et al.  The role of the kynurenine pathway in suicidality in adolescent major depressive disorder , 2015, Psychiatry Research.

[47]  O. Andreassen,et al.  Ongoing episode of major depressive disorder is not associated with elevated plasma levels of kynurenine pathway markers , 2015, Psychoneuroendocrinology.

[48]  B. Bogerts,et al.  Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses? , 2015, European Archives of Psychiatry and Clinical Neuroscience.

[49]  Teresa A. Victor,et al.  Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder , 2015, Brain, Behavior, and Immunity.

[50]  C. Lim,et al.  A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality , 2015, Brain, Behavior, and Immunity.

[51]  Qi-Xin Zhou,et al.  Upregulating serotonin transporter expression and downregulating monoamine oxidase-A and indoleamine 2, 3-dioxygenase expression involved in the antidepressant effect of sodium valproate in a rat model , 2014, Neuroreport.

[52]  Jiming Liu,et al.  Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range , 2014, BMC Medical Research Methodology.

[53]  J. Pedraza-Chaverri,et al.  Kynurenines with Neuroactive and Redox Properties: Relevance to Aging and Brain Diseases , 2014, Oxidative medicine and cellular longevity.

[54]  L. Pavón,et al.  Increase in nitric oxide levels and mitochondrial membrane potential in platelets of untreated patients with major depression , 2013, Psychiatry Research.

[55]  Michael Maes,et al.  Schizophrenia: Linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[56]  S. Janelidze,et al.  Connecting inflammation with glutamate agonism in suicidality , 2012, Neuropsychopharmacology.

[57]  Andrew C. Terentis,et al.  Human Indoleamine 2,3-Dioxygenase Is a Catalyst of Physiological Heme Peroxidase Reactions , 2012, The Journal of Biological Chemistry.

[58]  M. Maes,et al.  The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder. , 2012, Journal of affective disorders.

[59]  I. Ara,et al.  Citalopram decreases tryptophan 2,3-dioxygenase activity and brain 5-HT turnover in swim stressed rats , 2012, Pharmacological reports : PR.

[60]  M. Maes,et al.  Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression , 2012, Neuroscience & Biobehavioral Reviews.

[61]  M. Maes,et al.  Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. , 2012, Journal of affective disorders.

[62]  M. Kubera,et al.  Activation of cell-mediated immunity in depression: Association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression , 2012, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[63]  R. Amani,et al.  Riboflavin Status and Its Association with Serum hs-CRP Levels among Clinical Nurses with Depression , 2011, Journal of the American College of Nutrition.

[64]  B. Bogerts,et al.  Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? , 2011, Journal of Neuroinflammation.

[65]  J. Mann,et al.  Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder , 2011, Brain, Behavior, and Immunity.

[66]  B. Leonard,et al.  The new ‘5-HT’ hypothesis of depression: Cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[67]  Michael Maes.  Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[68]  M. Berk,et al.  A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[69]  J. Babb,et al.  The possible role of the kynurenine pathway in adolescent depression with melancholic features. , 2010, Journal of child psychology and psychiatry, and allied disciplines.

[70]  Robert A. Smith,et al.  5-Hydroxyanthranilic Acid, a Tryptophan Metabolite, Generates Oxidative Stress and Neuronal Death via p38 Activation in Cultured Cerebellar Granule Neurones , 2009, Neurotoxicity Research.

[71]  M. Maes,et al.  The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. , 2008, Neuro endocrinology letters.

[72]  M. Maes,et al.  The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression - and other conditions characterized by tryptophan depletion induced by inflammation. , 2007, Neuro endocrinology letters.

[73]  H. Steinbusch,et al.  Tryptophan breakdown pathway in bipolar mania. , 2007, Journal of affective disorders.

[74]  G. Tofler,et al.  The association of depression with platelet activation: evidence for a treatment effect , 2007, Journal of thrombosis and haemostasis : JTH.

[75]  H. Steinbusch,et al.  Kynurenine pathway in major depression: evidence of impaired neuroprotection. , 2007, Journal of affective disorders.

[76]  Changsu Han,et al.  Increased plasma nitric oxide level associated with suicide attempt in depressive patients , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[77]  S. Ryu,et al.  Increased Plasma Nitric Oxide Metabolites in Suicide Attempters , 2006, Neuropsychobiology.

[78]  S. Weis,et al.  Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder , 2006, Brain Research.

[79]  S. Tuinier,et al.  Bipolar mania and plasma amino acids: Increased levels of glycine , 2006, European Neuropsychopharmacology.

[80]  M. Maes,et al.  Serotonergic disturbances in autistic disorder: L-5-hydroxytryptophan administration to autistic youngsters increases the blood concentrations of serotonin in patients but not in controls. , 2005, Life sciences.

[81]  H. Meltzer,et al.  Increased Depressive Ratings in Patients With Hepatitis C Receiving Interferon-α–Based Immunotherapy Are Related to Interferon-α–Induced Changes in the Serotonergic System , 2002 .

[82]  A. Santamaría,et al.  Quinolinic acid induces oxidative stress in rat brain synaptosomes , 2001, Neuroreport.

[83]  L. Chylack,et al.  3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-crystallin cross-linking by metal ion reduction. , 2000, Biochemistry.

[84]  R. Schwarcz,et al.  3‐Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum , 1999, The European journal of neuroscience.

[85]  E. Bosmans,et al.  The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. , 1998, Journal of affective disorders.

[86]  H. Meltzer,et al.  Lower serum high‐density lipoprotein cholesterol (HDL‐C) in major depression and in depressed men with serious suicidal attempts: relationship with immune‐inflammatory markers , 1997, Acta psychiatrica Scandinavica.

[87]  H. Meltzer,et al.  Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs , 1997, Psychiatry Research.

[88]  H. Neels,et al.  Lower Serum L-Tryptophan Availability in Depression as a Marker of a More Generalized Disorder in Protein Metabolism , 1996, Neuropsychopharmacology.

[89]  H. Meltzer,et al.  Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: Further evidence for an immune response , 1994, Psychiatry Research.

[90]  A. Lesage,et al.  Suicide and mental disorders: a case-control study of young men. , 1994, The American journal of psychiatry.

[91]  H. Meltzer,et al.  Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression , 1993, Psychiatry Research.

[92]  J. Lönnqvist,et al.  Mental disorders and comorbidity in suicide. , 1993, The American journal of psychiatry.

[93]  J. Rabe-Jabłońska,et al.  [Affective disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association -- diagnostic and statistical manual of mental disorders]. , 1993, Psychiatria polska.

[94]  S. Markey,et al.  Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse , 1992, Neuroscience.

[95]  J. Quintana.  Platelet serotonin and plasma tryptophan decreases in endogenous depression. Clinical, therapeutic, and biological correlations. , 1992, Journal of affective disorders.

[96]  E. Bosmans,et al.  Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining , 1992, Psychological Medicine.

[97]  E. Bosmans,et al.  Depression‐related disturbances in mitogen‐induced lymphocyte responses and interleukin‐1β and soluble interleukin‐2 receptor production , 1991, Acta psychiatrica Scandinavica.

[98]  S. Scharpe,et al.  Anthropometric and biochemical assessment of the nutritional state in depression: evidence for lower visceral protein plasma levels in depression. , 1991, Journal of affective disorders.

[99]  P. Cowen,et al.  Decreased plasma tryptophan concentration in major depression: relationship to melancholia and weight loss. , 1990, Journal of affective disorders.

[100]  M. Maes,et al.  Suppressant effects of dexamethasone on the availability of plasma L‐tryptophan and tyrosine in healthy controls and in depressed patients , 1990, Acta psychiatrica Scandinavica.

[101]  P. Lachenbruch.  Statistical Power Analysis for the Behavioral Sciences (2nd ed.) , 1989 .

[102]  S. Møller.  Tryptophan to competing amino acids ratio in depressive disorder: relation to efficacy of antidepressive treatments , 1985, Acta psychiatrica Scandinavica. Supplementum.

[103]  W. J. Klein,et al.  Aggression, suicide, and serotonin: relationships to CSF amine metabolites. , 1982, The American journal of psychiatry.

[104]  W. Pardridge.  Tryptophan transport through the blood-brain barrier: in vivo measurement of free and albumin-bound amino acid. , 1979, Life sciences.

[105]  W. Oldendorf,et al.  EFFECT OF ALBUMIN BINDING AND AMINO ACID COMPETITION ON TRYPTOPHAN UPTAKE INTO BRAIN 1 , 1977, Journal of neurochemistry.

[106]  R. Wurtman,et al.  Correlation between brain tryptophan and plasma neutral amino acid levels following food consumption in rats , 1973 .

[107]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[108]  J. Oncley,et al.  The specific binding of L-tryptophan to serum albumin. , 1958, The Journal of biological chemistry.

[109]  M. Maes.  A review on citation amnesia in depression and inflammation research. , 2015, Neuro endocrinology letters.

[110]  Cochrane Handbook for Systematic Reviews of Interventions Edited by Julian P. T. Higgins & , 2006 .

[111]  K. Goda,et al.  Radical scavenging properties of tryptophan metabolites. Estimation of their radical reactivity. , 1999, Advances in experimental medicine and biology.

[112]  R. Reiter,et al.  Melatonin and tryptophan derivatives as free radical scavengers and antioxidants. , 1999, Advances in experimental medicine and biology.

[113]  G. De Backer,et al.  Increased plasma serine concentrations in depression. , 1995, Neuropsychobiology.

[114]  S. Møller.  Plasma amino acid profiles in relation to clinical response to moclobemide in patients with major depression. Danish University Antidepressant Group. , 1993, Journal of affective disorders.

[115]  D. Charney,et al.  Serotonin function and depression: neuroendocrine and mood responses to intravenous L-tryptophan in depressed patients and healthy comparison subjects. , 1991, The American journal of psychiatry.

[116]  P. Cowen,et al.  Decreased plasma tryptophan levels in major depression. , 1989, Journal of affective disorders.