title: Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients.
abstract: BACKGROUND
  Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression.
  
  
  METHODS
  Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22).
  
  
  RESULTS
  Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = -0.67, P = 0.002).
  
  
  CONCLUSIONS
  This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-D-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden. lilly.schwieler@ki.se.
authors.forename: Lilly
authors.initials: L
authors.lastname: Schwieler
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.|Department of Clinical and Experimental Medicine, Section of Psychiatry, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Samuelsson
authors.affiliation: Department of Psychiatry & Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: Protein Biomarkers, Personalized Healthcare & Biomarker Laboratories, Innovative Medicines, AstraZeneca, Gothenburg, Sweden.|Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Bhat
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.|Science for Life Laboratory, Proteomics & Nanobiotechn, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Jungholm
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anette G
authors.initials: AG
authors.lastname: Johansson
authors.affiliation: Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Carl M
authors.initials: CM
authors.lastname: Sellgren
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood; D003865:Major Depressive Disorder / Q000378:metabolism / Q000523:psychology / Q000628:therapy; D061218:Depressive Disorder, Treatment-Resistant / Q000378:metabolism* / Q000523:psychology / Q000628:therapy*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007737:Kynurenine / Q000378:metabolism*; D049449:Luminescence; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D014364:Tryptophan / Q000097:blood; D055815:Young Adult
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; D007737:Kynurenine; D014364:Tryptophan