TY - JOUR
T1 - Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia
AU - Yao, J. K.
AU - Dougherty, G. G.
AU - Reddy, R. D.
AU - Keshavan, M. S.
AU - Montrose, D. M.
AU - Matson, W. R.
AU - Rozen, S.
AU - Krishnan, R. R.
AU - McEvoy, Joseph Patrick
AU - Kaddurah-Daouk, R.
N1 - Funding Information:
This material is based on work supported in part by the grants from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory R&D (Merit Reviews (JKY) and Senior Research Career Scientist Award (JKY)), VA Pittsburgh Healthcare System (JKY, GGD, RDR), National Institute of Health (MH58141 (JKY), MH64118 (RDR), MH45203 (MSK), R24 GM078233 (RKD), c UL1 RR024153 and NIH/NCRR/ GCRC Grant M01 RR00056), Metabolomics Research Network (RKD); Stanley Medical Research Institute (RKD), and NARSAD (RKD). The authors are grateful to Drs Nina Schooler, Cameron Carter and Gretchen Haas, and the clinical core staff of the Center for the Neuroscience of Mental Disorders (MH45156, David Lewis MD, Director) for their assistance in diagnostic and psychopathological assessments, and to P Cheng, C Korbanic and J Haflett for their technical assistance.
PY - 2010/9
Y1 - 2010/9
N2 - Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper-and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n25) and healthy controls (HC, n30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values <0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp-5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N-acetylserotonin by serotonin N-acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp-5HIAA correlation. Considering N-acetylserotonin as a potent antioxidant, such increases in N-acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia.
AB - Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper-and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n25) and healthy controls (HC, n30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values <0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp-5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N-acetylserotonin by serotonin N-acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp-5HIAA correlation. Considering N-acetylserotonin as a potent antioxidant, such increases in N-acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia.
KW - 5-hydroxyindoleacetic acid
KW - N-acetylserotonin
KW - Trp
KW - first-episode neuroleptic naive
KW - schizophrenia
KW - targeted metabolomics
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U2 - 10.1038/mp.2009.33
DO - 10.1038/mp.2009.33
M3 - Article
C2 - 19401681
AN - SCOPUS:77956439232
SN - 1359-4184
VL - 15
SP - 938
EP - 953
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 9
ER -