Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder.
Increased concentrations of kynurenine pathway metabolites have been reported by several groups for disorders involving psychosis, including schizophrenia and bipolar disorder. To identify components of the pathway that may be relevant as biomarkers or may underlie the etiology of psychosis, it is essential to characterize the extent of kynurenine pathway activation and to investigate known regulators of one of the key kynurenine-producing enzymes, tryptophan 2,3-dioxygenase (TDO2), previously shown in this laboratory to be increased commensurate with kynurenine in postmortem anterior cingulate brain tissue from individuals with schizophrenia. Using this same anterior cingulate sample set from individuals with schizophrenia, bipolar disorder, depression and controls (N=12-14 per group), we measured the precursor of kynurenine and two downstream products. The precursor, tryptophan, was significantly increased only in the schizophrenia group (1.54-fold the mean control value, p=0.02), and through substrate-induced activation, may be one cause of the increased kynurenine and kynurenine metabolites. This finding for tryptophan differs from some, but not all, previous reports and methodological reasons for the discrepancies are discussed. A product of kynurenine metabolism, 3-OH-anthranilic acid was also significantly increased only in the schizophrenia group (1.68-fold the mean control value, p=0.03). 3-OH-anthranilic acid is a reactive species with cytotoxic properties, although the threshold for such effects is not known for neurons. Analysis of major pre- and post-mortem variables showed that none were confounding for these between-group experimental comparisons. Nicotinamide, a pathway end product, did not differ between groups but was associated with cause of death (suicide) within the bipolar group (p=0.03).
Miller
Christine L
CL
Stanley Division for Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Blalock 1105, Baltimore, MD 21287, USA. Cmiller2@jhmi.edu <Cmiller2@jhmi.edu>
Llenos
Ida C
IC
Cwik
Mary
M
Walkup
John
J
Weis
Serge
S
D015095:3-Hydroxyanthranilic Acid / Q000032:analysis / Q000378:metabolism; D000328:Adult; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001714:Bipolar Disorder / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007737:Kynurenine / Q000032:analysis / Q000378:metabolism*; D008875:Middle Aged; D009536:Niacinamide / Q000032:analysis / Q000378:metabolism; D011237:Predictive Value of Tests; D012559:Schizophrenia / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D013405:Suicide; D014364:Tryptophan / Q000032:analysis / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000032:analysis / Q000378:metabolism
D015415:Biomarkers; D015095:3-Hydroxyanthranilic Acid; D009536:Niacinamide; D007737:Kynurenine; D014364:Tryptophan; D014366:Tryptophan Oxygenase