title: Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients.
abstract: The association between the pro-inflammatory state of schizophrenia and increased tryptophan degradation into kynurenine has been reported. However, the relationship between metabolites from subdivisions of the kynurenine pathway, kynurenic acid and 3-hydroxykynurenine, remains unknown. The present study tested the relationship between these kynurenine metabolites in the plasma of medication-naïve (n=35) or medication-free (n=18) patients with schizophrenia at admission and following 6-week antipsychotic treatment compared to healthy controls (n=48). The plasma concentrations of kynurenic acid (nmol/l) were lower (difference=-8.44 (-13.22 to -3.65); p=0.001) and of 3-hydroxykynurenine (nmol/l) were higher (difference=11.24 (8.11-14.37); p<0.001) in the patients compared with the healthy controls. The kynurenic acid/kynurenine (difference=-2.75 (-5.115 to -0.336); p=0.026) and kynurenic acid/3-hydroxykynurenine (difference=-1.08 (-1.431 to -0.729); p<0.001) ratios were also lower in the patients. After the 6-week treatment, the patients' plasma kynurenic acid levels (difference=3.85 (-0.23 to 7.94); p=0.064) showed a trend towards an increase, whereas plasma 3-hydroxykynurenine levels (difference=22.41 (19.76-25.07); p<0.001) decreased. As a consequence, the kynurenic acid/3-hydroxykynurenine ratio (difference=-4.41 (-5.51 to -3.3); p<0.001) increased. Higher initial plasma kynurenic acid levels on admission or increased kynurenic acid/kynurenine ratio after treatment were associated with reduction of clinical symptoms scores upon discharge although higher kynurenic acid/kynurenine on admission may induce higher positive symptoms score. In contrast, higher 3-hydroxykynurenine is associated with lower positive symptoms score. These results indicate that there is an imbalance in the kynurenine pathway in schizophrenia. The 6-week antipsychotic treatment may partially reverse the imbalance in kynurenine metabolism and that in turn induces clinical response.
authors.affiliation: Division of Cellular Neuroscience, Department of Psychiatry and Neuropsychology, University of Maastricht, 6200 MD Maastricht, The Netherlands. AyeMu.Myint@med.uni-muenchen.de
authors.forename: A M
authors.initials: AM
authors.lastname: Myint
authors.forename: M J
authors.initials: MJ
authors.lastname: Schwarz
authors.forename: R
authors.initials: R
authors.lastname: Verkerk
authors.forename: H H
authors.initials: HH
authors.lastname: Mueller
authors.forename: J
authors.initials: J
authors.lastname: Zach
authors.forename: S
authors.initials: S
authors.lastname: Scharpé
authors.forename: H W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: B E
authors.initials: BE
authors.lastname: Leonard
authors.forename: Y K
authors.initials: YK
authors.lastname: Kim
mesh_terms: D000328:Adult; D000465:Algorithms; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010351:Patient Discharge; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D012565:Schizophrenic Psychology; D013056:Spectrophotometry, Ultraviolet; D016896:Treatment Outcome; D014364:Tryptophan / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid