title: The impact of electroconvulsive therapy on the tryptophan-kynurenine metabolic pathway.
abstract: BACKGROUND
  There is still limited knowledge about the mechanism of action of electroconvulsive therapy (ECT) in the treatment of depression. Substantial evidence suggests a role for the immune-moderated tryptophan (TRP)-kynurenine (KYN) pathway in depression; i.e. a depression-associated disturbance in the balance between the TRP-KYN metabolites towards a neurotoxic process. We, therefore, aimed to investigate the impact of ECT treatment on the TRP-KYN pathway, in association with ECT-related alterations in depressive symptoms.
  
  
  METHODS
  Twenty-three patients with unipolar or bipolar depression, treated with bilateral ECT twice a week were recruited. Blood serum samples, and depression scores using the Hamilton Depression Rating Scale-17 items (HDRS) as well as the Beck Depression Inventory (BDI) were collected repeatedly during the period of ECT and until 6 weeks after the last ECT session. TRP and KYN metabolites were analyzed in serum using the High Performance Liquid Chromatography. Four patients could not complete the study; thereby yielding data of 19 patients. Analyses were performed using multilevel linear regression analysis.
  
  
  RESULTS
  There was an increase in kynurenic acid (KYNA) (B=0.04, p=0.001), KYN/TRP ratio (B=0.14, p=0.001), KYNA/KYN ratio (B=0.07, p<0.0001), and KYNA/3-hydroxykynurenine ratio (B=0.01, p=0.008) over time during the study period. KYN (B=-0.02, p=0.003) and KYN/TRP (B=-0.19, p=0.003) were negatively associated with total HDRS over time. Baseline TRP metabolite concentrations did not predict time to ECT response.
  
  
  CONCLUSIONS
  Our findings show that ECT influences the TRP-KYN pathway, with a shift in TRP-KYN metabolites balance towards molecules with neuroprotective properties correlating with antidepressant effects of ECT; thereby providing a first line of evidence that the mechanism of action of ECT is (co)mediated by the TRP-KYN pathway.
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Sinan
authors.initials: S
authors.lastname: Guloksuz
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands.
authors.forename: Baer
authors.initials: B
authors.lastname: Arts
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands.
authors.forename: Sharon
authors.initials: S
authors.lastname: Walter
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: Drukker
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Rodriguez
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands; University Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Aye-Mu
authors.initials: AM
authors.lastname: Myint
authors.affiliation: University Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Schwarz
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Ponds
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands; King's College London, King's Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, United Kingdom.
authors.forename: Jim
authors.initials: J
authors.lastname: van Os
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands.
authors.forename: Gunter
authors.initials: G
authors.lastname: Kenis
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, EURON, School for Mental Health and Neuroscience, Maastricht, The Netherlands. Electronic address: b.rutten@maastrichtuniversity.nl.
authors.forename: Bart P F
authors.initials: BP
authors.lastname: Rutten
mesh_terms: D000328:Adult; D000368:Aged; D003866:Depressive Disorder / Q000097:blood* / Q000523:psychology / Q000628:therapy*; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000031:analogs & derivatives / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D014364:Tryptophan / Q000097:blood*; D055815:Young Adult
chemical_list: C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid
keywords: Depression; ECT; Immune; Indoleamine 2,3-dioxygenase; Kynurenic acid; Kynurenine; Kynurenine amino transferases; Neuroprotection; Tryptophan